The Immune System, Disorders of The Immune System ,Linear IgA disease and IgA EBA.

Immunity, Autoimmunity, and IgA Mediated Autoimmune Bullous Disease

2009-12-31T01:00:00.068Z

INTRODUCTION

Please see my blogs on .....

Linear IgA Bullous Dermatosis and Iga Mediated Epidermolysis Bullosa Aquisita, here...

http://wassail-allthatilove.blogspot.com/2008/03/linear-iga-immunoglobulin-antibody.html

OOKP Surgery ( Tooth In Eye Surgery) here .... http://sites.google.com/site/ookpsurgery/

Understand Autoimmunity here .....

http://wassail-allthatilove.blogspot.com/2008/03/disorders-of-immune-system-immune.html

I am presenting the following simply because it is in part the result of my own ongoing study and referencing, in my attempts to personally understand this very complex subject of Immunity, Autoimmunity, and Disorders of the Immune system. By doing this, it has helped me come to terms and acceptance with the loss of my sight, disfigurement, and resulting disability due to autoimmune bullous disease, through attempting to understand the reasons "why" over something which has completely bereft me of the life I once had. It is my personal opinion if one can understand HOW the immune system works as a whole, the function of each immune cell, and what can go wrong with the immune system, then one can understand WHY we have these autoimmune conditions, and what can be done to relieve the symptoms. THERE IS NO CURE! If these faulty genes can at some future point in time be identified and disabled, or altered genetically, then we may have a cure. I give reference to the areas of research at present, in these blogs. I have had active disease since 1993 to the present, 2010.

This then, is basically the results of my personal journey in understanding these processes. It is long, it's a huge subject, and I am just presenting an overview of the basics! I have endeavoured to present it as simply as possible, so that anyone can easily understand these complex processes, but as the subject is so vast, even the basics can be daunting. Please don't be too critical, for it is after all, just my own attempts at understanding the subject. Throughout the whole period of my autoimmune disease since 1993, despite having been seen, and being in the care of some of the top consultants in the UK, not once, in all of this time did any consultant ever suggest diet changes. On the contrary, it was specifically pointed out that diet would not, and indeed could not, cure autoimmunity, nor alter this genetic predisposition. I have not read one single article by doctors or researchers concerning autoimmunity, which state that diet will help, or can be offered as treatment, for autoimmune disease, except Dermatitis Herpetiformis. This particular autoimmune response is stimulated into action by Gluten enteropathy, a sensitivity to wheat. (see Gluten under Autoimmunity) So that specific Allergy, triggers the already present genetic predisposition. Remove the "Cause" of the allergy ie the Gluten, and lesions will improve, BUT, it takes many months for the resulting overdrive of production of these AUTO antibodies to stop.
It goes without saying, that I fully understand the desperation and helplessness, of people who are told by their derms, "there is no cure" , or "we can only control it with drugs", but that IS the case for the present, and nothing can alter that fact. Recent studies and trials concerning removing and altering one's own cells , and replacing them back into the host, is underway and being conducted at this very time. (see article under Autoimmunity -Treatments) I have known , and indeed continue to know, real desperation, due to the fact that I was going blind rapidly , and nothing , even the severest of chemo drugs, was helping. Even now I could go blind instantly if this prostethsis should collapse or fall out. It is already showing bone loss in recent scans. (See example pics in link in OOKP)
We feel the need to take control in order to help ourselves, especially if, as is the case, in some countries, one has no health insurance. There surely must be other ways of getting treatment, even if on benefits or low income for example, in the USA, or other countries who have this type of health system? Unfortunately we, in the UK do tend to take our health service for granted, and in comparison to some other countries, we are indeed very fortunate, despite our many complaints regarding our health service.

There are various reasons for seeking alternative treatments. The first is the patient not accepting what the derm is saying , especially if he does not have the time to explain these processes in detail. I myself have been guilty of that. However, I soon learned through being sent all over the UK ,for the input of other specialists, that it was MY lack of understanding, not the derm at all, and so I started to study the immune system, its structure and function, and I found it fascinating. The more I learned the more open and responsive my specialists became, and now I understand all that is being said to me.

The individual's lack of understanding is probably the main problem regarding the patient being non-compliant with the medical treatment decisions. We, are our only advocates, and the correct understanding of these autoimmune diseases, and why we have them, is essential in order to make educated decisions upon treatment, especially for those with rare conditions, and indeed for living a normal life as possible, and our overall well being. It also makes the patient realise and become more responsive to accepting the treatments offered , if they understand exactly how the treatment works and how it will benefit them. Other reasons are the drugs and their potential side affects, which are not neccessarily apparant whilst taking them, but can arise sometimes years after the treatment has long ended. For some, like myself there simply is no choice, but to take them, to try and suppress the results of the abnormal immune response, or die!

The main reason that this drug therapy is necessary, is because no food or any other form of treatment, can possibly alter the resulting malfunctioning immune cells, which have been produced from the transcription of these mutated genes, within an immune response to a combination of exogenous and endogenous factors, specific to the individual. That is a fact, not a hypothesis.

The main argument I have heard from friends overseas who must pay for healthcare, is that the health authorities do not want people to know about alternatives as the healthcare in those countries is big business for the drug industries. What they fail to realise is that money is not an agenda to the patient directly in every country.
Money is never mentioned when treating patients in the UK. Also, when asked to explain how the alternative treatment is supposed to work, pathologically, they cannot explain it as I explain concerning medical data, below in this blog, for the simple reason, there is no data which has undergone meta analysis, as all data concerning medical treatments must.

When reading some articles on the hypotheses of these doctors, concerning their treatments, one realises that the information they give concerning the true pathogenesis of these cells, and their functions, are presented in a way to suit their theories, when in fact that is not the way these cells function at all.

To give an example.... please note my notes in red next to the original quotes in italics.

Quote.....

To have an autoimmune disease is to know that you have an inadequate immune system, Totally incorrect, the immune system is working very well in every other way, except that these specific mutated genes were transcribed within this immune response, resulting in an abnormal immune response to self antigens.

dysfunctional, yes it is, but only within that specific response which occurred.

weak immune system. It most definately is not, it is anything but weak! Quite the opposite in fact, it is in overdrive!

People often think that when a derm says "there is no cure," that he doesn't know what he is talking about, that there simply must be ,when in fact he simply has not the time to explain this complicated subject, especially if he (rightly or wrongly) assumes the patient will not understand these processes anyway.

The following blog is my attempt in trying to explain these processes as simply as possible, because then the patient can understand exactly why they have these autoimmune conditions, and what can be done about it.

The links are to give evidence, as fact based reference.

Autoimmune disease only occurs in people who carry the genetic predisposition to ever having an abnormal immune response. This predisposition lies in the DNA of genes, and no diet, detox, chelation, or whatever, can alter that, it is a part of the genetic make-up of these individuals. In some cases there is also an hereditary gene to a specific disease itself, for example psoriasis, or diabetes.

Not everyone carrying these genes will ever have an autoimmune response, they are just more likely to. Control of the malfunctioning cells of the immune system ,is the keyword in all autoimmune conditions.

I have prepared this subject in three parts. The first is Immunity, and the structure and cells of the Immune System, (one needs to understand Immunity before one can possibly understand Autoimmunity.) The second is Autoimmunity, and the third is my own very rare autoimmune condition, IgA mediated Epidermolysis Bullosa Aquisita, and Linear IgA Bullous Dermatosis.

Links to my blogs on....

Disorders of The Immune System including Autoimmunity .....

http://wassail-allthatilove.blogspot.com/2008/03/disorders-of-immune-system-immune.html
Linear IgA Bullous Dermatosis & IgA Mediated Epidermolysis Bullosa Aquisita.......

http://wassail-allthatilove.blogspot.com/2008/03/linear-iga-immunoglobulin-antibody.html

The Immune System its Structure and Function ......

Genes http://wassail-allthatilove.blogspot.com/2008/03/genes.html
Cells http://wassail-allthatilove.blogspot.com/2008/03/structure-of-immune-system-organs-of.html
B Cells http://wassail-allthatilove.blogspot.com/2008/03/b-cells-b-cell-arises-from-hemopoietic.html
Phagocytes and Granulocytes http://wassail-allthatilove.blogspot.com/2009/12/chemotaxis-phagocytes-and-granulocytes.html
Cytokines http://wassail-allthatilove.blogspot.com/2009/12/cytokines-cytokines-are-chemical.html

The Immune System

The Immune System is the body's defence system, and like any other form of defence it has barriers to prevent invasion, by foreign or dangerous substances. The immune response is how the body recognizes and defends itself against bacteria, viruses, and substances that appear foreign and harmful to to it. Such substances include micro-organisms, (such as bacteria, viruses, and fungi,) parasites, (such as worms) cancer cells and even transplanted organs and tissues.
In order to have the ability to destroy invaders, the immune system must first recognize them . The immune system is amazingly complex, but it can recognize millions of different enemies, and it can produce secretions and cells to combat and wipe out each one of them. Any substance that can stimulate an immune response in the body, is called an Antigen. Antigens are molecules (usually proteins) on the surface of cells, and may be contained within or on bacteria, viruses, micro-organisms, (or even a part of a microbe) or cancer cells.
Immunity can also be influenced by inherited genes. When faced with the same antigen, some individuals will respond forcefully, others feebly, and some not at all.

The immune system produces many different cells to eliminate these invading cells, in particular the production of Antibodies. Antibodies, belong to a family of large molecules , known as Immunoglobulins. (see antibodies)
An antigen matches an antibody much as a key fits into a lock. Some match exactly, others fit more like a skeleton key. Whenever an antigen and antibody combine, or interlock, the antibody marks the antigen for destruction.

The surface portion of an antigen, capable of eliciting an immune response, and of combining with the antibody produced, to counter that response, is called an Epitope.

Immunity can be strong or weak, short lived, or long lasting, depending on the type of antigen, the amount of antigen, and the route by which it enters the body.
Tissues or cells from another individual, (except an identical twin) also carry nonself markers and act as antigens. This explains why transplanted tissues may be rejected as foreign. Antigens may also exist on their own, as pollen or food molecules. Non-living substances such as toxins, chemicals, drugs, and foreign particles, (such as a splinter of wood or a thorn) can also be antigens.

The cells of the body too have proteins that are antigens, each body cell carrying distinctive molecules that distinguish it as* self. *These include a group of antigens called HLA's or Human Leukocyte Antigens. As these antigens are of self, they are called autoantigens. They are endogenous (within and of the body) antigens . Cells of the immune system in normal circumstances, recognise them as being of self, and ignore them.

(see natural/self-tolerance, Tcell positive/negative selection and autoimmunity)

Markers of Self

...(note the little triangles on each type of self protein cell, ie:nerve cells, fat cells, epitheliel cells and muscle cells, are all of self. These are self antigens or autoantigens of self proteins)

The key to a healthy immune system is it's remarkable ability to distinguish between the body’s own (self) cells, and foreign cells. (non-self) To limit autoimmune responses and minimize the chances of harm, the body's immune system employs a number of mechanisms, referred to collectively as Natural or Self-tolerance.
Natural or Self Tolerance. Self Tolerance is the tendency of T or B lymphocytes, having the capability of ignoring the body’s own tissues. These lymphocytes are " taught" to ignore any cell which carries a "self marker" (antigen). All cells of the "host" in animals and humans carry markers of "self". Scientists are working at trying to understand how the immune system knows when to respond and when to ignore. Maintaining tolerance is important because it prevents the immune system from attacking it's own cells.
Tolerance occurs in at least two ways....

Central Tolerance (in the bone marrow) occurs during lymphocyte development. Very early in each immune cell’s life, it is exposed to many of the self molecules in the body. If it encounters these molecules before it has fully matured, the encounter activates an internal self-destruct pathway and the immune cell dies. This process, called clonal deletion, helps ensure that self-reactive T cells and B cells do not mature and attack healthy tissues. (see Tcells in cells of immune syst.)
Because maturing lymphocytes do not encounter every molecule in the body, they must also learn to ignore mature cells and tissues.

Peripheral Tolerance (around the body) Circulating lymphocytes might recognize a self molecule but cannot respond because some of the chemical signals required to activate the T or B cell are absent. This is called clonal anergy , and it keeps potentially harmful lymphocytes switched off.
Peripheral tolerance may also be by a special class of regulatory T cells that inhibits helper or cytotoxic cell activation by self antigens. The immune system must be able to distinguish between which cells are non-self and which are self. It can make this distinction, because all cells have *self* identification molecules on their surface.All foreign molecules, such as micro-organisms, carry distinctive markers, characteristic shapes, called Epitopes. These epitopes protrude from their surfaces, and are sometimes referred to as an "antigen determinant."
In humans, cells of the body also produce an epitope, but it is one of "self", and these identification molecules are called Human Leukocyte Antigens (HLA),or Major Histocompatibility Complex (MHC)molecules. (see genes) HLA molecules are called antigens because they can provoke an immune response in another person. (normally they do not provoke an immune response in the person who has them.)
Each person has unique human leukocyte antigens. A cell with molecules on it's surface that are not identical to those on the body's own cells, is identified as being foreign, and the immune system then attacks that cell. Such a cell may be a micro-organism, a cell from transplanted tissue, or one of the body's own cells that has been infected by an invading micro-organism.

A Normal Immune Response
This consists of recognising a foreign antigen, mobilizing forces to defend the body against it, and attacking it.Under normal circumstances, through these particular immune cell processes, and because of these self and non-self markers on cells, the immune system is able to ignore, or "tolerate" normal cell processes which are, and occur of *self*. However, when immune cells encounter cells or organisms carrying markers that say "foreign", they quickly launch an attack.The success of an immune response is due to an elaborate network of millions of communicating cells, which are organised into sets and subsets, passing information back and forth.When these immune cells receive an alarm, they undergo changes, and begin to produce powerful chemicals. These chemical substances allow the cells to regulate their own growth and behaviour, enlist other cells, and direct cells to troubled areas.

An Abnormal Immune Response (Autoimmune Response)
Under abnormal circumstances, an active response to an epitope which is of *self*, is called an Autoimmune Response, (auto=Greek=self) and is just as specific as an immune response. In an abnormal immune response, the immune system can mistake self for non-self and launch an attack against the body’s own cells or tissues. The result is called an autoimmune response, and the pathogenic result of an autoimmune response, is an autoimmune disease. In other cases, the immune system responds to a seemingly harmless foreign substance such as ragweed pollen. The result of this is an allergy, and this kind of antigen is called an allergen.

Markers of Non-Self

..(Note the little brown appendages on these antigens. Each antigen has different markers, and antibodies are produced to fit those markers exactly, like a key to a lock.These are fragments of the antigen itself,and are called Epitopes)

Microbes attempting to get into the body must first get past the skin and mucous membranes, which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies. Next, they must elude a series of nonspecific defences, cells and substances that attack all invaders regardless of the epitopes they carry. These include patrolling scavenger cells, complement, and various other enzymes and chemicals.

Infectious agents that get past the nonspecific barriers must confront specific weapons tailored just for them. These include both antibodies and cells. Almost all antigens activate both the nonspecific and specific parts of the immune response.

The most common disease causing microbes are bacteria, viruses and parasites. Each uses a different tactic to infect a person, and, therefore, each is thwarted by a different part of the immune system.
Most bacteria live in the spaces between cells and are readily attacked by antibodies, and all viruses, plus a few types of bacteria and parasites, must enter cells in order to survive. Parasites live either inside or outside of cells.

The most obvious defence barrier is the skin, which in itself is thick and hard to penetrate, and it also produces substances which are harmful to invaders. Other barriers are the cornea of the eye, the membranes lining the respiratory, digestive, urinary, and reproductive tracts; and these barriers are defended by secretions containing enzymes that can destroy bacteria.

Examples are tears in the eyes and secretions in the digestive tract and vagina.
All are protected by fluids or sticky mucus that capture harmful invaders, and the nasal passages also have tiny hairs, known as cilia, that trap and remove particles. Any invaders that get as far as the stomach are up against a sea of stomach acid that kills most of them. As long as these barriers remain unbroken, many invaders cannot penetrate them.

If a barrier is broken, (such as extensive burns damaging much of the skin), the risk of infection is increased. Despite these defences invaders do sometimes manage to break through. Some still manage to enter through the nose, and some in our food, and others may enter through a break in the skin. Every time this happens the body is at risk from a full blown invasion by bacteria or viruses.
When the skin is damaged, or when invaders manage to enter the body, cells are destroyed, and the dying cells trigger an immune response to the invasion, which is inflammation. The inflammation also causes blood vessels to dilate, increasing the blood flow.

Inflammation is the body's alarm bell. Once it goes off, it draws defensive cells to the damaged area in great numbers. Increased blood flow helps defencive cells reach the place where they're needed quickly, and it also accounts for the redness and swelling which ensues. This helps isolate the foreign substance from further contact with body tissues.
These barriers form the body's first line of defence. The next line of defence involves white blood cells that travel through the bloodstream and into tissues, searching for, and attacking micro-organisms and other invaders.

The Immune Response

The Immune Defence is divided into three parts:....
1) Non-specific also known as Innate Immunity. Innate immunity, is immunity that we are born with, and is the major system of host defence against pathogens, in nearly all living things. The innate system provides immediate defence against infection, and involves barriers that keep harmful materials from entering the body. These barriers form the first line of defence to invasion by foreign or harmful substances known as antigens, and include the skin, skin oils, cough reflex, enzymes in tears, mucus, secretions in the digestive tract, stomach acid, and tiny hairs in the nasal passages known as cilia, which trap and remove particles.
The most protective component of the innate immune system, should any foreign agent manage to break through, is the Complement System.
This involves a cascade of several types of white blood cells (9 to be specific, from C1-C9, there are a few sub sets) that act in a predestined sequence to destroy invaders.

There are four main functions of the Innate or non-specific immune system, and they include:
1)Recruiting immune cells to sites of infection and inflammation, through the production of chemical factors, including specialized chemical mediators, called Cytokines. (these are the messengers of the immune system)
2)clearance of dead cells or Antibody Complexes. (see Complement System)
3)The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells, such as Natural killer cells, mast cells, eosinophils, basophils; and the phagocytic cells, which include macrophages, neutrophils and dendritic cells, which function within the immune system by identifying and eliminating pathogens that might cause infection. (see cells of the immune system)
4)Activation of the Adaptive immune system through a process known as Antigen Presentation.

2)Specific also known as (Adaptive or Acquired) Immunity. The adaptive or "specific" immune system is activated by the “non-specific” innate immune system, through a process known as antigen presentation. The cells of the adaptive immune system, also known as "effector cells" (having the ability to alter the activities of other molecules) are a type of leukocyte, called a lymphocyte.
B cells and T cells are the two major types of lymphocytes.
The adaptive immune response provides the immune system with the ability to recognize and remember specific pathogens, (to actually generate immunity) and to mount stronger attacks each time the pathogen is encountered. It is adaptive immunity, because the body's immune system prepares itself for future challenges. Adaptive immunity consists of blood cells which work together to destroy invaders. Some of these cells do not directly destroy invaders , but enable other white blood cells to recognize and destroy them.
Cells of adaptive immunity are stimulated, when a pathogen evades the innate immune system and a certain level of antigen is reached. The three primary functions of the adaptive immune system are;
a) recognising specific "non-self" antigens in the presence of “self”, during the process of antigen presentation by Dendritic cells. b) to activate the responses that are tailored to eliminate specific pathogens or pathogen infected cells.
c) to stimulate the development of immunological memory, in which each pathogen is “remembered” by a "signature" antigen. These memory cells can be called upon to quickly eliminate a pathogen should subsequent infections occur.

The adaptive immune system allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen. The adaptive immune response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by Memory Cells.
Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it. The system is "adaptable" because of a process of accelerated "somatic mutations", and V (D)J recombination, (see genes) known as *Somatic Hypermutation*.
Somatic Hypermutation is an irreversible, genetic recombination of the antigen receptor, gene segments. This process allows a small number of genes to generate a vast number of different antigen receptors, which are then uniquely expressed on each individual lymphocyte. (see genes) This gene rearrangement leads to an irreversible change in the DNA of each cell, all of the offspring of that cell will then inherit genes carrying the same specific receptor including the Memory B cells and Memory T cells, that are at the core to long lived specific immunity.

*Somatic Hypermutation *(or SHM) is a mechanism inside cells, that is part of the way the immune system adapts to any new foreign microbes which confront it. SHM diversifies or alters the receptors that the immune system uses to recognize foreign antigens, and allows the immune system to adapt it's response to new threats during the lifetime of an organism. Somatic hypermutation, involves a programmed process of mutation, affecting the variable regions of immunoglobulin genes.
Unlike other types of mutation, SHM affects only individual immune cells, and the mutations are not transmitted to child offspring. (see genes) Mistargeted somatic hypermutation, is currently under investigation as a possible mechanism in the development of B cell Lymphomas.After stimulation by a Tcell, a Bcell divides into plasma and memory cells, and during this division, the immunoglobulin variable region DNA information, is transcribed and translated.The introduction of mutations in the rapidly proliferating population of B cells ultimately culminates in the production of thousands of B cells, possessing slightly different receptors and varying specificity for the antigen, from which the B cell with the closest affinities for the antigen, can be selected.
Those B cells with the closest or greatest affinity will then be selected to differentiate into long-lived plasma cells, which produce antibodies, and memory Bcells which "remember" invading antigens, and therefore enhance immune responses upon reinfection.
The hypermutation process also uses cells that auto-select against the 'signature' of an organism's own cells. It is hypothesized that failures of this auto-selection process may also lead to the development of an autoimmune response. Disturbances such as somatic (relating to the body) mutations in cells of the lymphoid system could in principle give rise to forbidden clones of cells that fail to recocognise self and instead react immunmocologically with normal tissues. (see under genes)

3)Passive Immunity.

Passive immunity is provided when the body is given antibodies rather than producing them itself, and is usually short-term, lasting between a few days and several months. A newborn baby has no prior exposure to microbes, and are particulary vunerable to infection, but they have passive immunity to several diseases, such as measles, mumps and rubella, from antibodies passed from it's mother via the placenta.
Passive immunity only lasts for a few weeks or months. In the case of measles, mumps and rubella it may last up to one year in infants, and this is why MMR Immunisation is given just after a child’s first birthday. Passive immunization involves transfusion of antiserum, containing antibodies that are formed by another person or animal. It provides immediate protection against an antigen, but does not provide long-lasting protection.
During pregnancy, the antibody IgG is passed from mother to baby via the placenta, so babies have quite high levels of antibodies at birth, with the same specific antigens as the mother. Breast milk too contains antibodies that are transferrred to the gut of the new baby, and will protect the child against bacterial infections, until it can form its own antibodies. This is passive immunity because the foetus does not actually make any memory cells or antibodies, it only borrows them. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum.

Nonspecific immunity and specific immunity interact, influencing each other directly or through substances that attract or activate other cells of the immune system, a part of the mobilization step in defence.

These substances include:
Cytokines, (which are the messengers of the immune system)

Antibodies,

Complement Proteins. ( which form the complement system)

These substances are not contained in cells but are dissolved in a body fluid, such as plasma, the liquid part of blood.
If microbes survive the body’s front-line defences, they still have to find a way through the walls of the digestive, respiratory, or urogenital passageways to the underlying cells. These passageways are lined with tightly packed epithelial cells covered in a layer of mucus, effectively blocking the transport of many organisms.

Mucosal surfaces also secrete a special class of antibody called IgA, which in many cases is the first type of antibody to encounter an invading microbe. Underneath the epithelial layer , a number of cells, including macrophages, B cells, and T cells, lie in wait for any germ that might bypass the barriers at the surface. Next, invaders must escape a series of general defenses, which are ready to attack, without regard for specific antigen markers. These include patrolling Phagocytes, NKiller cells, and Complement. Microbes that cross the general barriers then confront specific weapons tailored just for them. Specific weapons, which include both antibodies and T cells, are equipped with singular receptor structures that allow them to recognize and interact with their designated targets.

The human body can respond to antigens in many different ways. These fall into two major categories:
1) Humoral or Antibody-Mediated Immunity. Antibodies, dissolved in blood, lymph, and other body fluids bind the antigen and trigger a response to it;
and:-
2) Cell-mediated immunity. (Tcells, (lymphocytes) bind to the surface of other cells that display the antigen and trigger a response. The response may involve other lymphocytes and any of the other white blood cells (leukocytes).

Humoral Immunity

Definition of Humoral. (Pertaining to antibodies in the blood or other body fluids,) ie:

1) Phlegm (water)

2) Blood in particular serum
3) Gall (black bile secreted by the kidneys and spleen)
4) Choler (yellow bile secreted by the liver)
The humoral immune response is the part of the immune response which protects the body against free-floating foreign molecules (antigens), and involves Antibodies which are secreted by B cells. (see Bcells)
The B cells are activated when a specific antigen binds to the antibody, which is located on the surface of the B cells. This activation results in the production of memory B cells and plasma B cells that are specific for that antigen. Plasma B cells then release antibodies specific for the antigen. Memory B cells express the antibody on their surfaces and become important for the secondary immune response. The humoral immune response is also vital for vaccines.
The humoral response begins in the lymph nodes and the spleen.
The spleen filters antigens in the blood and
the lymph nodes filter antigens into the tissues.
The humoral response is split into two repsonses, Primary and Secondary .
A Primary humoral response results from the activation of naive lymphocytes (B cells). A primary response to antigen is characterized by a "lag time," which is the period of antigen encounter until the production of plasma cells and memory cells.(see B cells)
A Secondary humoral response results in the activation of memory lymphocytes.

Cell Mediated Immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages natural killer cells (NK), antigen specific cytotoxic T lymphocytes, and the release of various cytokines in response to an antigen.
Cellular immunity protects the body by:
1) activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis ,(cell death) in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumour antigens;
2) activating macrophages and natural killer cells, enabling them to destroy intracellular pathogens;
3) stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.
Cell-mediated immunity is directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, Protozoans, cancers, and intracellular bacteria. It also plays a major role in transplant rejection for thymus since it is the principal organ in the T cell's development.

The organs of the immune system are positioned throughout the body, and are home to lymphocytes, small white blood cells that are the key players in the immune system.
Bone Marrow which is the soft tissue inside the hollow centre of bones, is the source of all blood cells. They are derived from hematopoietic stem cells (blood cell forming stem cells) including white blood cells destined to become immune cells, which are known as Lymphocytes.
The immune system forms a huge arsenal of cells, not only lymphocytes, but also cell-eating Phagocytes , which include, Macrophages and Dendritic cells. Some immune cells take on all "foreign invaders" and others are directed to specific targets.

For the immune system to protect the body from invasion, all the immune cells need, and depend upon the cooperation of each other. Sometimes immune cells communicate by direct physical contact, or by releasing chemical "messengers", known as Cytokines. (see Cytokines)
The immune system stores just a few of each kind of the different cells needed to recognize millions of possible enemies. When an antigen appears, those few matching cells multiply into a full-scale army. After their job is done, they fade away, leaving "sentries" behind to watch for future attacks. All these immune cells respond to different cytokines and other signals to grow into specific immune cell types, such as T cells, B cells, or Phagocytes. Because stem cells have not yet committed to a particular future, they are an interesting possibility for treating some immune system disorders. Researchers are currently investigating if a person’s own stem cells can be used to regenerate damaged immune responses in autoimmune diseases and immune deficiency diseases.

The Structure Of The Immune System

The Lymphatic System
The lymphatic system is an important part of the body's immune system, providing defence against infection and some other types of disease, including cancer. The lymphatic system involves a transportation system of lymph vessels for transportation and storage of lymphocyte cells within the body, and these lymphocytes can travel throughout the body using the blood vessels, and through a system of lymphatic vessels that closely parallel the body’s veins and arteries.

A clear fluid called lymph bathes the body’s tissues and circulates through the lymphatic vessels, carrying Lymphocytes (white blood cells) around the body. Cells and fluids are exchanged between blood and lymphatic vessels, enabling the lymphatic system to monitor the body for invading microbes, feed cells into the body, filtering out dead cells, and invading organisms such as bacteria. The lymphatic vessels pass through lymph nodes, which are small, bean-shaped nodes clustered together and laced along the lymphatic vessels, with clusters in the neck, armpits, abdomen, and groin.

Each lymph node contains specialized compartments where immune cells congregate, and where they can encounter antigens. The lymph nodes contain large numbers of lymphocytes and act like filters, trapping infecting organisms such as bacteria and viruses. Immune cells and foreign particles enter the lymph nodes via incoming lymphatic vessels or the lymph nodes’ tiny blood vessels. All lymphocytes exit lymph nodes through outgoing lymphatic vessels.
Once in the bloodstream, they are transported to tissues throughout the body. They patrol everywhere for foreign antigens, then gradually drift back into the lymphatic system, to begin the cycle all over again.
When a person with a sore throat for eg; develops 'swollen glands' in the neck, the lymphatic fluid from the throat drains into the lymph nodes in the neck, where the infecting organism can be destroyed and prevented from spreading to other parts of the body.

The Spleen The spleen is a flattened organ at the upper left of the abdomen. Like the lymph nodes, the spleen contains specialized compartments where immune cells gather and work, and serves as a meeting ground where immune cells confront antigens. Clumps of lymphoid tissue are found in many parts of the body, especially in the linings of the digestive tract, airways, and lungs, which serve as gateways to the body. These tissues include the tonsils, adenoids, and appendix.

2009-12-30T14:32:00.053Z

Genes
All the genetic information needed to make millions of different antibodies actually fit into a limited number of genes, and this is made possible because antibody genes are pieced together from widely scattered bits of DNA, and the possible combinations are nearly endless. As this gene forms, it assembles segments that will determine the variable-V, diversity-D, joining-J, and constant-C segments of this antibody molecule, a typical IgM heavy chain.

Variable (V), and constant regions (C) are genetically encoded. As the immune system needs to be capable of responding to something in the region of over 1000 antigens, there is a need for an enormous number of genes to provide for this. The amount of DNA that this would involve would therefore be enormous too, but nature has solved this problem in a very clever and unique way. (see under Antibodies)

In the germline DNA, the V genes encoding the antigen combining sites need to combine with the C constant region genes. Diversity of specificity is produced by additional interposed or linking genes. For eg: ....
An immunoglobulin (Ig) molecule consists of two light chains, and two heavy chains. Light chains (L chains) exist in two classes, lambda and kappa. In light chains, the "linking genes" are the J genes, which link V to C; so this produces a combination of V-J-C. Joining is imprecise, causing further variation, or combination diversity. (see under antibodies)

In the case of Heavy chains, (H Chains) there is yet another region interposed between V and J, this is the D (for diversity), gene segment. Thus in H chains, there is V-D-J-C, again with combination diversity. If then, a light chain variable region consists of 25 lambda V (variable) genes, and 5 J (link) genes, then there are already 125 possible combinations, disregarding imprecision of joining.

For kappa light chains, there are 5 V genes and 70 J genes, yielding 350 combinations. For Heavy chains, there are 100 V genes, 50 D genes, and 6 J genes, giving 30,000 combinations.
L=light chains are separated from H=heavy chains by disulphide (S-S) links.
Intrachain S-S links divide H and L chains into domains which are separately folded.
Thus, an IgG molecule contains 3 H heavy chain domains, written CH1, CH2 and CH3. Between CH1 and CH2, there are many cysteine and proline residues.
This is known as the hinge region and confers flexibility to the Fab arms (the area of the molecule, where antibody joins with an antigen) of the Ig molecule.
This is used when antibody interacts with antigen.
Disregarding combination diversity, this yields more than 109 combinations. Multiply this by joining imprecision, plus a heightened mutation rate of genes in the hypervariable region, it can be seen that from 261 genes, this process can exceed at least 1018 variations. (See Antibodies)

Genetic factors can affect an individual's immune system and its responses to foreign antigens in several ways.
Genes determine the variety of MHC molecules that individuals carry on their cells, and genes also influence the potential array of T-cell receptors present on T cells.

Regulatory Complement Proteins. (RCP's)

The Functions of RCP's.

1) Switch genes on /off

2) Regulate the genetic information from DNA, ( the grey area in the picture)

3) Convert the genetic information into a strand of RNA. (the brown area in the picture)

4) They release Neutrophils from the bone marrow. (see neutrophils)

RNA's in turn translate that genetic information from DNA, into protein structures. (the yellow area in the picture) Most genes are expressed as proteins.

RCP's bind to specific regulatory sequences of DNA, and act to switch genes on and off, and thereby regulate the transcription of genes; ie:-
RCP's convert the genetic information in a strand of DNA, into a strand of RNA , especially messenger RNA. (see yellow area of picture)

DNA, which stands for deoxyribonucleic acid, is the long-chain molecule that contains the genetic material (encoded hereditary characteristics) in living organisms. (De-oxy-rye-bon-new-clee-ic) acid, is a long linear polymer (see definition below) found in the nucleus of a cell, formed from nucleotides, and shaped like a double helix. It is associated with the transmissionion of genetic information. DNA, is The "king" of molecules.
RNA, which stands for ribonucleic acid, is also a long linear polymer (a long-chain) of nucleotides, found in the nucleus, but mainly in the cytoplasm of a cell, where it is associated with microsomes. It transmits the genetic information from DNA, to the cytoplasm, and controls certain chemical processes in the cell.

The function of RNA is to translate the genetic material stored in DNA, into protein structures. RNA essentially carries out the instructions of DNA.
Most genes are expressed as proteins. The synthesis within a cell of a particular protein can be detected by antibodies able to bind to that protein.
Any step of gene expression may be modulated, from the DNA -RNA Transcription step, to post-transational modification of a protein.
Definition of a Polymer: ( A polymer is a naturally occurring compound, consisting of large molecules
made up of a linked series of repeated simple monomers. (it can be made artificially too)

The Major Histocompatibility Complex (MHC)
(A synonym for human leukocyte antigens. )
MHC's are a large gene family and play an important role in the immune system, autoimmunity, and reproductive success. In humans, these genes are referred to as human leukocyte antigen (HLA) genes, although people often use the abbreviation MHC to refer to HLA gene products.

To clarify the usage, some of the biomedical literature uses HLA to refer specifically to the HLA protein molecules and reserves MHC for the region of the genome that encodes for this molecule; however this convention is not consistently adhered to.
MHC molecules are important components of the immune response. They allow cells that have been invaded by an infectious organism to be detected by cells of the immune system called T lymphocytes, or T cells.

The MHC molecules do this by presenting fragments of proteins (peptides) belonging to the invader on the surface of the cell. The T cell recognizes the foreign peptide attached to the MHC molecule and binds to it, an action that stimulates the T cell to either destroy or cure the infected cell. In uninfected healthy cells the MHC molecule presents peptides from its own cell (self peptides), to which T cells do not normally react. However, if the immune mechanism malfunctions and T cells react against self peptides, an autoimmune disease arises.

Genes in the MHC region are the subset that encodes cell-surface antigen-presenting proteins. The most intensely-studied HLA genes are the nine so-called classical MHC genes: HLA-A, HLA-B, HLA-C, HLA-DPA1,HLA-DP1 HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1.
In humans, the MHC is divided into three regions: Class I, II, and III.
The A, B, and C genes belong to MHC class I,
The six D genes belong to class II.

The proteins encoded (to specify the genetic code for a protein molecule) by the MHC's, are expressed on the surface of cells and display both self antigens (peptide fragments from the cell itself) and nonself antigens (e.g. fragments of invading microrganisms) to a type of white blood cell called a Tcell. This Tcell has the capacity to kill or co-ordinate the killing of pathogens, infected or malfunctioning cells. (see link and HLA's) here... http://en.wikipedia.org/wiki/Major_histocompatibility_complex

The subsequent steps depend in part on which co-stimulatory molecules interact and how well they interact. Because these interactions are so critical to the response of the immune system, researchers are intensively studying them to find new therapies that could control or stop the immune system attack on self tissues and organs.

This same group of genes are also known as HLA's, Human Leukocyte Antigens. A group of molecules that are located on the surface of cells and are unique in each organism, enabling the body to distinguish self from nonself. (see quote below)
Human Leukocyte Antigens (HLA)
This group of genes (also known as MHC's ) control key steps in the immune response, especially those related to recognition by T cells of specific antigens
presented to them by antigen-presenting cells, such as the phagocytes=
macrophages, and Dendritic cells .

The MHC region is divided into three subgroups called MHC class I, MHC class II, and MHC class III.
The major HLA antigens are essential elements in immune function, and the different classes of HLA's, have different functions.
1) class I antigens (A, B & C) -Present peptides from inside the cell (including viral peptides if present.) These are self antigens, which are recognised and usually ignored. (An autoantigen is any constituent of the body's own tissues, capable of stimulating autoimmunity)
2)class II antigens (DR, DP, & DQ) -Present phagocytosed antigens from outside of the cell to T-lymphocytes. (These are self antigens which present fragments of non-self, antigens, to Tcells) Class II proteins are found only in the membranes of lymphocytes and phagocytic antigen presenting cells.
3)class III -Encodes for other immune components, such as complement components ( C2, C4, factorB) and some that encode cytokines.

The MHC proteins display fragmented pieces of an antigen on the host cell's surface. These antigens may be self or nonself. If they are nonself, there are two ways by which the foreign protein can be processed and recognized as being "nonself".

If the host is a leukocyte such as a monocyte or neutrophil, it may have engulfed the particle (be it bacterial, viral, or particulate matter), broken it apart using lysozymes, and displayed the fragments on Class II MHC molecules.
On the other hand, if a host cell was infected by bacteria or a virus, or was cancerous, it may have displayed the antigens on its surface with a Class I MHC molecule.
In particular, cancerous cells and cells infected by a virus have a tendency to display unusual, nonself antigens on their surface.

These nonself antigens, regardless of which type of MHC molecule they are displayed on, will initiate the "specific immunity" of the host's body.
It is important to note that cells constantly process endogenous proteins and present them within the context of MHC I.
Immune effector cells are trained not to react to self peptides within MHC, and as such are able to recognize when foreign peptides are being presented during an infection or cancer.

Picture shows an antigen presenting cell, which has enveloped an invading cell and having taken a bit of the antigen, presents a piece of it on its classII self antigen , (which hold nonself antigens on their surface ) so that a T cell can recognise it. This is the only way a T cell can recognise non-self antigens.

The MHC region is being scrutinized by immunologists for its pivotal role in the immune system, the MHC has also attracted the attention of many evolutionary biologists, due to the high levels of allelic diversity found within many of it's genes. Much theory has been devoted to explaining why this particular region of the genome harbors so much diversity, especially in light of its immunological importance .
HLAs (MHC's) also have a role in:
1) disease defence,
2) reproduction (may be involved in mate selection)
3) cancer (may be protective or fail to protect),
4) human disease,
5) in autoimmunity, (known to mediate many autoimmune diseases,)
6) as antigens, (are responsible for organ transplant rejection.)
Apart from the genes encoding these 6 major antigens, there are a large number of other genes, many involved in immune function located on the HLA complex. Diversity of HLA in human population is one aspect of disease defence, and, as a result, the chance of two unrelated individuals having identical HLA molecules on all loci is very low. (see link below)
Human leukocyte antigen - Wikipedia, the free encyclopedia

Genetic Polymorphisms, are a genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is altered. Polymorphisms arise through mutation. The mutation may be due to a change from one type of nucleotide to another, an insertion or deletion (collectively known as indels), or a rearrangement of nucleotides. (See under antibodies ) Once formed, a polymorphism can be inherited like any other DNA sequence, allowing its inheritance to be tracked from parent to child. (read Genetics Encyclopedia polymorphisms in links below)
http://www.ncbi.nlm.nih.gov/About/primer/snps.html
http://www.answers.com/topic/polymorphism

2009-12-29T13:01:00.026Z

Cells Of The Immune System

The Complement System
The Complement System is the first part of the immune system that meets invaders of the body, such as bacteria, and it is very quick to act, and deadly. It is called complement because it helps, (complements) antibodies to kill these invaders. Complement is a cascade of about twenty five-thirty proteins, which flow freely in the blood, and can quickly reach the site of an invasion, where they can react directly with antigens. (molecules that the body recognizes as foreign substances).
Complement, marks any cell which does not have protective proteins on their surface; (see HLA's) whereas antibodies lock on to specific foreign invaders, and in many cases , activates complement. Complement markers, with or without antibody, attract white blood cells, known collectively as Phagocytes.

When activated, the complement proteins can...
1) stimulate inflammation
2) facilitate antigen phagocytosis by attracting phagocyte eater cells such as macrophages to the area
3) coat (opsonize) intruders, so that eater cells are more likely to devour them.
4) kill some cells directly, with various immune functions, such as lyses (destroys and kills)
5) attract neutrophils to a trouble spot.
6) enhance the effectiveness of antibodies.

Complement is not "antigen specific", it is activated immediately in the presence of a pathogen and therefore it is considered as a part of innate immunity. ( Immunity which we are born with) Complement is in fact the major humoral component, of the Innate immune response. It is a part of humoral immunity because antibodies can activate some complement proteins . Complement, is also a very powerful inflammatory agent, and therefore it's activity is tightly regulated. (see link below)
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Complement.html

Complement proteins circulate in the blood in an inactive form, and this combination of proteins are important in humoral immune responses. Complement proteins are activated by the antibodies IgM and IgG, which are located on the membrane of B cells. When these antibodies recognize and bind to antigens, a change of the IgM or IgG occurs. This means that its structure is slightly altered. This alteration results in the binding site for the first complement protein, Cl, to be exposed.

Once Cl binds to the "antigen -antibody" complex, (Ag-Ab Complex=the joining of antigen and antibody) more complements proteins can also bind. Once complement proteins 1-6 bind to the Ag-Ab complex, this forms what is called the MAC complex. MAC stands for Membrane Attacking Complex. This complex, as it implies, perforates, or punches holes in the target cell that is expressing the antigen. This allows surrounding water to flow into the cell and electrolytes to flow out of the cell resulting in cell death and therefore antigen death.(see picture below)

The "complement cascade" is set off when the first complement molecule, (C1), encounters an antibody bound to an antigen, in what is referred to as an "antigen-antibody complex". Each of the complement proteins performs it's specialized job in turn, acting on the molecule next in line. (going from C1 to C9) The end product is a cylinder that punctures the cell membrane and, by allowing fluids and molecules to flow in and out, dooms the target cell.

This group of proteins in blood serum, interact systematically as part of the body's immune response to destroy disease-causing antigens, especially bacteria. Complement proteins interact with antibodies and other chemical substances to cause the disintegration of foreign cells, and enhance other immune functions such as phagocytosis. (in which the blood cell engulfs the foreign body or damaged cell).

Fragments flung off during the course of the cascade can produce other consequences. One byproduct causes mast cells and basophils to release their contents, producing the redness, warmth, and swelling of the inflammatory response.
Another stimulates and attract neutrophils. Yet another, C3b, opsonizes or coats target cells so as to make them more palatable to phagocytes, which carry a special receptor for C3b.
The C3b fragment also appears to play a major role in the body's control of immune complexes. By opsonizing (coating) antigen-antibody complexes,(that are joined,) C3b helps prevent the formation of large and insoluble (and thus potentially damaging) immune aggregates. Moreover, receptors for C3b are also present on red blood cells, which appear to use the receptors to pick up complement-coated immune complexes and deliver them to the Kupffer cells in the liver.

Immune Complexes and the Complement System
Imune complexes are clusters of interlocking antigens and antibodies. Under normal conditions, immune complexes are rapidly removed from the bloodstream by macrophages in the spleen and Kupffer cells in the liver. In some circumstances, immune complexes continue to circulate, eventually becoming trapped in the tissues of the kidneys, lung, skin, joints, or blood vessels.
Where in the body these complexes actually end up, probably depends on the nature of the antigen, the class of antibody, for instance, IgG instead of IgM, and the size of the complex. There, they set off reactions that lead to inflammation and tissue damage. Immune complexes work their damage in many diseases. Sometimes, they reflect persistent low-grade infections.

Frequently, immune complexes develop in autoimmune disease, where the continuous production of autoantibodies overloads the immune complex removal system.

A group of specialized molecules that form the complement system helps to remove immune complexes. The different types of molecules of the complement system, which are found in the bloodstream and on the surfaces of cells, make immune complexes more soluble. Complement molecules prevent formation and reduce the size of immune complexes so they do not accumulate in the wrong places (organs and tissues of the body).
Rarely, some people inherit defective genes for a complement molecule from their parents. Because these individuals cannot make a normal amount or type of complement molecule, their immune systems are unable to prevent immune complexes from being deposited in different tissues and organs.

Lymphocytes (T cells and B cells) white Blood Cells.
All blood cells, Leukocytes (White blood cells), and cells destined to become immune cells begin life as immature cells, produced by Hematopoietic (hema-toe-poy-etic) Stem Cells (blood cell forming, stem cells) in the bone marrow. There are two major types of immune cell which stem from immature precursor Myeloid cells, and immature precursor Lymphoid cells.

Myeloid cells, form the second part to the innate immune system, a group typified by the large , cell and particle-devouring white blood cells, known as phagocytes. Phagocytes are and include, monocytes, macrophages, neutrophils dendritic cells, and mast cells.
Other myeloid descendants, become granule-containing inflammatory cells, such as eosinophils, and basophils. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact, or by engulfing and then killing micro-organisms.
Innate cells are also important mediators in the activation of the adaptive immune system.

Some lymphocytes remain in the bone marrow and mature there, and become B cells. Other lymphocytes shortly after birth, migrate to the Thymus, an organ in the top of the chest, where they mature to become T cells. Both T cells and B cells play an important role in recognising and destroying, infecting organisms such as bacteria and viruses.
Once mature, these lymphocytes enter the circulation and peripheral (around the body) lymphoid organs, the thymus, spleen and lymph nodes, where they survey for invading pathogens and/or tumour cells. Lymphocytes are responsible for specific or aquired immunity, (see immune system ) including producing antibodies by B lymphocytes, and distinguishing self from nonself by T -lymphocytes.

T cells and B-cells are the major cellular components of the adaptive/aquired immune response.
T cells are involved in cell-mediated immunity, (see cell mediated immunity) and B cells are responsible for humoral immunity. (see humoral immunity)

The function of T cells and B cells is to recognize specific “non-self” antigens, during a process known as antigen presentation, which is carried out by macrophages and dendritic cells. Once they have identified an invader, the cells generate specific responses that are tailored to eliminate specific pathogens or pathogen infected cells.
B cells respond to pathogens by producing large quantities of antibodies which then neutralize foreign objects like bacteria and viruses. In response to pathogens, some T cells, called Helper T cells, produce cytokines that direct or stimulate the immune response, whilst other T cells, called cytotoxic T cells, or Killer Tcells, produce toxic granules that induce the death of disease infected cells.
These B and T lymphocytes involved in adaptive/aquired immunity differentiate even further after exposure to an antigen.
They form Memory lymphocytes and Effector lymphocytes.
(an Effector cell is a molecule that binds to an enzyme, with an effect on its catalytic activity, i.e. either as an activator or inhibitor)

Following activation, B cells and T cells leave a lasting legacy of the antigens they have encountered, in the form of these memory cells. Throughout life, these memory cells will “remember” each specific pathogen encountered, and are able to mount a strong response if the pathogen is detected again.
Memory cells, remain in the peripheral (around and about the body) tissues and circulation, for an extended time, ready to respond to the same antigen should they encounter it again in the future. They live weeks to several years which is very long compared to other leucocytes. Effector lymphocytes function to eliminate the antigen, either by:- 1) Releasing antibodies (in the case of B cells) 2) Releasing cytotoxic granules (in the case cytotoxic T cells) 3) Signalling to other cells of the immune system (as in the case of helper T cells). Each B cell and T cell is specific for a particular antigen. This means that each is able to bind to a particular molecular structure, by a specific receptor for antigen. (A receptor selectively receives and binds a specific substance.)

A Receptor is a molecule on a cell's surface, that allows only molecules that fit precisely to it, (just as a key fits in a lock) and thereby able to attach to it. Both B and T cells have surface receptors for antigen. Each cell has thousands of receptors of a single specificity; that is, with a binding site for a particular epitope. T-cell receptors (TCRs) enable the cell to bind to and, if additional signals are present, to be activated by and respond to an epitope presented by another cell called the antigen-presenting cell or APC. B-cell receptors (BCRs) enable the cell to bind to and, if additional signals are present, to be activated by and respond to an epitope on molecules of a soluble antigen. The response ends with descendants of the B cell, secreting vast numbers of a soluble form of its receptors. These are antibodies. There are many different receptors. The B cell receptor for antigen is called a (BCR) and the T cell receptor is called a (TCR).

T CELLS
T cells are the cells, which modulate pathogenic immune responses. Studies suggest that the regulatory T cell population is diminished or functionally impaired in patients and animals with autoimmune disease.
T cells are distinguished from other lymphocyte types, such as B cells and Natural killer cells (NKC's ) by the presence of a special receptor on their cell surface called the T cell receptor (TCR).
Tcell receptors
The surface of each T cell displays thousands of identical receptors (TCRs) that bind to antigen fragments nestled in MHC molecules. T cells will respond to antigens. Some of them (CD4+) secrete lymphokines which act on other cells involved in the immune response. Others (CD8+, cytotoxic) are able to cause lysis (the death) of infected cells.
There are two types of T cells that differ in their TCR.
1) alpha/beta (αβ) T cells. Their TCR is a heterodimer of an alpha chain with a beta chain. Each chain has a variable (V) region and a constant (C) region. The V regions each contain 3 hypervariable regions that make up the antigen-binding site. (see Genes)
2) gamma/delta (γδ) T cells. Their TCR is also a heterodimer of a gamma chain paired with a delta chain (see antibodies)

The following is a list of the alpha/beta (αβ) T cells, and the least understood one, the gamma/delta (γδ) T cells, will be placed last in this list.

All cells express ClassI MHC molecules containing fragments derived from self proteins. (see genes)
Many cells express ClassII molecules that also contain self peptides. (see genes)
This presents a risk to the host (the individual body) of the T cells recognizing these self-peptide/self-MHC complexes and mounting an autoimmune attack against them.
Fortunately, this is usually avoided by a process of selection that goes on in the thymus (where all T cells develop).
In most cases, T cells only recognize an antigen if it is carried on the surface of a cell by one of the body’s own , major histocompatibility complex, molecules. (MHC's/HLA's amounts to the same thing) MHC molecules are proteins recognized by T cells when distinguishing between self and nonself. A self MHC molecule provides a recognizable scaffolding to present a foreign antigen to the T cell. Although MHC molecules are required for T-cell responses against foreign invaders, they also pose a difficulty during organ transplantations.
Virtually every cell in the body is covered with MHC proteins, but each person has a different set of these proteins on their cells.
If a T cell recognizes a nonself MHC molecule on another cell, it will destroy the cell. Therefore, doctors must match organ recipients with donors who have the closest MHC makeup, otherwise the recipient’s T cells will likely attack the transplanted organ, leading to graft rejection. (see genes MHC's)

Positive and Negative Selection
The "progenitors" or precursors of T cells which have migrated to the cortex of the Thymus, do not have a complete T cell Receceptor (TCR). In the thymus, they expand by cell division to make a large population of immature thymocytes. These early thymocytes have neither CD4 nor CD8 receptors, and are therefore classed as...
1) double-negative (CD4-CD8-minus) (DNcells).

As they progress through their development they become

2) double-positive thymocytes (CD4+CD8+plus) (DPcells), and finally mature to..

3) single-positive (CD4+CD8- or CD4-CD8+) (SPcells).
These single positive T cells (thymocytes) are then released from the thymus to peripheral (around the body) tissues. About 98% of thymocytes die during the development processes in the thymus, by failing either positive selection or negative selection. The other 2% survive and leave the thymus to become mature immunocompetent T cells. (Having the normal bodily capacity to develop an immune response following exposure to an antigen).

Positive Selection
In the cortex of the thymus the double -positive thymocytes are presented with self-antigens (ie: self antigens that are derived from molecules belonging to the host of the Tcell). Only those thymocytes that bind MHC/antigen complex, with adequate affinity, (or bind tightly enough), will receive a vital "survival signal" It is also determined during positive selection, whether a thymocyte becomes a CD4+ cell or a CD8+ cell.
Double-positive cells that are positively selected on MHC class II molecules will become CD4+ cells, and cells positively selected on MHC class I molecules become CD8+ cells.
These cells must be able to interact with MHC and peptide complexes in order to effect immune responses. During these developments, thymocytes that do not have adequate affinity ( do not bind tightly enough) cannot serve useful functions in the body, and therefore they die by apoptosis (programmed cell-death), in effect they commit suicide! Their remains are then engulfed by macrophages. This whole process is called positive selection.
However, this process does not remove from the population, thymocytes that would cause autoimmunity or a reaction with one's own cells. The removal of such cells is dealt with by Negative selection.

Central tolerance is not always complete. It is estimated that as many as 25–40% of T cells reactive to a self-peptide escape clonal deletion in the thymus. These T cells include low-affinity, autoreactive T cells, and T cells specific for self-antigens not presented in the thymus. T cells must remain tolerant (to ignore) to harmless environmental antigens found in the respiratory tract or intestines.
The existence of autoreactive T cells into the periphery (around the body) necessitates the role for DCs (Dendritic Cells) in peripheral tolerance to prevent autoimmunity.
The existence of self-reactive T cells circulating in the periphery is not problematic if T cells are naïve and if they remain within lymphoid tissues and do not enter normal tissues to induce tissue damage.
Self-reactive, naïve T cells therefore do not lead to disease, as long as they ignore or are separated from self-antigens. However, naïve, self-reactive T cells are potentially a problem during infection or inflammation.
Dendritic Cells will capture and present pathogenic antigens to induce T cell immunity, and they will also co-present numerous self-antigens captured during the steady-state.

There is an inherent risk that Dendritic cells (antigen presenting cells, ) co-presenting self-antigens during infection, might activate self-reactive T cells that recognize an autoantigen leading to effector T cell formation and the initiation of autoimmunity. In establishing peripheral tolerance in the steady-state by filtering out autoreactive T cells before an acute infection, Dendritic cells can effectively focus adaptive immunity on the pathogen and so avoid autoimmunity.

Negative Selection
The thymocytes which have survived positive selection move to the medulla of the thymus. There, those thymocytes whose TCR binds very strongly to complexes of self-peptide and self-MHC are destroyed by receiving an apoptosis signal, which results in their death. A small minority of the surviving cells are selected and will become Regulatory T cells (suppressor cells).
This process of negative selection is important as it eliminates self-reactive Tcells capable of generating autoimmune disease in the host.
It is one of the ways in which immune tolerance (the ignoring of) to self antigens is achieved.
The T cells which have survived these processes, will be able to recognise non-self antigens, which have undergone phagocytosis, by macrophages and dendritic cells, (see phagocytes) and fragments presented in combination, on the surface of a "self" receptor called a major histocompatability complex (MHC) molecule. (see Antigen below)
After a little more maturation, they exit the thymus to perform their role in immune responses.
http://en.wikipedia.org/wiki/Immune_tolerance

An Antigen is a substance that is foreign to the body. A T lymphocyte, part of the immune surveillance system, cannot directly recognize an antigen. Therefore, the antigen is first engulfed by an antigen-processing cell called a macrophage. (see macrophage) Enzymes in the macrophage break the antigen into fragments, which it then presents on the surface of major histocompatibility complex molecules. This new antigen formation moves to the surface of the macrophage, is recognized by the T-lymphocyte receptor, and binds with the T lymphocyte. (see picture below)

1)Helper Tcells (or Th cells.) These cells co-ordinate immune responses by communicating with other cells. Some stimulate nearby B cells to produce antibody, others call in microbe-eating cells called phagocytes, still others activate other T cells.
Helper T cells only recognize antigens coupled to Class II molecules. Helper T cells regulate both the innate and adaptive immune responses and help determine which types of immune responses the body will make to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They control the immune response by directing other cells to perform these tasks. Antigen presenting cells (APC's) present antigen on the Helper T cell's Class II MHC molecules (MHC2).

The MHC2/antigen complex is also recognized by the Helper cell's CD4 co-receptor, (CD4+), which recruits molecules inside the T cell that are responsible for the T cell's activation.

The activation of a resting helper T cell, causes it to release cytokines and other stimulatory signals, that stimulate the activity of macrophages, Killer T cells, and B cells, the latter producing antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells.

Helper T cells have a weaker association with the MHC:antigen complex than for killer T cells; meaning that many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell; while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell.

The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types.
Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells. Through interaction with helper Tcells, Cytotoxic killer cells, can be transformed into suppressor Tcells, which prevent autoimmune diseases. (see killer Tcells and regulating Tcells.) In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, which provide extra stimulatory signals typically required to activate antibody-producing B cells.

2) Killer T cell (also known as CD8+ /cytotoxic Tcells.) Through interaction with helper Tcells, these cells can be transformed into suppressor Tcells, which prevent autoimmune diseases. Killer T cells only recognize antigens coupled to ClassI molecules.(MHC1). Killer T cells are a sub-group of T cells, that kill cells infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional cells. Each type of T cell recognises a different antigen, (as do B cells) and are activated when their T cell receptor (TCR) binds to this specific antigen, in a complex with the MHC Class I receptor of another cell. Recognition of this MHC antigen complex, is aided by a co-receptor on the T cell, called CD8. This T cell then travels throughout the body in search of cells where the MHC I receptors, bear this antigen.

When an activated T cell contacts such cells, it releases cytoxines such as perforin which form pores in the target cell's plasma membrane, allowing ions, (water and toxins) to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis (cell death.) T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by Helper T cells.

3)Natural Killer (NKt) Cells. These are another, special kind of lethal white cell, or lymphocyte that bridge the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigen, presented by Major Histocompatibility Molecules(MHC), NKT cells recognize glycolipid antigen presented by a molecule called CDId. Once activated, these cells can perform functions ascribed to both cytokine production, and release of cytolytic/cell killing molecules. Like killer T cells, NK cells are armed with granules filled with potent chemicals. While killer T cells look for antigen fragments bound to self-MHC molecules, NK cells recognize cells lacking self-MHC molecules. Thus, NK cells have the potential to attack many types of foreign cells. Both kinds of killer cells slay on contact. The deadly assassins bind to their targets, aim their weapons, and then deliver a lethal burst of chemicals.

4) Memory T cells. These are a subset of antigen-specific T cells that persist a long time after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: 1) central memory T cells (TCM cells) and 2) effector memory T cells (TEM cells). (able to alter the function of other cells) Memory T cells may be either CD4+ T ( regulating Tcells) or CD8+. killer Tcells)

5) Regulatory (or Suppressor) T cells . These are white blood cells that helps to end an immune response. Through interaction with helper Tcells, these cells can be transformed into suppressor Tcells, which prevent autoimmune diseases. These are the cells which are under intense research. An important question in the field of immunology is how the immunosuppressive activity of regulatory T cells is modulated during the course of an ongoing immune response.

The immunosuppressive function of regulatory T cells prevents the development of autoimmune disease. Reg Tcells are crucial for the maintenance of immunological tolerance. (Having the ability to ignore self antigens and respond to only non-self antigens.) Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells are:- 1) Innate occurring T-reg.cells, and the adaptive T-reg cells. Naturally occurring (innate) T-reg cells (also known as CD4+CD25+FoxP3+ Treg cells) arise in the thymus. 2) adaptive T-reg. cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response.
Naturally occurring (innate) T-reg.cells can be distinguished from other T cells by the presence of an intracellular molecule called FOX P3. Naturally occurring regulatory T cells represent five to ten percent of CD4+ T cells and possess potent immunoregulatory functions essential to peripheral (around the body) self-tolerance. (the ability to recognise and ignore self antigens)

Regulatory T cells express Foxp3. Foxp3a is a Master Control gene for regulatory T cells, and identifies these cells as a distinct subset of T cells.
Genetic insufficiency of Foxp3 causes autoimmune and inflammatory disease. In humans, defects in the Foxp3 gene underlie loss of self-tolerance and immune dysregulation. These results raise the prospect of novel approaches to controlling autoimmunity.
Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal Autoimmune disease IPEX .

6)Autoaggressive Tcells.
These are a unique T cell subset that are characterized by the expression of CD40. CD40 is associated with antigen-presenting cells, but is also expressed on a subset of T helper cells. Th40 cells are found in all individuals but occur at drastically expanded percentages in autoimmune subjects. This is true of autoimmune humans and mice.
For eg:- Th40 cells from type 1 diabetic subjects respond to known self-antigens, whereas Th40 cells from non-autoimmune subjects do not respond to those antigens.

A crucial role of CD40 on T cells is to induce RAG1 and RAG2, the VDJ (variable, Diversity, & linking ) recombinase proteins, (see genes) responsible for altering the T cell receptor. The TCR is the means by which T cells are able to recognize antigens. It is required that RAG1 and RAG2 be expressed only in the thymus, during T cell development. However, RAGs are re-expressed in peripheral T cells, and CD40 engagement on Th40 cells induces RAGs expression. Following RAG expression, changes in TCR occur. This means that Th40 cells are capable of adapting throughout an individual's lifetime. This process of altering TCR expression in the periphery is called TCR revision. Revision can be responsible for expanding the T cell repertoire, but also could result in the generation of autoaggressive T cells. TCR revision is therefore another means of T cell self-tolerance.

7)Gamma/Delta (γδ) T Cells
A minor sub-type are the γδ T cells that recognise intact antigens that are not bound to MHC receptors.
The function of the γδ T cells within the human immune system is largely unknown. Gamma/Delta Tcell receptors (γδ TCRs ) seem to recognize antigen directly, similar to immunoglobulins (Igs), but they do not require presentation by an MHC protein or other molecules and do not depend on antigen processing.
The diversity of the γδ TCR is limited, suggesting that the ligands (see below) for the γδ TCR are conserved and invariant.
γδ T cells have been shown to recognize self-peptides, such as stress-associated antigens expressed on epithelial cells, tumor lines, and primary carcinomas.
Recognition of self-peptides and the production of cytokines early during an immune response indicate that γδ T cells play a role in the development of an immune response against self-tissue, ie : Autoimmune response.
Definition of Ligand= (When a protein binds to another molecule, that molecule may be referred to as a ligand. The site where the ligand is bound is known as the binding or active site of the protein.)

Gamma/delta T cells differ from the alpha/beta in several ways:
1) Their TCR is encoded by different gene segments.
2) Their TCR binds to antigens that can be intact proteins. (just as antibodies do) as well as a variety of other types of organic molecules.
3) Are not "presented" within class I or class II histocompatibility molecules;
4) Are not presented by "professional" antigen presenting cells(APCs) such as Dendritic cells
5)Most of these T cells have neither CD8 nor CD4 on their surface. This makes sense because they have no need to recognize class I and class II histocompatibility molecules.
6) Gamma/ Delta Tcells like alpha/beta T cells, develop in the thymus. From there, they migrate into body tissues, especially epithelia (eg.intestine, skin, lining of the vagina), and don't recirculate between blood and lymph nodes. (they represent no more than 5% of the T cells in the blood and are even rarer in lymph nodes)
7) They encounter antigens on the surface of the epithelial cells that surround them rather than relying on the Antigen presenting cells found in lymph nodes.

The Function of γδ Gamma Delta T cells
That is still something of a mystery. Situated as they are at the interfaces between the external and internal worlds, they may represent a first line of defence against invading pathogens. Their response does seem to be quicker than that of αβ (Alpha Beta) T cells.
Curiously, many of the antigens to which γδ T cells respond, are found not only on certain types of invaders (eg. Mycobacterium tuberculosis, the agent of tuberculosis) but also in host cells that are under attack by pathogens.
Knockout Mice that cannot make γδ T cells are slower to heal injuries to their skin. They are also much more susceptible to skin cancers than normal mice. Perhaps,immune surveillance is one of the functions of γδ T cells?

CD Markers. Cluster of Differentiation (CD)
What those CD numbers mean:
The cluster of differentiation (CD) is a protocol used for the identification and investigation of cell surface molecules present on leukocytes. CD molecules can act in numerous ways, often acting as receptors or ligands (the molecule that activates a receptor) important to the cell. A signal cascade is usually initiated, altering the behavior of the cell. Some CD proteins do not play a role in cell signalling, but have other functions, such as cell adhesion. There are approximately 250 different proteins.
Uses as cell markers
The CD system is commonly used as cell markers; this allows cells to be defined based on what molecules are present on their surface. These markers are often used to associate cells with certain immune functions or properties.

While using one CD molecule to define populations is uncommon (though a few examples exist), combining markers has allowed for cell types with very specific definitions within the immune system.
It is important to note that, while CD molecules are very useful in defining leukocytes, they are not merely markers on the cell surface. While only a fraction of known CD molecules have been thoroughly characterised, most of them have an important function. In the example of CD4 & CD8, these molecules are critical in antigen recognition.
CD molecules are utilized in cell-sorting using various methods including flow cytometry. Cell populations are usually defined using a '+' or a '–' symbol to indicate whether a certain cell fraction expresses or lacks a CD molecule. For example, a "CD34+, CD31–" cell is one that expresses CD34, but not CD31. This particular CD combination, typically corresponds to a stem cell, opposed to a fully-differentiated endotheliel cell.
Types of cells, and their CD markers.
Stem Cells
CD34+, CD31-
All Leukocyte Groups
CD45+
Granulocytes
CD45+, CD15+ Monocytes CD45+,CD14+
T Lymphocytes
CD45+,CD3+
T Helper Cell CD45+,CD3+,CD4+
Cytotoxic Tcell CD45+,CD3+,CD8+ B Lymphocyte CD45+,D19+ CD45+, CD19+ or CD45+,CD20+
Thrombocyte
CD45+,CD61+
Natural Killer cell
CD16+, CD56+, CD3-
Two commonly used CD molecules are CD4 and CD8, which are, in general, used as markers for helper (CD4) and cytotoxic T cells, (CD8) respectively. When defining T cells, these molecules are defined in combination with CD3+. Other leukocytes also express these particular CD molecules. Some macrophages express low levels of CD4. Dendritic cells (antigen presenting cells) express high levels of CD8. The relative abundance of CD4+ and CD8+ T cells is often used to monitor the progression of an HIV infection. http://en.wikipedia.org/wiki/List_of_human_clusters_of_differentiation

2009-12-28T21:27:00.007Z

B cells
A B cell arises from haemopoietic stem cells (blood forming stem cells) and matures in the bone marrow.
The B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole pathogens without any need for antigen processing.
Each B cell is specific for a particular epitope, or site, on a foreign protein or carbohydrate. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors (BCR's) represent all the antibodies that the body can manufacture.
Each B cell is programmed to make one specific antibody.
For example, one B cell will make an antibody that blocks a virus that causes the common cold, while another produces an antibody that attacks a bacterium that causes pneumonia.
If a particular BCRs binds to the a bacterial antigen, the antigen molecules will be engulfed into the B cell by a process called receptor-mediated endocytosis.
The antigen is then broken down into peptide fragments. These peptide ragments are then displayed at the cells surface in the grove of a molecule called Class II MHC. ( see genes)

Helper T cells with a T cell receptor that recognizes the displayed peptide fragment binds to the B cell, and releases lymphokines (a type of cytokine) that stimulate the B cells to proliferate, differentiate, and become an antibody producing cell.
The interaction with T cells maintains the specificity of the B cell response and also leads to the switch of antibodies from the IgM isotype to the more efficient IgG isotype. (see antibodies)
The activated B cell then begins to divide into two, producing plasma cells, which secrete immunoglobulins (antibodies), and Memory Bcells. (see Lymphocytes,B&Tcells)

B cells work chiefly by secreting substances called antibodies into the body’s fluids. They wait until they can ambush antigens circulating the bloodstream. They are powerless, however, to penetrate cells. The job of attacking target cells, either cells that have been infected by viruses or cells that have been distorted by cancer, is left to T cells or other immune cells (described below).

Plasma Cells
When a B cell encounters its triggering antigen, it gives rise to many large cells known as plasma cells. Every plasma cell is essentially a factory for producing an antibody. Each of the plasma cells descended from a given B cell manufactures millions of identical antibody molecules and pours them into the bloodstream.The plasma cells secrete millions of copies of the antibody (immunoglobulin)that recognizes a specific antigen. B cells are the only cells in the body that produce antibodies. They then enter the blood stream and circulate through the body.
These antibodies can :-
1) circulate in blood plasma and lymph
2)bind to pathogens expressing the antigen marking them for destruction by complement activation, (see Complement System) or for uptake and destruction by phagocytes.
3) Neutralize challenges directly, by binding to bacterial toxins
4) interfering with the receptors that viruses and bacteria use to infect cells. (see Antibodies Below)

Memory cells
When B cells and T cells are activated and begin to replicate, some of their offspring will become long-lived memory cells. Throughout a life time , these memory cells will remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive immunity" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen, and prepares the immune system for future challenges. Immunological memory can either be in the form of passive short-term memory or active long-term memory .

Antibodies
Antibodies are (Immunoglobulins, abbreviated Ig) and are also any of the structurally related glycoproteins. Immunoglobulins (antibodies) are found in serum and in secretions from mucosal surfaces.
They are produced and secreted by plasma cells which are found mainly within lymph nodes, and which do not circulate. Plasma cells are derived from B lymphocytes: (see Bcells) An immunoglobulin (Ig) molecule (an antibody) consists of two light polypeptide chains and two heavy polypeptide chains. A polypeptide chain is the structural element of a protein, consisting of a series of amino acid residues , known as peptides, joined together by peptide bonds.

Both the heavy and light chains consist of these amino acid sequences.
A Heavy chain, known as the H chain, is any of the large polypeptide chains of five isotypes, (classes eg: IgG, IgA. see isotypes) that, paired with the light chains, make up the antibody molecule.
Heavy chains bear the antigenic determinants that differentiate the immunoglobulin classes. (IgA, IgG etc.) A light chain, is known as an L chain. Light chains exist in two classes, lambda and kappa. Each antibody molecule has either lambda or kappa light chains, not both, and are unrelated to immunoglobulin class differences.
An L chain is either one of the two small polypeptide chains that, when linked to heavy chains by disulfide bonds, make up the antibody molecule. (as noted above with the H chain.) (see D & J links in Genes)
Antibodies are unique molecules, derived from the 'immunoglobulin supergene'.
One end of the Ig binds to antigens known as the Fab portion,( so called because it is the Fragment of the molecule which is antigen binding), and the other end which is Crystallizable, and therefore called Fc, is responsible for "effector" functions. (meaning having the capability in altering the activity of a molecule)

The regions on the Immunoglobulin molecule concerned with antigen binding, are extremely variable, whereas in other regions of the molecule, they are relatively constant. Thus, each heavy chain and each light chain possess a variable and a constant region. (see under Genes)
IgA exists in monomeric (a single segment) and a dimeric form,( combination of two identical molecules.)
IgA molecules also receive a secretory component from the epithelial cells into which they pass. This is used to transport them through the cell and remains attached to the IgA molecule, within secretions at the mucosal surface.
An IgM molecule is in pentameric form,(a molecule composed of approx. 5 linked monomers (single) units ) Both IgA and IgM are polymers. ( A polymer is a naturally occurring compound, consisting of large molecules made up of a linked series of repeated simple monomers ) The links between the "monomers" are made by a J polypeptide chain. (see genes)
L=light chains are separated from H=heavy chains by disulphide (S-S) links. Intrachain S-S links divide H and L chains into domains which are separately folded. Thus, an IgG molecule contains 3 H heavy chain domains, written CH1, CH2 and CH3. Between CH1 and CH2, there are many cysteine and proline residues. This is known as the hinge region and confers flexibility to the Fab arms of the Ig molecule, which is used when antibody interacts with antigen. (see under genes)

Isotypes
The Isotype of an immunoglobulin is determined by the constant region. (See genes) Isotypes are antigenic determinants that characterize classes and subclasses of heavy chains and types and subtypes of light chains.
Both Heavy and light chains are found on the constant region of a molecule, but Heavy chain classes of immunoglobulin are located on the Fc portion of the constant region of the molecule. These are responsible for effecting functions of a cell , meaning that they have the capability in altering the activity of a molecule .
Isotypes are found in all normal individuals in the species. The prefix "Iso" means "same in all members of the species."
Some individuals with immunodeficiencies may lack one or more isotypes, (such as IgA deficiency) but normal individuals have all isotypes.

There are 5 classes (Isotypes) of Immunoglobulin, (antibody) based on their structure and biological activity.
These are, IgM, IgG, IgA, IgD and IgE, plus 4 subtypes of IgG (IgG1-4), and 2 of IgA (IgA1, IgA2).
Different types Play different Roles in Immune defence.
IgG, (immunoglobulin G), works efficiently to coat microbes, speeding their uptake by other cells in the immune system. IgG is the most abundant class of antibodies found in blood serum and lymph and active against bacteria, fungi, viruses, and foreign particles. Immunoglobulin G antibodies trigger action of the Complement System.
IgM, is very effective at killing bacteria.
IgA, concentrates in body fluids, such as tears, saliva, the secretions of the respiratory, and the digestive tracts, and guarding the entrances to the body.
IgE, whose natural job probably is to protect against parasitic infections, is the villain responsible for the symptoms of allergy.
IgD remains attached to B cells and plays a key role in initiating early B-cell response.
Apart from having a name, these antibodies also have specific symbols.
Heavy Chain
α - IgA1+2
δ - IgD
γ - IgG1, 2, 3, 4
ε - IgE
μ - IgM
Light Chain
κ
λ

Idiotypes
The term idiotype is sometimes used to describe the collection of multiple idiotopes, and therefore the overall antigen binding capacity, possessed by an antibody.
Idiotypes are unique antigenic determinants (Epitopes), present on individual antibody molecules or on molecules of identical specificity. Identical specificity means that all antibodies molecules have the exact same hypervariable regions. If an antibody binds to an antigen's epitope, the Paratope (the site in the variable region of an antibody or T cell receptor, that binds to an epitope of an antigen.) could become the epitope for another antibody that will then bind to it.
Idiotypes, are the antigenic determinants created by the hypervariable regions of an antibody, and the anti-idiotypic antibodies are those directed against the hypervariable regions of an antibody.
Idiotypes are located on the Fab fragment of the Ig molecules, (which is the antigen binding portion.) Specifically, they are localized at or near the HyperVariable Regions of the heavy and light chains. (HVR's)

In many instances the actual antigenic determinant (idiotype) may include some of the framework residues near the hypervariable region. Idiotypes are usually determinants created by both heavy and light chain HVR's although sometimes isolated heavy and light chains will express the idiotype.
1)Variable region marker - Idiotypes, are a useful marker for a particular variable region.
2) Regulation of immune responses - there is evidence that immune responses may be regulated by anti-Idiotype antibodies directed against our own Idiotypes.
3)Vaccines - In some cases anti-idiotypic antibodies actually stimulate B cells to make antibody and thus they can be used as a vaccine. This approach is being tried to immunize against highly dangerous pathogens that cannot be safely used as a vaccine.
4) Treatment of B cell tumors - Anti-idiotypic antibodies directed against anti-idiotypes on malignant B cells can be used to kill the cells. Killing occurs because of complement fixation or because toxic molecules are attached to the antibodies.

Evidence has been presented that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody, and a host (self) cell receptor for the virus in question. In this case, the host(self) -cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host (self) cells.
Immunoglobulin class switching, can be used to change the class of the heavy chain, but not of the light chain.

Allotypes
The prefix "Allo" means "different" in individuals of a species.
Allotypes are hereditary allotypic markers associated with the heavy chains of IgG.
In man the allotypic differences are localized to the constant region of the heavy and light chains.
They are genetically determined variations in plasma proteins which may be recognized as antigenic by other members of the same species.
In other words they are genetic hereditary proteins specified by allelic forms of the Ig genes, which would be seen as antigens in another person.

They are commonly applied to subclasses of immunoglobulins. Allotypes represent slight differences in the amino acid sequences of heavy or light chains of different individuals. Even a single amino acid difference can give rise to an allotypic determinant, although in many cases there are several amino acid substitutions that have occurred.
Individual allotypes are found in individual members of a species.
All allotypes are not found in all members of the species.
Human Ig allotypes are named on the basis of the heavy or light chain on which it is located. Thus, an allotype on a Gamma 1 heavy chain is given the name: G1m(3). An allotype on a Kappa light chain is given the name: Km(1).

Nomenclature, is a system of names used in science:

2009-12-27T16:40:00.014Z

Phagocytes and Granulocytes.

Phagocytes is the collective name for Macrophages and Dendritic cells. Phagocytes are large white cells that can engulf and digest foreign invaders.
Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines.
Only professional antigen-presenting cells, (macrophages, B lymphocytes, and dendritic cells) are able to activate a helper T-cell which has never encountered its antigen before.

Some immune cells have more than one name. For example:-
Phagocytes, refers to the large immune cells that can engulf and digest foreign invaders, and
Granulocytes, refers to immune cells that carry granules laden with killer chemicals.
Phagocytes include :-
Monocytes, which circulate in the blood;
Macrophages, which are found in tissues throughout the body. Macrophages are versatile cells. Besides acting as phagocytic scavengers, they secrete a wide variety of signaling cytokines (called monokines) that are vital to the immune response.
Dendritic cells, which are more stationary, monitoring their environment from one spot such as the skin. Dendritic cells are the most potent of all the antigen-presenting cells.
Neutrophils, are in fact both a phagocyte and granulocyte cell that circulate in the blood but move into tissues when they are needed. They contain granules filled with potent chemicals. which in addition to destroying micro- organisms, play a key role in acute inflammatory reactions. Other myeloid descendants become granule-containing inflammatory cells known as Granulocytes.
Types of Granulocytes include:-
Eosinophils and Basophils, which degranulate by spraying their chemicals onto harmful cells or microbes.
The Mast cell is a twin of the basophil, except it is not a blood cell. Rather, it is responsible for allergy symptoms in the lungs, skin, and linings of the nose and intestinal tract.
A related structure, the blood platelet, is a cell fragment. Platelets, too, contain granules. They promote blood clotting and wound repair, and activate some immune defences.
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/Endocytosis.html

The Functions of these cells- fall into three categories,
1) Phagocytosis
2) Secretion of cytokines. Diverse and potent chemical messengers secreted by the cells of the immune system, and are the chief tool of T cells.
3) Antigen presentation.

Phagocytosis
These cells listed below, which arise from the bone marrow, have a variety of functions in the immune response:
The cells performing these various functions have differing microscopic appearances but they are grouped together as the Mononuclear Phagocytic System.
Phagocytosis is sometimes described as 'cell eating' but it is not really a process by which the cell obtains nourishment. White blood cells called neutrophils and other cells of the immune system carry out phagocytosis to keep the body clear of unwanted bacteria and parasites.
When the phagocytic white cell detects bacteria, it moves its cytoplasm and cell wall towards the bacteria, in a sort of creeping motion. The extensions of the cell that form during this movement are called pseudopodia meaning "false feet."
The cell membrane of the white cell completely surrounds a bacterium, enclosing it in a self contained vesicle called a phagosome. This vesicle is inside the white cell but the bacteria is a prisoner, surrounded by an internal cell wall to keep it away from the cell's cytoplasm. The cell then moves lysosomes, vesicles full of digestive enzymes, towards the phagosome and these discharge into the inside of the bacterium's vesicle, where they kill it and degrade it. The cell then spits the bits out.
The debris is moved towards the cell membrane and the membrane of the vesicle fuses with the cell membrane, pushing the debris out of the cell. Phagocytosis is the engulfment and digestion of bacteria and other antigens by phagocytes.

Monocytes
Monocytes are a type of agranulocyte, which are in turn a type of leucocyte (white blood cells). Agranulocytes (including monocytes) are distinguished from the other category of leucocytes because agranulocytes do not contain chemical-filled cytoplasmic vesicles called "granules".
An important function of monocytes is combatting microbes by the process of phagocytosis (after transforming into fixed or wandering macrophages).

When a monocyte enters damaged tissue through the endothelium of a blood vessel, (a process known as the leukocyte adhesion cascade) it undergoes a series of changes to become a Macrophage.
Monocytes are attracted to a damaged site by chemical substances through chemotaxis triggered by a range of stimuli including damaged cells, pathogens, histamine released by mast cells, basophils, and cytokines released by macrophages already at the site.
http://en.wikipedia.org/wiki/Monocyte

Macrophages
A large cell that is derived from a white blood cell called a monocyte, that ingests bacteria and other foreign cells, and that helps white blood cells identify microorganisms and other foreign substances.

Macrophages act as scavengers, they secrete a wide variety of powerful chemicals, and they play an essential role in activating T cells. Unlike short-lived neutrophils the life span of a macrophage ranges from months to years. Macrophages are cells within the tissues that originate from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes acting in both non-specific defence (or innate immunity) as well as specific defence (or cell-mediated immunity) of vertebrate animals.
Their role is to phagocytose (engulf and then digest) cellular debris and pathogens either as stationary or mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen.
Macrophages cells reside within tissues and produce a wide array of chemicals including enzymes, complement proteins and regulatory factors, such as interleukin1.
Macrophages also act as scavengers, ridding the body of worn-out cells and other debris. Macrophages are also antigen presenting cells that activate the adaptive immune system.
http://en.wikipedia.org/wiki/Macrophage

Dendritic Cells
Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment, therefore, they are located mainly in the skin nose, lungs, stomach and intestines.
They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous system.
Dendritic cells serve as a link between the innate and adaptive immune systems, as they present antigen to T cells; one of the key cell types of the adaptive immune system.
The principal function of dendritic cells is to act as the central command and central encyclopedia of the immune response, or similar to servers in a computer network.
They collect and store the immune system's "knowledge",enabling them to instruct and direct the adaptive arms in response to challenges.
Dendritic Cells process antigen material and present it on the surface to other cells of the immune system, thus functioning as Antigen-presenting cells. Dendritic cells are present in small quantities in tissues that are in contact with the external environment, mainly the skin, ( where they are often called Langerhans cells) and the inner lining of the nose, lungs, stomach, and intestines.They can also be found in an immature state in the blood. Once activated, they migrate to the lymphoid tissues where they interact with T cells and B cells to initiate and shape the adaptive immune response. At certain development stages they grow branched projections, the dendrites that give the cell its name. Immature dendritic cells are also called veiled cells, in which case they possess large cytoplasmic 'veils' rather than dendrites.
http://en.wikipedia.org/wiki/Dendritic_cell

Neutrophils
Neutrophils are fast acting, an "eater" (but do not survive after ingestion)
Neutrophils are not only phagocytes but also granulocytes. They contain granules filled with potent chemicals. These chemicals, in addition to destroying micro-organisms, play a key role in acute inflammatory reactions. Neutrophils, also known as polymorphonuclear leukocytes, are found in the tissues during acute inflammatory processes. Neutrophil Polymorph's are also involved in the effector side of the immune response. ( cells which mediate an immune response, or a molecule that binds to an enzyme with an effect on its catalytic activity, i.e. either an activator or inhibitor.)

They are the most common type of white blood cell ,known as Granulocytes which make up about 50-70% of all white blood cells. They are phagocytic, meaning that they can ingest other cells, though they do not survive the act.
Neutrophils are the first immune cells to arrive at a site of infection, through a process known as chemotaxis. (movement by a cell or organism in reaction to a chemical stimulus) In this response to chemotactic signals, they leave capillaries by a complex process, flowing nearer to the endothelial lining of blood vessels, rolling and then attaching. (margination)
They then emigrate between the endothelial cells (extravasation, or diapedesis), in which several mediators are involved.
These include substances produced by micro-organisms, and by the cells participating in the inflammatory process. One such, is a substance called interleukin-1 (IL-1), which is released by macrophages as a result of infection or tissue injury.
Another is histamine, released by circulating basophils, tissue mast cells, and blood platelets. It causes capillary and venular dilatation (small veins which connect capillaries to large veins).
The activation of Complement produces C3a and C5a which are chemotactic for phagocytic cells.(causing by chemical stimulation, in this case the Neutrophil to move along the pathway.see picture)

Chemotaxis Another group of substances produced are the acute phase proteins. As a consequence of tissue damage, the liver produces a substance called C-reactive protein (CRP), which is so called on account of its ability to attach to the C-polysaccharide component of the cell wall of bacteria and fungi.
This activates the complement system by the classical pathway, and as a result C3a is formed and coats the organism, facilitating it's phagocytosis. (the process in which phagocytes engulf and digest micro-organisms and cellular debrisa defence against infection)
Though neutrophils are short lived, with a half life of four to ten hours when not activated, and immediate death upon ingesting a pathogen, (disease causing cell), they are plentiful and responsible for the bulk of an immune response.
They are the main component of pus and responsible for its whitish color.
Neutrophil Granulocytes are released from the bone marrow, by Regulatory Complement Proteins, (RCP's) and are present in the bloodstream until signaled to a site of infection by chemical cues in the body.
They are fast acting, arriving at the site of infection within an hour.

Other Types of Granulocytes are.... Eosinophils, Basophils. and Mast cells are granule-containing cells in tissue.

Eosinophils are so named because their cytoplasmic granules stain red with the dye eosin. They are also known as eosinophilic leukocytes.
Eosinophil granulocytes, usually called eosinophils (or, less commonly, acidophils), are white blood cells of the immune system that are responsible for combating infection and parasites in verterbrates. They also control mechanisms associated with allergy and asthma. They are granulocytes that develop in the bone marrow before migrating into blood.
Within their cellular cytoplasm are a diverse collection of chemical mediators, such as histamine, and proteins such as eosinophil peroxidase, RNase, DNases, lipase, plasminogen, and Major Basic Protein.These mediators are released by a process called degranulation, following activation of the eosinophil, and are toxic to both parasite and host tissues.
They are found in the medulla and the junction between the cortex and medulla of the thymus and, in the lower gastrointestinal tract, ovary, uterus, and spleen, and lymph nodes, but not in the lung, skin or oesophagus, or some other internal organs under normal conditions. The presence of eosinophils in these latter organs is associated with disease. Eosinophils persist in the circulation for 8-12 hours, and can survive in tissue for an additional 8-12 days in the absence of stimulation.

Basophils
Basophils are the least common of the granulocytes and contain large cytoplasmic granules. The Mast Cell, (see mast cells) a cell in tissues, has many similar characteristics. For example, both cell types store histamine, a chemical that is secreted by the cells when stimulated.
(histamine causes some of the symptoms of an allergic reaction).
Like all circulating granulocytes, basophils can be recruited out of the blood into a tissue when needed.
When activated, basophils degranulate to release histamine, proteoglycans,(eg:heparin and chondroitin) and proteolytic enzymes (eg: elastase and lysophospholipase). They also secrete lipid* (see definition below) mediators, like leukotrines, and several cytokines. Histamine and proteoglycans are pre-stored in the cell's granules while the other secreted substances are newly generated. Each of these substances contributes to inflammation. Recent evidence suggests that basophils are an important source of the cytokine, interleukin-4, perhaps more important than T cells. Interleukin-4 is considered one of the critical cytokines in the development of allergies and the production of IgE antibody by the immune system.
There are other substances that can activate basophils to secrete, which suggests that these cells have other roles in inflammation. A low basophil count (Basopenia ) is difficult to demonstrate as the normal basophil count is so low; it has been reported in association with autoimmune Urticaria (a chronic itching condition).
Definition of *lipid (Any of a group of organic compounds, including the fats, oils, waxes, sterols, and triglycerides, that are insoluble in water but soluble in nonpolar organic solvents, are oily to the touch, and together with carbohydrates and proteins constitute the principal structural material of living cells.)

Mast Cells
Mast cells reside in connective tissues and mucous membranes and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis.
Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma. Natural killer cells (NK's), are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses
A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin.
Although best known for their role in allergy and anaphylaxis, (hypersensitivity reaction to the ingestion or injection of a substance (a protein or drug) resulting from prior contact with a substance), mast cells play an important protective role as well, being intimately involved in wound healing and defence against pathogens. Mast cells are very similar to basophils in blood.
The similarities between mast cells and basophils has led many to speculate that mast cells are basophils that have "homed in" on tissues. However, current evidence suggests that they are generated by different precursor cells in the bone marrow. Both mast cells and basophils are thought to originate from bone marrow precursors expressing the CD34 molecule.
The basophil leaves the bone marrow already mature while the mast cell circulates in an immature form, only maturing once in a tissue site.
The tissue site an immature mast cell chooses to settle in, probably determines it's precise characteristics.
Two types of mast cells are recognized.
1) those from connective tissue
2)and a distinct set of mucosal mast cells.
The activities of the mucosal mast cells are dependent on T-cells. Mast cells are present in most tissues in the vicinity of blood vessels, and are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs, and digestive tract, as well as in the mouth, conjunctiva and nose.
Mast cells are also involved in the effector side of the immune response. (cells which mediate an immune response, or a molecule that binds to an enzyme with an effect on its catalytic activity, i.e. either an activator or inhibitor) Recent evidence suggests that mast cells may be important mediators of regulatory t cell dependent peripheral (around the body) tolerance.

2009-12-26T01:59:00.002Z

Cytokines

Cytokines are Chemical Messengers, a diverse and potent group of proteins and peptides that are signalling compounds, produced by immune cells to communicate with one another. They act via cell-surface cytokine receptors, and are the chief communication signals of T cells.

Cytokines include interleukins, growth factors, and interferons.
Interferons are naturally occurring cytokines that may boost the immune system's ability to recognize cancer as a foreign invader.
When cytokines attract specific cell types to an area, they are called chemokines. These are released at the site of injury or infection and call other immune cells to the region to help repair damage and defend against infection.

Cytokines secreted by lymphocytes, (both T-cells and B-cells) are called lymphokines.
Cytokines secreted by phagocytes (monocytes and macrophages) are called monokines
Cytokines with chemotactic activities ( able to stimulate chemotaxis- the movement of cells through chemical stimulation )are called chemokines.
Cytokines made by one leukocyte and acting on other leukocytes are called interleukins, serving as a messenger between white cells, (or leukocytes.)
Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action).
Cytokines are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines.

Cytokines can also act synergistically (two or more cytokines acting together) or antagonistically (cytokines causing opposing activities).
Cytokines, binding to specific receptors on target cells, recruit many other cells and substances to the field of action.

Cytokines encourage cell growth, promote cell activation, direct cellular traffic, and destroy target cells -- including cancer cells.

The cytokine family consists mainly of smaller water-soluble proteins and glycoproteins (proteins with an added sugar chain.) They act like hormones and neurotransmitters, but whereas hormones are released from specific organs into the blood, and neurotransmitters are produced by neurons, cytokines are released by many types of cells.

Due to their central role in the immune system, cytokines are involved in a variety of immunological, inflammatory, and infectious diseases. However, not all their functions are limited to the immune system, as they are also involved in several developmental processes during embryogenesis. (The development and growth of an embryo, especially the period from the second week through the eighth week following conception)
When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells, and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines.

Cytokines have been recently divided into two groups according to the population of cells whose functions they promote:

ie:- The proliferation and functioning of helper T-cells, type 1 and type 2.

A key focus of interest has been that the second category (type2) of cytokines, tend to inhibit the effects of those in the other. This tendency is under intensive study for its possible role in the pathogenesis of autoimmune disease.(ie;in prevention of exaggeration of pro-inflammatory immune responses.

2009-12-22T14:07:00.040Z

Disorders Of The Immune System
(please note that I have presented Autoimmunity Seperately on another page). (See link bottom of this page)
In order to understand any disorders of the immune system, especially autoimmunity, it is essential to first understand the structure and function of the immune system, and the function of each of the cells, which together, through their interaction, signalling, and regulation, make up the body's defence system.
The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation. Failures of host defence do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.
The immune system may not work correctly, either from birth, or as a result of illness, leaving people prey to life threatening infection. It may become overactive and react against anything, harmful or otherwise.
This is the basis of allergic conditions, such as asthma, hayfever and eczema. Thirdly it may mutiny and attack the body , damaging vital tissues, as in such conditions as multiple sclerosis and Lupus erythametosus.

Immunodeficiencies
Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence, and possibly a reason why the majority of autoimmune diseases manifest for the first time around this age group. Immunodeficiency defines the following, all of which are serious conditions, excepting immunosenescence.

Immunosenescence.
The elderly suffer from an increased susceptibility to infectious disease and to certain types of cancer. It is hypothesized that ageing of the immune system, particularly the T cell compartment, contributes to this state of affairs due to immunosenescence. It is further hypothesized that because repeated intermittent or chronic antigen exposure may to lead to T cell clonal exhaustion (reflecting the inability of T cell clones to divide indefinitely), this process plays a part in the compromized immunity of the elderly, who have accumulated a lifetime´s exposure to infectious agents, autoantigens and cancer antigens. Therefore, this type of clonal exhaustion caused by antigen-stimulated proliferative stress, coupled with decreased or negligible thymic output and ageing of naive cells, may contribute to age-associated immunodeficiency. Defining age-associated alterations in T cell immunity will allow in these conditions, and facilitate onsequences of ageing which may compromise immunity include the following :
1) decreased remaining, replacative capacity of individual T cell clones.
2)The balance of different clones, especially influenced by viruses
3)Dysregulated signal transductionpathways
4)Increased levels of growth arrested cells
5) Altered Cytokine secretion patterns and all surface molecules
6) Increased levels of DNA damage and decreased DNA repair
7) Increased levels of Anergy, and Apoptosis of antigen -specific cells. (see Anergy and Apoptosis)
8)Accumulation of mutations, including mitochondrial mutations. (Polymorphisms)
Mitochondria: The mitochondria are normal structures called organelles in cells. They are located in the cell's cytoplasm outside the nucleus.
The mitochondria are responsible for energy production, and are in fact the principal energy source of the cell. (see Polymorphisms under Genes and Polymorphisms below)

Primary Immune Deficiency Disorder. This is known as Hypogammaglobulinaemia (Hypo-gamma-glob-you-lin- eem-ee-ya). These people are born with certain abnormal genes, which means that they do not produce all the immune cells, in this case an individual does not makeIgG antibodies. In a similar manner some people do not make sufficient IgA antibodies. Treatment of this deficiency is corrected by injections of the missing protein. The most serious immune deficiency condition, is.. Severe Combined Immunodeficiency (SCID) In this condition , none of the key immune cells are present. Affected children have to live in a germ-free "bubble", until they can have a bone-marrow transplant to give them the missing cells.

Leukaemia. Leukaemia can affect any of the immune cells granulocytes, monocytes or lymphocytes. The disease produces large numbers of these cells, but they do not work properly and function normally, and therefore are unable to protect the body from infection. Treatment by drugs and radiation to kill the abnormal cells, and encourage new healthy ones; further depletes the immune defence, making the person vunerable to serious infection, and must in consequence avoid exposure to infection, and take antibiotics andantiviral drugsat the very first sign of illness.

Organ Transplants. A situation which is used in organ transplants, to avoid rejection of the foreign tissue, is immunosuppression. This suppresses the normal immune response, again making the person vunerable to infection.

Poor Immune Function: In developed countries, obesity, alcoholism, and illegal drug abuse are common causes of poor immune function. However, malnutrition is the most common cause of immunodeficiency in developing countries.
Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Deficiency of single nutrients, such as iron, copper, zinc, selenium , vitaminsA, E, C, and B6 and folic acid (vitamin B9) also reduces immune responses, but any such deficiencies in these natural essential nutrients , will be seen in blood tests.
The loss of the thymus at an early age through genetic mutation or surgical removal, results in severe immunodeficiency and a high susceptibility to infection.
Immunodeficiencies can be inherited or acquired. Chronic Granulomatous Disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital immunodeficiency.
AIDS and some types of cancer cause acquired immunodeficiency.

Hypersensitivity (Overactive Immune System) Hypersensitivity is an immune response that damages the body's own tissues. They are divided into four classes:
1) Type I based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE released from mast cells and Basophils. (see these under cells of the immune system)

2) Type II hypersensitivity occurs when antibodies bind to antigens on the patient's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG, IgM or IgA antibodies.

3)Type III hypersensitivity reactions trigger Immune Complexes (aggregations of antigens, complement proteins, and IgG, IgA and IgM antibodies) deposited in various issues .

4) Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis, (poison Ivy). These reactions are mediated by Tcells, monocytes and macrophages.

Allergies: In allergies, the immune system reacts to an external substance that would normally be harmless. An allergy is a harmful immune response elicited by an antigen that is not itself intrinsically harmful.
The most common example of cell-mediated hypersensitivity to external antigens is the contact dermatitis caused in some people when their skin is exposed to a chemical to which they are allergic. Some examples are :
1)the catechols found in poison ivy, poison oak, and poison sumac
2)nickel (often used in jewelry)
3)some dyes
4)certain organic chemicals used in industry
When a person is unsure of what chemical is causing the dermatitis, the physician can try a patch test. Pieces of gauze impregnated with suspected allergens are placed on the skin. After 48 hours, they are removed and each site is examined for a positive response (a reddened, itching, swollen area).
*In every case, these simple chemicals probably form covalent bonds* (see link below) with proteins in the skin, forming the antigen that initiates the immune response. Dendritic cells in the skin take up the complex, process it, and "present" it to CD4+ T cells in nearby lymph nodes. * http://www.answers.com/topic/covalent-bond?cat=technology

People with allergic conditions make large numbers of immune cells in response to harmless invaders, such as pollen , fur, and dust. This starts off a chain of events leading to symptoms of wheezing in asthma, runny nose in hay fever and a rash in eczema. Most allergies are treated with drugs to relieve symptoms, since the underlying genetic abnormality in the immune system, cannot be corrected.
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Allergies.html#ICdisordersxtrinsic Antigens

Atopy Atopy is an inherited predisposition which causes a tendency to suffer from one or more of the following “atopic diseases”: allergic asthma, allergic rhino-conjunctivitis, and atopic dermatitis. The diagnosis of “atopy” is not based on one single distinctive clinical feature or laboratory test, but rather results from a combination of patient and family history and clinical findings. These features include:
1)Family and patient history with regard to eczema, allergic rhinitis and allergic asthma
2)Patient history with regard to milk crust, sweat-induced pruritus, intolerance of certain cloth fabrics or metals, and photophobia.
3)Present or past clinical findings such as xerosis cutis, ear fissures/ eczema, dyshidrosis or dyshidrotic hand eczema,pityriasis alba, atopic winter feet, nipple eczema, angular cheilitis.
4)Atopic stigmata such as palmer hyperlinearity, Hertoghe's sign, keratosis pilaris. 5)White dermographism, and acrocyanosis. As mentioned above, atopy may lead to the eczematous disease “atopic dermatitis”. It may also facilitate the development of irritant contact dermatitis.

Genetics of atopic dermatitis: The risk for AD is doubled in children whose father or mother have a history of atopy and it is more than 50% if both parents have at least one atopic disease. Interestingly AD is rather associated with maternal than paternal atopy. Several genes are suspected to be linked to AD such as 5q31-33 with a cluster of cytokine genes.

Immunology of atopic dermatitis: The best founded explanation for the increase of AD is the so called “hygiene hypothesis”, which assumes that atopic diseases are prevented by infections in early childhood contracted e.g. through contact with other siblings or playing outside. This theory is supported by the already known potential risk factors for AD like small family size, increased income and use of antibiotics or migration to urban environments. Immunological findings also sustain the “hygiene hypothesis“.
Allergic responses are pushed by the T helper-cell type (TH)2 immune response. On the other hand infections are induced by TH 1 immune responses. TH 1 responses antagonise the development of TH 2 cells. This could be the explanation why a decreased number of infections during early childhood could boost the TH 2 allergic responses.

Triggering factors of atopic dermatitis: Although the predisposition for atopic dermatitis is genetically determined, several trigger factors may influence the outbreak of skin changes. These trigger factors include:

1)Respiratory allergy. In affected individuals, respiratory allergy to house dust mites, pollen and animal epithelia may cause an outbreak or worsening of skin changes if they come into contact with the allergen. 2)Food allergies. Food allergy is more frequent in infants and children with atopic dermatitis. In affected individuals, common allergens such as cow milk, eggs, fish, soy or peanuts may cause an outbreak or worsening of skin changes if they come into contact with the allergen. 3)Microbial agents. Staphylococcus aureus colonises more than 90% of AD skin lesions. Proteins of Staphylococcus aureus may function as foreign antigens, their exotoxins operating as superantigens and thus exacerbate AD. 4)Dry skin induced e.g. by long bathing, cold dry climate, insufficient use of emollients may lead to exacerbation of eczema. 5)Itching and subsequent scratching. 6)Sweating induced by e.g. impermeable clothing, hot work places or stress may lead to worsening of skin changes. 7)Chemical/physical irritants like smoking or clothes also may lead to exacerbations. 8)Severe Psychological stress.

Research and Treatment. Interleukin (IL)-10 plays a key regulatory role in allergic diseases. It is produced by many of the inflammatory cells involved in allergic inflammation, including macrophages, regulatory T lymphocytes, dendritic cells, mast cells and eosinophils. IL-10 suppresses allergic inflammation by inhibiting the expression (production) of inflammatory cytokines, Helper Tcell(Th2) cell-derived cytokines, chemokines and inflammatory mediator enzymes. In addition, it suppresses antigen presentation and increases the production of endogenous (internal )anti-inflammatory molecules. There is increasing evidence for defective production of IL-10 in allergic diseases, including asthma and rhinitis and this is associated with disease severity. This may lead to amplification of the inflammatory response in allergic diseases. It may be determined by polymorphisms of the IL-10 promoter linked to low endogenous IL-10 production. IL-10 itself may be a therapeutic approach to allergic disease, but because of side effects stimulation of endogenous IL-10 production may be a more useful approach. Corticosteroids restore the impaired IL-10 secretion in asthma and specific immunotherapy increases IL-10 production by regulatory T cells. Novel therapies in the future might include drugs that selectively activate IL-10 signal transduction pathways.

Overactive Immune Responses comprise the other end of immune dysfunction, particularly Autoimmune Disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with “self” peptides. One of the functions of specialized cells (located in the Thymus and Bone Marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens , preventing autoimmunity. (See postive and negative selection under Tcells)

AUTOIMMUNITY
Auto=Greek for *self*

What an autoimmune disease is.....

Although there are many autoimmune conditions, they all have the same underlying problem, and that is, that the person carries a genetic predisposition to ever having an abnormal immune response, (autoimmune response). The condition/disease manifest, is simply the pathogenic result of that abnormal immune response, in an individual. Symptoms of an autoimmune disease vary widely from person to person and depend on the specific disease. The type of autoimmune disorder or disease that occurs and the amount of destruction done to the body depends on which systems or organs are targeted by the autoantibodies, and how strongly. This genetic predisposition to the potential of ever having an abnormal immune response, resulting in autoimmune disease, arises from a mutated or faulty gene or genes. Mutations in genes, in turn, cause malfunctions in the pathogenesis, of cells of the immune system, and in combination result in the abnormal immune response and the loss of *self *- tolerance. Only people with these faulty or mutated genes can have an autoimmune disease, although it is not a certainty that a person with mutated genes will ever have an autoimmune condition, they are just more predisposed to having one. Autoimmune diseases tend to wax and wane in severity, and may have short or long periods of remission. A person can have more than one autoimmune disease, presenting in an entirely different way from one another. Some autoimmune diseases are hereditary, the person carrying a gene that is predisposed to a specific disease itself , for eg. psoriasis, or diabetes. The aetiology (A) and development of autoimmune disease is that an individual with an underlying genetic predisposition is exposed to one or many triggering factors, which stimulate the loss of self-tolerance and the initial production of autoantibodies. (B)
With time and epitope (C) spreading, the autoimmune response propagates and eventually clinical symptoms arise. Definitions:-
(A) Aetiolgy=The study of the causes. For example, of a disorder. The word "etiology" is mainly used in medicine, where it is the science that deals with the causes or origin of disease, the factors which produce or predispose toward a certain disease or disorder. Today in medicine one hears (or reads) that "the etiology is unknown." Translation -- we don't know the cause. Aetiology is the preferred spelling in some countries, including the UK, whereas "etiology" without an "a" has taken over in the US. The word comes from the Greek "aitia", cause + "logos", discourse.
(B) Autoantibodies= (Abnormal Antibodies.)A normal immune system requires the activation of B cells by T cells before the former can produce antibodies. The malfunctioning of regulatory T cells, in turn causes the B cells to malfunction and as a result the production of abnormal antibodies (autoantibodies) are targeted to *self* tissues. (C)Epitope =An epitope is a part of an antigen to which an antibody binds. Also called an antigenic determinant. Epitopes are sometimes cross-reactive.This property is exploited by the immune system in regulation, by anti-idiotypic antibodies (originally proposed by Nobel laureate Niels Kaj Jerne.) If an antibody binds to an antigen's epitope, the paratope (the antigen binding site on the antibody)could become the epitope for another antibody that will then bind to it. (SEE Idiotypes/Cross reaction below)

Quote:-The principal function of the immune system is to eliminate infectious agents, while not attacking the body’s own tissues. Invading bacteria and virus cells have proteins on their surfaces (as do all cells) called antigens, and antibodies produced within the immune response , recognise intruders , latch onto them and destroy them.
Quote:-Autoimmunity is an abnormal immune response to *self *. It results in autoimmune disease which is the pathologic consequence of an autoimmune response. Autoimmune diseases are not contagious.
The term "autoimmune disease" refers to a varied group of more than 80 serious, chronic illnesses that involve almost every human organ system. It includes diseases of the nervous, gastrointestinal, and endocrine systems as well as skin and other connective tissues, eyes, blood, and blood vessel. In all of these diseases, the underlying problem is similar, in that the body's immune system becomes misdirected, attacking the very organs it was designed to protect.
Quote:-Autoimmune diseases are a diverse group of complex diseases characterized by loss of self-tolerance causing immune-mediated tissue destruction and affect up to 5% of the population.

What causes autoimmunity? The immune system normally can distinguish "self" from "non-self." Some lymphocytes are capable of reacting against self, resulting in an autoimmune reaction. Ordinarily these lymphocytes are suppressed. Autoimmunity occurs naturally in everyone to some degree; and in most people, it does not result in diseases. Autoimmune diseases occur when there is some interruption of the usual control process, allowing lymphocytes to avoid suppression, or when there is an alteration in some body tissue so that it is no longer recognized as "self" and is thus attacked. The exact mechanisms causing these changes are in research.

Quote:-Autoimmune problems can involve any system, organ or tissue of the body, and are a consequence of impaired immune function that results from interactions of genetic and environmental factors such as drugs, viruses , and/or endogenous factors such as hormones or malfunctions in other cells. Autoimmune diseases are multifactorial and caused by an interaction of genetic and environmental factors, and share a number of characteristics that suggest common aetiological pathways or mechanisms. Their shared pathophysiology and their co-occurrence in families have led to the hypothesis that autoimmune diseases share some genetic background .

This has been strengthened by observations through meta-analyses of whole-genome scans that there is non-random clustering of disease susceptibility loci for autoimmune diseases. Genetic susceptibility to autoimmune diseases has been established in the human leucocyte antigen (HLA) region of chromosome 6.

Although the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene has shown unequivocal evidence for a role in some autoimmune diseases with the exclusion of the HLA region, attempts to identify genetic variants , that confer risk of multiple autoimmune diseases have proven difficult.
http://rheumatology.oxfordjournals.org/cgi/content/full/46/1/49

Autoimmune reactions can be Stimulated in several ways: 1) The majority of autoimmune diseases occur Idiopathically (D) 2)A substance in the body that is normally strictly contained in a specific area (and thus is hidden from the immune system) is released into the general circulation. For example, the fluid in the eyeball is normally contained within the eyeball's chambers. If a blow to the eye releases this fluid into the bloodstream, the immune system may react against it. 3)A normal body substance is altered. For example, viruses, drugs, sunlight, or radiation may change a protein's structure in a way that makes it seem foreign.
The immune system responds to a foreign substance that is similar in appearance to a natural body substance and inadvertently targets the body substance as well as the foreign substance. 4)Something malfunctions in the cells that control antibody production. For example, cancerous B lymphocytes may produce abnormal antibodies that attack red blood cells. With autoimmune disorders, the immune system reacts to internal normal body tissues. http://www.endo-resolved.com/autoimmune.html

(D) Idiopathic= (Idioipathic cases of autoimmunity occur of self ,spontaneously and for no known reason.)Latin Greek idiopathia =(primary disease) = idiopatheia idio=(one's own) + patheia=(feeling) idios =(personal) pathic= suffering)

Some autoimmune diseases can be stimulated by an allergy to enviromental factors such as drugs or viruses, in a predisposed person. Systemic illness or infections , including the body’s reaction to the causative organisms, the taking of certain medications, allergies to gluten, (see gluten) or contact with substances not previously exposed to.

Aetiology of Autoimmune Disease Most autoimmune diseases occur Idiopathically, but in some cases, this underlying predisposition may be stimulated by an allergy to an exogenous (E) factor such as cigarette smoke, environmental silica, (see link below) infectious exposures, and certain drugs. Endogenous (F) factors include reproductive and hormonal factors, and malfunctioning mutated genes and cells as listed below. (E) Exogenous = Having a cause external to the body. (F) Endogenous = (within): a substance that is capable of being produced by the body naturally. eg: hormones, insulin etc. The causes of autoantibody production are varied and not totally understood. These autoantibodies, are abnormal antibodies which are produced against a *self antigen*, (found on all of the body's cells) are called rheumatoid factors.
They are also found in people with rheumatoid arthritis (hence the name) and, for a time, in people with mononucleosis.)
In all these cases of autoimmunity, immune complexes form and are deposited either in the skin, joints, and kidneys where they initiate inflammation. Some autoantibody production is due to a genetic predisposition combined with an environmental trigger (such as a viral illness or a severe prolonged exposure to certain toxic chemicals). There is generally not a direct genetic link however. While families may be susceptible to autoimmune conditions, (because they carry the genetic predisposition) individual family members may have different autoimmune disorders, or may never develop an autoimmune condition. Researchers believe that there may also be a hormonal component as many of the autoimmune conditions are much more prevalent in women of childbearing age.
These predisposed people develop antibodies against a wide variety of self components, such as:
1) their own DNA and RNA (see genes)
2) Chromatin =A components to store the huge DNA in the small nucleus. It's wrapped around certain proteins (Histones). These again are rolled together and form a structure called Chromatin.Chromatins again form Chromosomes
3) Ribosomes =A ribosome is an organelle in cells that assembles proteins. It translates messenger RNA (mRNA) into a polypeptide chain (e.g., a protein). It can be thought of as a factory that builds a protein from a set of genetic instructions. Ribosomes can float freely in the cytoplasm (the internal fluid of the cell) or bind to the endoplasmic reticulum, or to the nuclear envelope. Since ribosomes are ribozymes, it is thought that they might be remnants of the RNA world.
4) Red Blood platelets
5) Their own isotype molecules, eg: IgG, IgA molecules.

It is currently thought that all or some of the processes listed below are the cause of autoimmune disease; the pathogenic result of these malfunctions being the specific disease/condition manifested.:- (G) T-Cell Bypass, (H) Somatic mutations (I) Dendritic Cell Apoptosis (cell death) (J) Polymorphisms (see genes) (K)Cytokine Dysregulation (L) Disregulation of Macrophages and Neutrophils (M) Hormonal and reproductive factors (N) Environmental factors-Allergies, viral exposures, etc. (O) Molecular Mimicry (P) Idiotype Cross-reaction (Q)Comorbidity :- Comorbid= Coexisting or concomitant (One that occurs or exists concurrently with another, with an unrelated pathological or disease process).

(G)T-Cell Bypass A normal immune system requires the activation of B cells by T cells before the former can produce antibodies in large quantities. This requirement of a T-cell can be bypassed in rare instances, such as infection by organisms producing super antigens which are capable of initiating polyclonal (multiclonal) activation of B-cells, or even of T-cells; by directly binding to the β-subunit of T-cell receptors, in a non-specific fashion. These are Integrins, a family of receptors that mediate physical support for cells to maintain cohesion, to permit the generation of traction forces to enable movement, and to organise signalling complexes to modulate differentiation and cell fate. Studies have shown integrins to contribute to the progression of many common diseases,in inflammatory, neoplastic, traumatic and infectious conditions.
There is thus intense interest in determining the molecular basis of integrin function to identify approaches for regulating integrin function in disease.
The roles of specialized immunoregulatory cell types, such as regulatory T cells, NKT cells (natural Killer T-cells) γδ T-cells = Gamma/Beta, in the pathogenesis of autoimmune disease are under current investigation.
http://regulatory_t_cell.totallyexplained.com/

research into t-cells
http://arthritis-research.com/content/7/S2/S4

(H)Somatic (relating to the body) Mutations , are disturbances in cells of the lymphoid system, and could in principle, give rise to forbidden clones of cells that fail to recocognise self and instead react immunmocologically with normal tissues. (see Immunity)

(I)Dendritic cell Apoptosis - immune system cells called dendritic cells present antigens to active lymphocytes. Dendritic cells that are defective in apoptosis (cell death) can lead to inappropriate systemic lymphocyte activation, and consequent decline in self-tolerance, which results then in loss of self tolerance, being an abnormal immune response to self. (autoimmune response)
Defective apoptosis of dendritic cells can be a critical component of autoimmune diseases. Altered function of dendritic cells is also known to play a major or even key role in allergy and autoimmune diseases like lupus erythematosus.

Apoptosis=(Cell death) http://www3.interscience.wiley.com/cgi-bin/fulltext/117872729/PDFSTART http://www.bcm.edu/fromthelab/vol05/is3/06apr_n4.html

(J)Polymorphisms: These are a genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is altered. Polymorphisms arise through mutation. The mutation may be due to a change from one type of nucleotide to another, an insertion or deletion (collectively known as indels), or a rearrangement of nucleotides. Once formed, a polymorphism can be inherited like any other DNA sequence, allowing its inheritance to be tracked from parent to child. .read Genetics Encyclopedia polymorphisms in link below
http://www.answers.com/topic/polymorphism

Human mitochondrial DNA (mtDNA) is information-rich, encoding some 22 tRNAs, a 12S and a 16S rRNA, and 13 polypeptides involved in oxidative Phosphorylation. A human cell may have several hundred or more mitochondria, each with more than one copy of mtDNA. Each cell actually contains a population of mtDNA molecules. In many individuals, the mtDNA sequence is essentially clonal, but some individuals carry more than one mtDNA sequence, a condition known as heteroplasmy. Mitochondrial DNA is maternally inherited, and has a mutation rate estimated to be tenfold higher than single copy nuclear DNA. The determination of a complete human mitochondrial DNA sequence over 15 years ago has had a tremendous influence on studies of human origins and evolution, and the role of mutations in degenerative diseases.
Some polymorphisms occur within a protein coding sequence, and contribute to phenotype by affecting protein structure. The defect may be neutral, beneficial or detrimental, or both beneficial and detrimental, depending on the circumstances. Other polymorphisms occur in noncoding regions but may exert phenotypic effects indirectly via influence on replication, transcription, and translation. A single polymorphism may affect more than one phenotypic trait. Likewise, a single phenotypic rate may be affected by polymorphisms in different genes. Further, some polymorphisms predispose an individual to a distinct mutation that is causally related to a certain phenotype.

Some disease traits are already known to be mitochondrially inherited. Some such disease traits result, at least in part, from stop codons in structural genes. Such mutations have been mapped and associated with diseases, such as Leber's hereditary optic neuropathy, neurogenic muscular weakness, ataxia and retinitis pigmentosa. Other mutations (nucleotide substitutions) occur in tRNA coding sequences, and presumably cause conformational defects in transcribed tRNA molecules. Such mutations have also been mapped and associated with diseases such as Myoclonic Epilepsy. Other genetic diseases having unmapped genetic component(s) may also result in part from variations in mitochondrial DNA. Some of those diseases include, e.g., agammaglobulimenia, diabetes insipidus, muscular dystrophy, polycystic kidney disease, hereditary spherocytosis, tuberous sclerosis, osteogenesis imperfecta, and acute intermittent porphyria.

Other phenotypic traits that may derive, at least in part, from variations in mitochondrial DNA include symptoms of, or susceptibility to, multifactorial diseases of which a component is or may be genetic, such as Alzheimer's disease, autoimmune diseases,
inflammation, cancer, diseases of the nervous system, and infection by pathogenic micro-organisms. Some examples of autoimmune diseases include rheumatoid arthritis, multiple sclerosis, diabetes (insulin-dependent and non-independent), systemic lupus erythematosus and Graves disease. Some examples of cancers includes cancers of the bladder, brain, breast, colon, esophagus, kidney, leukemia, liver, lung, oral cavity, ovary, pancreas, prostate, skin, stomach and uterus. Phenotypic traits also include characteristics such as longevity, appearance (e.g., baldness, obesity), strength, speed, endurance, fertility, and susceptibility or receptivity to particular drugs or therapeutic treatments.

(K) Cytokine Dysregulation: Under normal circumstances , cytokines are any of a group of soluble proteins that are released by a cell to send messages which are delivered to the same cell (autocrine) an adjacent cell (paracrine), or a distant cell (endocrine). The cytokine binds to a specific receptor and causes a change in function or in development (differentiation) of the target cell. Cytokines are involved in reproduction, growth and development, normal homeostatic regulation, response to injury and repair, blood clotting, and host resistance (immunity and tolerance). Malfunction of this process is known as Cytokine Dysregulation.
http://www.answers.com/topic/cytokine?cat=health

(L)Disregulation of Macrophages and Neutrophils : Macrophages and neutrophils circulate in the blood and survey the body for foreign substances. When they find foreign antigens, such as bacteria, they engulf and destroy them. Macrophages and neutrophils destroy foreign antigens by making toxic molecules such as reactive oxygen intermediate molecules. If production of these toxic molecules continues unchecked, not only are the foreign antigens destroyed, but tissues surrounding the macrophages and neutrophils are also destroyed. For example, in individuals with the autoimmune disease called Wegener's granulomatosis, overactive macrophages and neutrophils that invade blood vessels produce many toxic molecules and contribute to damage of the blood vessels. In rheumatoid arthritis, reactive oxygen intermediate molecules and other toxic molecules are made by overproductive macrophages and neutrophils invading the joints. The toxic molecules contribute to inflammation, which is observed as warmth and swelling, and participate in damage to the joint.

(M)Hormones: Differences in the immune response of men and women may be related to sex hormones such as androgens and eostrogens. Eostrogens can stimulate B cell growth, antibody production,and cytokine release, and may be important stimulators of B cell immunity and increased susceptibility to autoimmune disease. In multiple sclerosis, the incidence is twice as high in women as in men. A protective effect of pregnancy has been observed, suggesting that reproductive hormones may help reduce symptoms of autoimmunity. Eostrogen treatments have been found to be beneficial for both sexes in animal models of this disease. These effects may be mediated via the expansion of regulatory T cells, which maintain tolerance in normal individuals.

Understanding these effects is particularly important, in light of the increasing number of people exposed to a wide range of synthetic chemicals with eostrogenic or anti-estrogenic activity. These include hormone supplements , hormone blockers, pesticides, insecticides, fungicides, and food and herbal products. The sexually dimorphic pituitary hormones, prolactin and growth hormone, as well as liver derived insulin-like growth factor-1, also affect autoimmune disease. Women have higher levels of these hormones than men. Prolactin and growth hormone enhance autoimmunity, whereas insulin-like growth factor-1 promotes the recovery and repair of injured neural tissue. These hormones may act directly on immune cells or they may mediate their effects through modulation of the hypothalamic-pituitary-adrenal/gonadal axis. In type 1 diabetes the gender ratio is close to even; however, females predominate in many other juvenile autoimmune diseases and in those with onset after menopause. These observations suggest that changes in hormone levels may be an overly simplistic explanation for the observed gender differences.

Microchimerism refers to the presence of a population of cells in one individual derived from another. Microchimerism can result when cells pass between mother and feotus during pregnancy. After pregnancy, some of these foreign cells may remain in both mother and child. These cells (usually male cells) have been detected in mothers up to 20 years following the birth of a child. Some studies have reported the presence of feotal progenitor cells in women with scleroderma, Hashimoto’s thyroiditis, and primary biliary cirrhosis, suggesting that persistent microchimerism may allow the development of autoimmune disease. Other studies suggest that microchimerism may occur more commonly than previously thought, including among women who do not develop autoimmune disease. Additional research is needed to determine more conclusively whether feotal cells have a causal role in autoimmune disease, or if they might serve as a predictive biomarker.

(N)Environmental Factors: (Areas of research) Some of these events arise from the randomness that characterizes human exposures, and others from the diversity of the immune system itself ; a diversity that enables the immune system to recognize a broad range of bacteria and viruses. These environmental factors account for the occurrence of autoimmune disease in only one member of a pair of genetically identical animals or identical twins. Certain environmental agents play a clear role in instigating autoimmune processes. Pathogens , are any disease-producing agent especially a virus or bacterium or other micro-organism, capable of altering a normal body substance. For example, viruses, drugs, sunlight, or radiation may change a protein's structure in a way that makes it seem foreign. Other pathogens yet to be identified, acting through independent biologic pathways, and interacting with multiple genetic polymorphisms (see genes ) give rise to these diseases in a predisposed person, the disease being the pathogenic result of that abnormal immune response misdirected to "self". (autoimmune response)

1)Drugs, such as procainamide and hydrolyzine can induce a lupus-like syndrome in genetically-susceptible individuals, that remits when the drug is discontinued. Other drug-induced autoimmune diseases have been described, including some of the hemolyticanemias, thrombocytopenias, and leukopenias.

2)The possible role of exposure to various metals in autoimmune disease has been explored, primarily through laboratory and animal studies. Generally, metals inhibit immune cell proliferation and activation, with notable exceptions. Mercury, gold, and silver, for example, can induce lymphocyte proliferation and subsequent autoimmunity in mice. Genetically-susceptible mice develop a lupus-like condition when dosed with mercury, silver, or gold. It is likely, however, that the autoimmune disorders that result from exposure to various metals occur through distinct mechanisms. The studies confirm that the result was dose related; the mice having been given massive doses of mercury in a short period of time.

Further studies have proven that there is no harmful affects from amalgam fillings in teeth, owing to the amount of mercury in amalgam being insignificant, and if there were to be any problems at all regarding mercury in a filling, it would be in the breaking of the filling to remove it. None of these studies regarding mercury have involved tests on humans.

3) Abnormal immune responses may also be due to a deficiency of a specific substance. For example, selenium deficiency has been linked with autoimmune thyroiditis and cardiomyopathyin humans. Some people with these disorders improve when given selenium supplements. As with studies of the role of metals, the mechanism of action remains unclear.

4) Some epidemiologic information suggests an association between dietary iodine and iodine-thyroiditis, and between silica and both scleroderma and lupus in certain industrial settings.

5) Additional research has explored possible relationships between autoimmune disease and exposures to organic compounds, principally the halogenated hydrocarbon trichloroethylene (TCE) and polychlorinated biphenyls(PCBs). TCE metabolites have been associated with systemic lupus erythematosus, systemicsclerosis, and other autoimmune disorders. The evidence for PCB effects is sparse. A few epidemiologic studies have examined occupational exposures to dioxins; however, firm epidemiologic evidence of a cause and effect has yet to be shown.

6) Investigations of exposure to pesticides and eostrogenic compounds area are of considerable interest, but require much more research.

7) Ultraviolet radiation from sun exposure can exacerbate disease in patients with systemic lupus erythematosus. Other epidemiologic studies suggest that ultraviolet exposure maybe protective in multiple sclerosis and rheumatoid arthritis; however, conflicting animal studies indicate that ultraviolet exposure may increase autoimmune disease risk in genetically predisposed individuals.

8)In other instances,micro-organisms or local inflammation may alter antigens of the host so that the immune system sees them as foreign. Infections may also increase immune cell expression of co-stimulatory molecules and thus promote autoimmune responses .
Other environmental exposures have been studied, but associating such exposures with specific disorders has proven is difficult.

9)Infectious agents are the most often cited environmental factors implicated as triggers of autoimmune diseases. Despite these leads, the exact mechanisms by which infection induces a particular autoimmune disease are unknown. In the case of streptococcus, it is believed that an antigen of the micro-organism resembles an antigen present in the heart, and that a cross-reactive immune response to the infecting micro-organism causes immune-mediated damage to the heart. This phenomenon is referred to as molecular mimicry.

( P) Idiotype Cross-Reaction: An invading pathogen may express antigens that resemble "self" . These activate T and B cells. When the infection is under control, these cells may then turn against self antigens. Idiotypes are antigenic epitopes found in the antigen-binding portion (Fab) of the immunoglobulin molecule. Evidence has been presented that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody, and a host (self) cell receptor for the virus in question. In this case, the host(self) -cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host(self) cells.
There is evidence that immune responses may be regulated by anti-Id antibodies directed against our own Id's. In some cases anti-idiotypic antibodies actually stimulate B cells to make antibody and thus they can be used as a vaccine. This approach is being tried to immunize against highly dangerous pathogens that cannot be safely used as a vaccine. Anti-idiotypic antibodies directed against anidiotype on malignant B cells can be used to kill the cells. Killing occurs because of complement fixation or because toxic molecules are attached to the antibodies. (see idiotypes under antibodies)

Gluten Enteropathy: Enteritis specifically refers to an inflammation of the small intestine, and is thus a more specific term than "enteropathy", the two phrases are sometimes used interchangeably. Enteritis is the inflammation of the small intestine, whereas colitis refers to inflammation of the large intestine. Gluten intolerance is the only food sensitivity, in the past 50 years, throughout the vast and never-ending food chain, to be medically and scientifically proven, to be able to stimulate the already present (and always will be,) genetic predisposition to autoimmunity, in such cases for example as Dermatitis herpetiformis and coeliacs disease. In order to be classed as a fact, the same food must stimulate this abnormal response , in people with exactly the same condition , ie:Linear Iga Disease, Psoriasis, or any of their phenotypes (classes such as ppp); in a significant number of people, over a significant number of years. While these conditions are caused by a reaction to wheat proteins, it is not the same as wheat allergy.

Quote...Gluten sensitivity and gluten intolerance refer to gluten-sensitive enteropathy (GSE). More recently, patients show gluten sensitivities in which no pathology is observed and genetics does not confine patients to the GSE subset. This GSE subset is primarily defined, but other gluten-sensitive idiopathic neuropathies, is expanding, warranting the more inclusive idiopathic gluten sensitivity (IGS). However, some of these gluten sensitivities, when explored, turn out to be allergies to gluten.

Gluten-sensitive Enteropathy (GSE), or coeliac disease. This describes the physical changes within the gut, ultimately destructive, that occur as a result of cellular immunity to gluten. This involves both an innate immune response and T-helper cell response. Coeliac disease is an autoimmune disorder of the small bowel that occurs in genetically predisposed individuals in all age groups after early infancy.

Idiopathic Gluten- Sensitivity is without a defined GSE or allergic cause, and typically shows elevated anti-gliadin antibodies. (Idiopathic=means arising spontaneously or from an obscure or unknown cause.....)

Gluten Allergy (GA) This is a subset of allergic (Mast cell and IgE) responses that are directed toward to gluten. GAs are not especially different from other allergies, but sensitivity to gluten may be diagnosed at first, before a final diagnosis of GA is reached, because some gluten proteins are not always detected as allergens, using certain procedures, and some of the modes which the reaction occurs are not always obviously allergic. A bowel biopsy is necessary to determine coeliacs disease.

Gluten-Free Dieting . This needs to be separated from gluten-sensitivity. The gluten free diet has become increasingly popular, and wheat-free aspects have become popular parts of other diets, such as the A-B-O diet.

Excepting gluten allergies, most people who require a gluten-free diet are genetically predisposed by the HLA-DQ genetics, (human leukocyte antigens found on all host cells- genetic markers of *self*. (HLA DQ is a protein/peptide-antigen receptor and graft-versus-host disease antigen ) and this has nothing to do with the A-B-O genetics.

A gluten-free diet is a diet completely free of ingredients derived from gluten-containing cereals: wheat (including Kamut and spelt), barley, rye, and triticale. Since bleached wheat flour is a major source of fast carbs in western societies many improvements may be seen with wheat product reduction, but starch (polysaccaride) is not a gluten (protein) and does not cause a protein mediated immune response.

Gluten sensitivity differs from diseases of affluence that are largely mediated by excess simple sugars, starches and saturated fats in the diet, in that the primary targets of GSE are proteins (prolamins) and (glutelins) of the grass tribe Triticeae, and in some allergic sensitivities, albumins and globulins.

Triticeae:- Wheat flour glutens are seed storage proteins found in mature seeds of the grass tribe Triticeae. Wheat is more dangerous because it has an enriched level of glutens derived from three ancestral species of wheat or goat grasses.

Wheat:-a prime source of gluten.

Gluten :-is an amorphous mixture of ergastic (non-living) proteins found combined with starch in the endosperm of some cereals, notably wheat, rye and barley. It constitutes about 80% of the protein contained in wheat, and is a mixture of gliadin and glutenin.

Prolamins :-are a group of globulin proteins found in grasses, most prominently the cereal crops such as wheat (gliadin), barley (secalin), rye (hordein) and oats (avenin).
Glutelins :-are soluble in dilute acids or bases, detergents, chaotropic or reducing agents.

Globulin is one of the two types of serum proteins, the other being albumin.

Albumin can refer to ovalbumin, the principal protein in egg white albumins, a group of proteins including serum albumin and together constituting roughly 60% of the protein in blood plasma. http://www.nationmaster.com/encyclopedia/Gluten-sensitivity

Upon exposure to gliadin, the enzyme, tissue transglutaminase ,modifies the protein, and the immune system cross-reacts. (see Idiotype cross-reaction above (P) .

Other food allergies will exascerbate any already presenting autoimmune disease and therefore avoiding that food allergy will obviously improve the manifestation of that allergy. Other allergies to certain foods may trigger off the autoimmune predisposition in a single case, but it will not rid one of the predisposition to having an autoimmune disease, and there is no real data that lesions of an autoimmune condition itself improve, except in gluten enteropathy. Even in Dermatitis Herpetiformis, a bullous disease often confused with Linear IgA disease, treatment includes drugs such as dapsone to suppress the production of autoantibodies, although a gluten free diet resolves the triggering of this particular disease. http://www.medscape.com/viewarticle/547107_ http://www3.interscience.wiley.com/cgi-bin/fulltext/117872732/PDFSTART

Q) Comorbid Sometimes, one disease can trigger another, and are often comorbid, eg: Coeliac disease in Dermatitis Herpetiformis.

Given the complexities of Autoimmune disease, it's aetiology is likely to be multifactorial, and multigenic. (a mixture of faulty genes ,subsequent malfunctioning cells , and both endogenous and exogenous factors. Disorders caused by organ specific autoantibodies, those that primarily target a single organ, such as the thyroid in Graves' disease and Hashimoto's thyroiditis, are often the easiest to diagnose as they frequently present with organ related symptoms.

Tumor immunology
Another important role of the immune system is to identify and eliminate tumors. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources. Some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer, while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells melanocytes into tumors called melanomas..A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.
The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells.Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal. NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors. Sometimes antibodies are generated against tumor cells allowing for their destruction by the Complement System. Some tumors evade the immune system and go on to become cancers, avoiding detection by killer T cells. Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes. Immunological tolerance (the acceptance of and thereby ignoring of self antigens) may develop against tumor antigens, so the immune system no longer attacks the tumor cells, seeing them as self, allowing them to proliferate. Paradoxically, macrophages can promote tumor growth when tumor cells send out cytokines that attract macrophages which then generate cytokines and growth factors that nurture tumor development. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis (A growth from the main source) and thereby assists spread of cancer cells. The tendency to develop an autoimmune disease is in part hereditary. Initially, clinicians observed that a single patient may develop more than one autoimmune disease and that related members of the same family may share an autoimmune disease. Heredity is estimated to account for about one-third of the risk of developing an autoimmune disease.

In contrast to other inherited diseases that result from disease-causing mutations in a single gene, most autoimmune diseases result from the combined effects of several genes that must act in concert to determine disease susceptibility. The disease-related versions of these genes may be relatively common in the population, but unless present in combination they are not associated with disease.

Some genes affect the immune response itself, whereas others increase the vulnerability of the target organ to autoimmune attack. Of all such genes identified to date, the most completely characterized are members of the family of genes of the Major Histocompatibility Complex, or MHC. These genes are determinants of tissue compatibility and are thus responsible for tissue graft rejection.

This group of genes in humans are referred to as HLA (Human Leukocyte Antigens) HLA's also control key steps in the immune response, especially those related to recognition by T cells of specific antigens presented to them by antigen-presenting cells. ie:Dendritic Cells, Macrophages and B Cells.
http://sprojects.mmi.mcgill.ca/immunology/APC_text.htm

Multigenic
Linkage analysis and genetic mapping studies in murine models of the two diseases mentioned here, suggest that as many as 20 genes contribute to the development of type I diabetes mellitis in mice , while as many as 30 genes contribute to the development of SLE systemic lupus erythematosus.
it seems reasonable to assume that certain genes may provide a permissive background upon which autoimmunity is more likely to occur, whereas other genes may determine whether the resultant autoimmunity is systemic, as in SLE, or restricted to one organ, as in DM.
http://www.jimmunol.org/cgi/content/full/172/8/4834

Quote:-Autoimmune diseases are characterized by inflammation and by the development and maintenance of antibodies and T lymphocytes against “self” antigens. Although the etiology of these diseases is unknown, they have a number of cellular and molecular mechanisms in common. A strong genetic association exists between a number of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and insulin-dependent diabetes mellitus (IDDM) and the expression of certain alleles or haplotypes of the major histocompatibility complex (MHC). The current explanation for this association proposes that disease-associated MHC molecules efficiently bind autoantigens involved in the pathophysiology of the disease. This results in a peripheral (from around the body) T cell-mediated immune response to the autoantigens and autoimmune sequelae. (A pathological condition resulting from a disease). Individual susceptibility to autoimmune diseases may be determined by a combination of specific polymorphisms of genes encoding multiple cytokines, MHC antigens, adhesion molecules, and cellular proteins. This condition may lead to abnormal expression of immunoregulatory molecules and finally result in the development or exacerbation of the disease. Recent research studies into the role of viral sequences in the pathogenesis of autoimmunity, has been mainly involved in molecular mimicry. http://www.medigraphic.com/ingles/i-htms/i-iner/i-in2004/i-in04-2/im-in042i.htm

Self-reactive B and T lymphocytes: Self-reactive T and B lymphocytes are eliminated during their development in the bone marrow or thymus by negative selection. (see Tcells under Cells of the Immune System) This process, referred to as central tolerance, (bone marrow) is somewhat “leaky” and a few self-reactive B and T cells escape into the blood of all individuals. Peripheral tolerance (around and about rest of the body) is the process by which autoreactive cells are controlled so as not to damage cells and tissues.
Anergy, immunologic ignorance, and active regulation are three major mechanisms involved in peripheral tolerance.

Anergy occurs when self-reactive lymphocytes encounter their particular antigen without the help of the secondary co-stimulatory signals needed to initiate an immune response. Under these conditions, the lymphocytes may remain in a state of prolonged unresponsiveness until the co-stimulatory signals are provided. The missing co-stimulatory signals may be provided by tissue inflammation due to infection, which would then trigger a destructive autoimmune response.

Immunologic ignorance occurs when self-reactive lymphocytes encounter very low levels of their corresponding antigen or fail to detect antigen, perhaps because they do not localize in the appropriate site. Under these conditions, lymphocytes remain in an unresponsive state, but retain the ability to respond if appropriately stimulated. Localization of lymphocytes is influenced by production of attraction molecules and adhesion molecules on the lining of blood vessels; together, these determine the pattern of lymphocyte migration through the body.

Local injury or infection may stimulate the production of these molecules, causing self-reactive lymphocytes to migrate to the site where they will encounter their antigen and initiate an autoimmune response.
Regulatory mechanisms include specialized populations of T cells and antigen-presenting cells that control immune responses. These cells secrete cytokines and other factors that directly or indirectly reduce the activity of any potentially autoreactive T and B cells nearby or block the migration of pathogenic T cells into target organs. Other regulatory cells release substances that counteract tissue injury or promote healing. Another prominent group of genes associated with the incidence of autoimmune diseases encode components of co-stimulatory pathways such as cytotoxic T lymphocyte antigen4 (CTLA-4). This surface molecule on T cells initiates a series of events that limit lymphocyte proliferation, so that blocking CTLA-4, or deleting it genetically, enhances autoimmune disease in experimental animals. Other genetic traits that determine inherited susceptibility to autoimmune disease act through particular cytokines, which are molecules, immune system cells use to communicate among themselves.

Important progress has been made in identifying key genes that predispose individuals and families to autoimmune diseases. The research has focused both on how these genes may work to initiate the disease process or exacerbate symptoms and on the potential of these discoveries to lead to new interventions that minimize or reverse the negative effects of genetic influences. In the future, research in this area may provide the basis for gene repair strategies.

TREATMENT
Autoimmune diseases are often chronic, requiring lifelong care and monitoring, even when the person may look or feel well. Currently, very few autoimmune diseases can be cured or made to "disappear" with treatment. However, many people with these diseases can live normal lives when they receive appropriate medical care. In some people, a limited number of immuno-suppressive medications may result in disease remission.

Remission is the medical term used for "disappearance" of a disease for a significant amount of time. Even if their disease goes into remission, patients are rarely able to discontinue medications. The possibility that the disease may restart when medication is discontinued must be balanced with the long-term side effects from the immunosuppressive medication.

Disorders due to systemic autoantibodies can be elusive. Although the associated autoimmune disorders are rare, the signs and symptoms they cause are relatively common. Symptoms may include: arthritis-type joint pain, fatigue, fever, rashes, cold or allergy-type symptoms, weight loss, and muscular weakness. Associated conditions include vasculitis (inflammation of blood vessels) and anemia.

Even if they are due to a particular systemic autoimmune condition, the symptoms will vary from person to person, vary over time, vary with organ involvement, and they may taper off or flare unexpectedly. Add to this the fact that a person may have more than one autoantibody, have more than one autoimmune disorder, and/or have an autoimmune disorder without a detectable level of an autoantibody and you have a complex maze that a consultant dermatologist must often take a patient through, to arrive at a diagnosis.

Medical science is striving to design therapies that prevent autoimmune diseases. To this end, a significant amount of time and resources are spent studying the immune system and pathways of inflammation . There is no cure for autoimmune disease, unless a drug can be discovered to alter or repair a faulty gene or genes. Treatment depends on the pathogenic result of the abnormal immune response, being the disease presented. Suppression of the immune system with immunosuppressants, and antinflammatory drugs such as systemic steroids, and the use of topical steroids, creams etc. in skin diseases and (including eyes nose and mouth). Unfortunately these oral or IV drugs are unable to suppress only the production of antibodies, and suppress the whole of the immune system.These drugs are not without sometimes severe side effects and risks.

Unfortunately, the effects of having taken these drugs may not show until many years after the treatment has ended.

Because the majority of them act non-selectively, the immune system is less able to resist infections and the spread of malignant cells. There are also other side-effects, such as hypertension, (high blood pressure) dyslipidemia, (An abnormal concentration of lipids or lipoproteins in the blood.) hyperglycemia, (Abnormally high blood sugar), peptic ulcers , liver and kidney damage. The immunosuppressive drugs also interact with other medicines and affect their metabolism and action. Sometimes antibiotics and antifungals are added to the regime, especially in skin diseases, because where there is traumatised skin , it is open to infection, especially fungal infection. The immune system is unable to fight off infection quite as well, if it is being suppressed by drugs, making the body more vunerable to infection.

The goal of treatment for all autoimmune disease is to regulate and control it, whilst still maintaining adequate normal immune response to infection.

The goal of chemotherapy in the treatment of autoimmune and inflammatory disorders is to dampen the activity of the immune system rather than to kill abnormal cells. To achieve this goal and minimize side effects, the doses used are lower than those used in treating cancer.
Among the most widely used drugs is methotrexate, an antimetabolite that interferes with various aspects of normal cellular metabolism. Methotrexate has become the standard therapy for moderate to severe rheumatoid arthritis. Methotrexate also plays a role in the management of numerous other autoimmune diseases, including psoriatic arthritis, polymyositis, Crohn disease, and certain types of vasculitis (blood vessel inflammation). It is also used for severe cases of psoriasis—a disorder marked by inflammation and abnormally rapid turnover of skin cells.
Azathioprine (Imuran), an immunosuppressive antimetabolite that is a derivative of the cancer drug 6-mercaptopurine, is also used to treat many autoimmune and inflammatory diseases and was one of the first drugs used to prevent organ transplant rejection.
Another example is cyclophosphamide (Cytoxan)—a more stable, orally active form of nitrogen mustard. It is considerably more toxic than methotrexate and azathioprine, so its use outside of oncology is not as widespread. This drug has played a seminal role in reducing the mortality of some particularly serious nonmalignant diseases. It is used in combination with corticosteroids for inducing remission and preserving kidney function in people with severe lupus nephritis (kidney inflammation) one of the most serious complications of systemic lupus erythematosus (lupus) and for inducing remission of Wegener granulomatosis, a rare and once lethal form of vasculitis.

Many autoimmune and inflammatory diseases have traditionally been treated with high-dose, long-term corticosteroid therapy, which has serious side effects. Something was needed to lower the dose of corticosteroids, and the immunosuppressive agents have been the usual answer to that. In most cases, chemotherapy drugs are used off-label for treating autoimmune and inflammatory diseases.

Today the treatment of autoimmune disease and cancer is in transition as researchers are developing new, more targeted therapies in place of or as adjuncts to broad-acting cytotoxic and immunosuppressive drugs. Many of these therapies are so called biologics, monoclonal antibodies and other molecules that are derived from or resemble naturally occurring molecules in the body. Some new and still-experimental cancer therapies, including biologic agents, are showing promise for treating autoimmune diseases.
Biologic therapies that inhibit the actions of the "inflammation causing cytokines," starting in 1998, began transforming the way doctors treat autoimmune diseases. These and other biologic agents block specific components of the immune response, therefore there was no general suppression of the immune system that occurs with immunosuppressive drugs; and as a consequence, the side effects tended to be substantially less.
Various biologics initially developed for treating cancer are also being investigated as potential therapies for autoimmune diseases.

One prominent example is ritixumab (Rituxan), a monoclonal antibody used for treating B-cell non-Hodgkin lymphoma. Ritixumab targets CD20, a protein found exclusively on the surface of B lymphocytes, and causes rapid and specific B-cell depletion. B cells are thought to play a central role in the pathogenesis of many autoimmune diseases, and preliminary findings from a number of small, clinical studies suggest that ritixumab may be effective for treating diseases including lupus and rheumatoid arthritis.
A more rigorous randomized, double-blind, placebo controlled clinical trial of ritixumab for rheumatoid arthritis was carried out, and the results, provide evidence of improved efficacy with ritixumab in combination with methotrexate compared to methotrexate alone. The drug has been advanced into clinical development for a number of other indications, including lupus and multiple sclerosis.

Researchers are studying a monoclonal antibody originally developed to treat T-cell leukemia as a possible therapy for several autoimmune diseases. The antibody, daclizumab (Zenapax), is a humanized version of a mouse monoclonal antibody to the interleukin 2 (IL-2) receptor. The receptor for IL-2 is expressed on activated helper T cells, which normally help fight infection but also turn out to play a central role in initiating the autoimmune response in uveitis (a potentially blinding inflammation of tissues in the eye).
This last finding suggested that daclizumab, which blocks the growth factor IL-2 from ‘seeing’ its receptor, can be used where activated T cells cause disease. Daclizumab is now in phase II clinical trials for uveitis, multiple sclerosis, Wegener granulomatosis, and aplastic anemia.

Agents that inhibit angiogenesis (the formation of new blood vessels) may also find a place in the treatment of some autoimmune and inflammatory diseases. In rheumatoid arthritis, angiogenesis plays a key role in the abnormal proliferation of cells in inflamed joints that leads to invasion and destruction of cartilage and bone.
Angiogenesis inhibitors, particularly those that inhibit vascular endothelial growth factor (VEGF) activity, may also be helpful for treating psoriasis. Research shows that new blood vessel growth in the skin plays a role in psoriasis and that VEGF levels are elevated in psoriatic lesions.
Not all emerging cancer therapies that also have potential for treating autoimmune disease are biologics.
Histone deacetylase (HDAC) inhibitors are a group of naturally occurring and synthetic compounds that alter gene expression by modulating chromatin structure. Several of these compounds, which induce growth arrest and apoptotic cell death in tumor cells, are in clinical trials for various solid and hematologic cancers. Tests show that HDAC inhibitors can downregulate expression of inflammatory cytokines and reduce signs of kidney disease in a mouse model of lupus, suggest that these compounds might also be of benefit for treating lupus. Preclinical studies are still in progress, but Mishra and his colleagues hope to move one of these compounds, trichostatin A (TSA), into clinical trials for lupus.

Recent Article, concerning Research 2008
ARTICLE
One injection 'vaccine' cure for arthritis within five yearsA single injection that could cure rheumatoid arthritis is being developed by British scientists. By Rebecca Smith, Medical EditorLast Updated: 6:36AM BST 14 Aug 2008Rheumatoid arthritis is difficult to treat because it is caused by a malfunctioning immune system. Paul Grover :- The treatment works like a vaccine and could be available within five years. Cells would be taken from the body, altered, and injected back into the affected joint. A team at Newcastle University will now test the vaccine on volunteers with the disease. Scientists in the field are extremely excited about the development. There are 350,000 people in the UK with rheumatoid arthritis, which is a condition where the body's immune system attacks the joints, unlike oestoarthritis which is more like wear and tear of the joints. Rheumatoid arthritis is difficult to treat because it is caused by a malfunctioning immune system, causing inflammation in the wrong places. Prof Alan Silman, medical director of the charity Arthritis Research Campaign, which funded the research, said: "This is an important potential cure . It is possible one injection could switch off the abnormal immune response. "If it works it could reverse the disease and stop further episodes." The Newcastle team will test the effectiveness of the new vaccine in eight volunteers with rheumatoid arthritis from the Freeman Hospital as part of a pilot study, which could then lead to larger trials. The vaccine works by reprogramming the body's own immune cells. Using chemicals, steroids and Vitamin D, the team has devised a way to manipulate a patient's white blood cells so they surpress, rather than activate, the immune system. It is thought the cells will then act as a brake on the over-reacting immune system and stop it attacking its own joints. Although a similar technique has been used in cancer research, this is the first time it has been adapted to rheumatoid arthritis. John Isaacs, Professor of Clinical Rheumatology at Newcastle University's Musculoskeletal Research Group, who is leading the team, said that although the work was in a very early, experimental stage it was "hugely exciting". "Based on previous laboratory research we would expect that this will specifically suppress or down regulate the auto-immune response," he said. Samples will be taken two weeks after the injection to establish whether it has induced the expected response. The team also hope to find out if the vaccine is effective only in the joints it is injected into, or whether the new cells spread throughout the body. Prof Silman said the treatment may prove expensive as each patient would have to have their own cells taken and manipulated rather than a drug which can be made in bulk *and prescribed to all people with a condition. *He said it would be unlikely that the vaccine could be offered in normal local hospitals because of the expertise necessary to manipulate the cells in the laboratory. . It raises fears the vaccine would have to go through the National Institute for health and Clinical Excellence cost effectiveness tests. But if the vaccine did work with a one off injection and completely stop the disease it is likely to offer such a huge benefit to the patient that even a relatively large price may be deemed acceptable. Prof Silman said he expected the jab to cost less than £25,000. (not to the patient but to the hospital trust) The research is being funded by medical research charity the Arthritis Research Campaign, which is providing £216,000 over 18 months.

Future Trends and Challenges
Although many of the more targeted therapies now being developed for autoimmune and inflammatory diseases are biologic agents, a large interest for the future is to look at small molecules that may have similar effects on the inflammatory response, if for no other reason than biologic therapies are costly. They also must be administered intravenously or by injection.
Better regimens are being developed that can induce remission, by using available drugs and dosing them better, or in the hope that some of the newer agents under development, when given in combination with drugs already in use will induce a better clinical response. Recent studies show that combining biologic therapies with traditional chemotherapy drugs is more effective than either type of therapy alone, in particular for rheumatoid arthritis.
The challenge, is to predict which patients could benefit from particular therapeutic approaches, and this is where researchers can learn from oncologists, by learning how to stage diseases better. In rheumatology, for example, researchers are just beginning efforts to identify biological markers of disease that could be used for this purpose.
As in cancer research, much work is ongoing in the area of pharmacogenomics to identify which patients are likely to respond to certain therapies.
The initial finding that cancer drugs could also be used to treat autoimmune diseases was due simply to the fact that cytotoxic drugs inhibit the immune system as part of their action.

Certain commonalities in the pathogenesis of autoimmunity and cancer could be of relevance in the development of new therapies.
With autoimmune diseases, it is a failure to control a benign class of cells, namely cells that normally function to fight infection, whereas in cancers, it’s a failure to control a malignant class of cells. In both cases, the method of control is to kill the cells by apoptosis, where the control system isn’t working correctly.

Thus, some of the more targeted therapies developed in the future that will be useful for both cancer and autoimmune disease may act through common pathways. A lot of chemotherapy right now is just killing cells. If scientists could block their activities, instead of killing these cells, then maybe it would be possible to achieve beter outcomes with less toxicity.
Other drug therapies used to treat Autoimmune disease are, Prednisolone, Prednisone, Cyclosporin, IV Methyl Prednisolone, interferon (injection) Dapsone, Sulphapyridine.

Below applies to all autoimmune conditions
read Immunological tolerance, Genetic Factors, and Pathogenesis. in link below.
http://en.wikipedia.org/wiki/Autoimmunity

It is considered that mutations in genes cause malfunctions in cell pathogenesis, and in combination result in the abnormal immune response (Autoimmune response) and the loss of self-tolerance.
Read Pathogenisis in link below
http://www.thedoctorsdoctor.com/diseases/linear_iga_disease#pathogenesis http://users.ox.ac.uk/~path0116/tig/tolg1.html#introe
reprogramming the immune system in autoimmune disease
picture = http://users.ox.ac.uk/~path0116/tig/infai.gif

Infectious tolerance in treating autoimmunity
If we could induce this form of infectious tolerance, perhaps by using monoclonal antibodies to T-lymphocyte molecules such as CD4 we would not only have a potential treatment for autoimmune disease, but the infectious nature of the tolerance should ensure that any tendency for new T-lymphocytes (which are constantly being produced by the thymus) to cause further autoimmune disease would be suppressed, perhaps leading to an effective cure.

Alternative and Complementary Medicine
Quote
While these diseases are obviously physiological in origin, psychological treatments such as stress management can sometimes lessen severity and occurrence. Additionally, other methods (such as acupuncture) can be used to shift focus away from the uncomfortability and itchiness during an attack. Many people suffering from chronic conditions ,tend to use some form of alternative medicine, because they feel they need to take control, in part, due to their lack of understanding of the immune system, it's structure and function, and what occurs and why, when there is a dysfunction.
There is little to no data to support the effectiveness of most of these therapies. Autoimmune diseases are intermittent and idiopathic, they wax and wane in severity and there can be long or short remission periods. They can be exascerbated by stress, which amplifies the placebo effect. As such, many alternative treatments may appear to work well, when in reality it is only a combination of the placebo effect, and a chance remission in the disease.
Diet changes are often tried by people in attempts to stop what is presumed to be a food allergy. Also, people often try changing their laundry detergents, shampoos, soaps etc. While food and other allergies can cause hive outbreaks in some people, it is important to note that outbreaks often and do occur on their own, idiopathically, spontaneously, and for no obvious reason, with no connection to food or other allergy. The fact that all autoimmune diseases are intermittent and idiopathic, can fool people into thinking that it is caused by an allergy to food or product.
People with these chronic conditions, often feel they need to be in control in order to help themselves. They try alternative treatments, add supplements to their diet, abstain from certain foods, without having any scientific proof that they have indeed an allergy, or that their blood specs prove to be deficient of certain essential nutrients. This creates the placebo effect, which is a very real psychological phenonoma. Excellent article on autoimmunity in "layman's" terms)
http://www.aarda.org/common_thread_art.html

2009-12-20T19:44:00.053Z

Linear IgA (Immunoglobulin Antibody) Bullous Dermatosis
Please note :-that links and passages in italics, are given as fact-based Reference.

Certain phrases are underlined and in red, to draw specific attention to the fact. I went totally blind myself due to Iga bullous disease , and many lessons were learned, hitherto unknown, throughout the progression of the disease, and therefore it is essential that patients and clinicians alike , take specific note of those phrases, in order to give the patient the best possible outcome.
It is totally wrong to assume that it is only certain types of bullous disease that affect the eyes. ANY bullous disease can affect the eyes, it is after all just mucous membrane, and given the fact that over 90% of patients with IgA mediated bullous disease , have mucosal involvement, and given that the IgA antibody is normally found in tears, it stands to reason, and common sense, that these patients are at high risk of having ocular involvement.
Bear in mind the added problem of the use of systemic steroids, (used to treat the inflammatory processes of bullous disease), also frequently cause sub-capsular cataracts, the removal of which again put the patient at risk of having blisters appear in the cornea, due to invasive surgery and contact, both of which are known, and have proven to excite the condition.Links to other blogs...
http://wassail-allthatilove.blogspot.com/2008/03/immune-system.html

Autoimmune Diseases only occur in people who carry the genetic predisposition to an abnormal immune response ever occuring. The disease manifest, is simply the pathogenic result of the abnormal immune response. The "trigger" causing the mounting of an immune response, and stimulating these faulty genes, differs from person to person, even if the resulting disease is the same. For eg: An allergy to a drug may be the trigger resulting in the stimulation of these faulty genes, in one person, and possibly a hormone dysfunction in another, but both resulting in the same disease. Usually the cause is in fact multifactorial, however.
Some autoimmune diseases are hereditary, but neither Linear IgA disease ,nor IgA mediated Epidermolysis Bullosa Aquisita (a phenotype of EBA which mimics Liga) are not. The main typical form of EBA is IgG mediated and is hereditary. These Bullous Diseases are not contagious. They are known as heterogenous diseases, which means having a variety of characteristics, abilities, or appearances.
The underlying causes of these bullous diseases are the same as for any other autoimmune disease.
(see -Disorders of The Immune System- Autoimmunity)
http://wassail-allthatilove.blogspot.com/2008/03/disorders-of-immune-system-immune.html
http://www.medicine.org.hk/hksdv/journal/200103-08.pdf

Linear Immunoglobulin Antibody Bullous Dermatosis (LigA)
Linear Immunoglobulin Antibody (IgA) Bullous Dermatosis (LAD)This is a very rare, blistering , Autoimmune Disorder,which manifests as blistering of the skin and the mucous membranes. The childhood version is called Linear IgA Bullous Disease of Childhood (LABDC), and is immunologically identical to the adult disease.There is no difference clinically , or immunopathologically , between Linear IgA disease in adults, and LigA of childhood. (see Ref.Below)
From The British Association Of Dermatology Journal...Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap.Wojnarowska F, Marsden RA, Bhogal B, Black MM.Department of Dermatology, Slade Hospital, Oxford, England.Linear IgA disease of adults, chronic bullous disease of childhood, and the rare childhood cicatricial pemphigoid currently are regarded as separate clinical entities despite their many shared features. All are sulfone-responsive subepidermal bullous diseases associated with linear IgA deposition at the basement membrane zone. In this paper we present a long-term study of 25 cases of adult linear IgA disease, 25 cases of chronic bullous disease of childhood, and four cases of childhood cicatricial pemphigoid, which has revealed further similarities among all three groups. The morphology and distribution of the cutaneous and mucosal lesions were similar; mucosal involvement was present in 80% of patients with adult linear IgA disease, 64% of those with chronic bullous disease of childhood, and 100% of those with childhood cicatricial pemphigoid, and ocular scarring affected patients in all groups.Remission occurred in 64% of those with chronic bullous disease of childhood (the disease was active in 12% after puberty), 48% of those with adult linear IgA disease, and in no cases of childhood cicatricial pemphigoid. HLA B8 and circulating IgA anti-basement membrane zone antibody were more common in chronic bullous disease of childhood than adult linear IgA disease. There were no absolute differences among the three groups, and we suggest that adult linear IgA disease, chronic bullous disease of childhood, and childhood cicatricial pemphigoid are the same disease, with childhood cicatricial pemphigoid being a more severe form of chronic bullous disease of childhood.

In LigA bullous disease, there is a defect or mutation in the genes, (as is the case in all autoimmune diseases) that promote the formation of ("express") a protein found in all human skin known as a Keratinocyte. This protein which is important in maintaining the integrity of the skin, is found in the lower layers of the epidermis. (Base Membrane Zone (BMZ) )As a result of these gene defects or mutations, the pathogenesis of other cells of the immune system, within this abnormal immune response, malfunction. B lymphocytes, (a type of white blood cell) malfunction, and produce this IgA antibody abnormally (now referred to as an IgA autoantibody). The IgA autoantibody produced because of malfunctioning cells, binds with this protein, and it results in acantholysis (the cells come apart, leading to fluid accumulation between layers of skin and forming blisters, inflammation and tissue damage,) being the manifestation of this disease. (See under Disorders of the Immune System-Autoimmunity)

Linear IgA disease onset in the majority of cases, usually occurs idiopathically. Idioipathic cases of autoimmunity usually occur spontaneously and for no known reason, and possibly by endogenous factors such as hormones or other gland/cell secretions. However, it sometimes follows infection and is rarely caused by drug allergy. (exogenous factors)
The word Idiopathic....Latin Greek idiopathia =(primary disease) = idiopatheia idio=(one's own) idios = (personal) patheia=(feeling) pathic =(suffering)

OR.....It can also be stimulated (only in an already genetically predisposed person), by an allergy to certain non-self exogenous enviromental factors such as.... certain drugs,( the most often cited being (vancumycin,) or a virus, these being the most likely of enviromental factors, concerning this disease. Drug-induced disease usually resolves with withdrawal of the offending agent or other enviromental factor, but it can take from months to years before the results of the autoimmune response stops. Given the rarity of the disease, common infections are unlikely to be the only factors if at all, involved in the pathogenesis of this disease.
Linear Iga disease, on first examination can be confused with Dermatitis herpetiformis,(DH) an IgA mediated autoimmune disease stimulated by an allergy to Gluten. Dermatitis Herpetiformis does not have circulating antibodies (whereas LigA does) and the blisters which are manifest in DH are usually much smaller, in a herpetiform (clustering) pattern.There is granulated deposition of Iga antibody in the dermal papillary tips of the BMZ, (Base membrane zone) in dh, and there are no circulating antibodies in blood serum. Blistering improves on omitting gluten from the diet, but it can take many months for the manifestation of the autoimmune response to disappear.

PRESENTATION
Patients with linear IgA dermatosis can present with lesions resembling epidermolysis bullosa aquisita, bullous pemphigoid, lichen planus, or cicatricial pemphigoid. One argument for this heterogeneity (mixed) of presentations is the possibility that multiple antigens may serve as targets for disease manifestation. Which means that it affects skin and mucous membranes, and therefore wherever in the body these tissues are present, then it can affect it. (see most common areas in list below) The location of these targets can yield clinical presentations that are associated with the aforementioned cutaneous diseases. A 97-kDa protein, which is identical to a portion of the extracellular domain of the 180-kD ,a bullous pemphigoid antigen (BPAG2, collagen XVII), has been determined to serve as the antigen commonly targeted in linear IgA dermatosis.
http://www.med.nyu.edu/dermatology/sem_conf/111604-6.html
The lesions of Linear iga disease sometimes, in some cases, have a heterogeneous (mixed) presentation, comprising urticated plaques, papules, vesicles and blisters. Blisters can arise from normal skin and from urticated plaques, they may vary in size, and can appear in two distinct ways, either in a linear (line) presentation like a string of beads, or in a ring , forming the “crown of jewels” effect. Sometimes there are also inflamed pink/red papules, like small hard swellings.
Medical Terminology .....
herpetiform (clustering)
cutaneous diseases (skin diseases)
heterogeneous (Having a variety of characteristics, abilities, or appearances.)
urticated plaques (itching, inflamed areas)
papules (small solid circumscribed bump in the skin )
vesicles and blisters (contain fluid).

Areas of the body that can be affected in Iga Bullous Disease
It is totally untrue that Liga does not affect the "inside" of the body, as I have seen reported. It most certainly can!! Wherever there is "skin", or type of skin, like mucous membranes. It usually affects "skin inside," that leads to an opening to the outside, simply because IgA is the dominant antibody guarding these passages.
It can affect the basement membranes in:- cornea, & conjunctiva & lacrimal glands (the eye) oral mucosa gums and pallate & salivary glands(mouth) oesophagus, (gullet) intestine, (gut) kidney collecting ducts ureter, bladder, & urethra, thymus. larynx & pharynx (throat basically) trachea (windpipe) & bronchial mucosa. (air passages to the lungs) nasal passages vagina, cervix, & rectum

Diagrams of Skin and Mucous Membrane

Diagram Of Epithelial Cells lining the small intestine and the principal types of cell junctions that connect them.

As in all epithelia, the basal surface of the cells rests on the basal lamina, a fibrous network of collagen and proteoglycans that supports the epithelial cell layer. The apical surface faces the intestinal lumen. Tight junctions, lying just under the microvilli, prevent diffusion of substances between the intestinal lumen and the blood via the extracellular space between cells.Gap junctions allow movement of small molecules and ions between the cytosol of adjacent cells. The remaining three types of junctions, adherens junctions, spot desmosomes, and hemidesmosomes are critical to cell-cell and cell-matrix adhesion.
NB: It is the loss of this adhesion due to these cells being targeted by the malfunctioning antibodies that causes the seperation of these cells and the subsequent filling with fluid causing blisters.

See fact based references below concerning areas affected in different patient cases
1) This study characterizes a novel basement membrane component that is the target of autoantibodies in patients with linear IgA bullous dermatosis. Tissue surveys showed that this protein localized to the epidermal side of 1 M NaCl split skin and to basement membranes in cornea, oral mucosa, esophagus, intestine, kidney collecting ducts, ureter, bladder, urethra, and thymus. http://www.ncbi.nlm.nih.gov/pubmed/8618013?dopt=Abstract

2) Two cases of linear IgA bullous dermatosis initially presenting as ulcerative lesions in the larynx and pharynx are reported. http://www.medscape.com/medline/abstract/15949090

3) A 54-year-old man is described, suffering from adult linear IgA bullous dermatosis with involvement of the bronchial mucosa. The main respiratory symptoms were recurring haemoptysis, episodic narrowing of the airways and persistent non-specific bronchial hyperreactivity. https://lirias.kuleuven.be/handle/123456789/15310

4) Two cases of adult linear IgA disease (LAD) with oral and colonic involvement are presented.Lesions in mucous membranes heal with scarring and therefore pose considerable morbidity, as scarring in this type of tissue continues to grow, and can cause serious problems in the throat or gullet, by closing off the airway or digestive tract, and if in the eyes, can result in blindness. Cutaneous (skin) lesions normally heal without scarring. http://cat.inist.fr/?aModele=afficheN&cpsidt=3656092

SYMPTOMS
Linear Iga disease affects all types of skin including Mucous Membranes.Symptoms vary from mild to severe pruritis accompanied by a burning sensation, and blisters. These symptoms can affect any part of the body. Contact and friction from such articles as clothes, labels inside clothes, underwear, shoes, waistbands, surgical stockings, and spectacles can cause blistering. The use of surgical tape used in dressings is a particular problem. Surgery and medical procedures also excite blistering, for example, use of airway apparatus during anaesthesia, taking blood samples, injections, dental procedures and pap smears.

Mucous Membranes Cover all body cavities with exterior openings
Quote :-Proff. Neil Cox Consultant Dermatologist Carlisle Cumbria England (only in italics)People with iga mediated disease are more likely to get mucosal involvement, because the iga antibody, which is also found in tears and saliva, is the dominant antibody of these tissues.These tissues line the tracts of the body that come into contact with external, "out of the body" organisms.

Mucosal involvement is common, affecting 80% of adults and 64% of children. Hoarseness is an indication of pharyngeal or laryngeal involvement. Excess mucous, bleeding, an indication of nasal involvement. In these tissues, it causes ulcers, erosions, and blisters, involving the oral mucosa,(mouth), gums, which results in, Desquamative gingivitis (thereby damaging teeth), pharynx, larynx, trachea & Bronchi, salivary glands, nasal passages, rectum, vagina, oesophagus, intestine, kidney collecting ducts, ureter, bladder, urethra, thymus, eyes (cornea and conjunctiva), and lacrimal glands.

Potential Ocular (eye) involvement, including the lacrimal glands, is different and far more serious, and can lead to Blindness. It should not be assumed that only certain phenotypes of IgA mediated disease affect the eye. IGA Mediated disease affects mucous membranes, it therefore can affect the conjunctiva , and the cornea gets "caught up" with the inflammation of this affected tissue .

Quote: Mr. G. Ainsworth Consultant Ophthalmologist Csle.Cumbria England (in italics only.) Please note that All bullous (blistering ) diseases can affect the eyes. a) because it is mucous membrane, b) 80% of liga cases have mucosal involvement. c) The dominant antibody for these tissues is IgA

Some patients do not have mucosal involvement on presentation , but can develop it later, ranging from a few months to 2 or more years after initial diagnosis.Changes can occur, which may be actually present in the absence of ocular symptoms, such as fine scarring, or other defects due to involvement of the lacrimal glands and diminished tear production; both of which even independantly, can lead to blindness.
The progression of ocular Linear iga can prove to be very rapid and is indistinguishable from Cicatricial Pemphigoid when involving mucous membranes, and epitheliel tissue.
Symptoms develop of acute and chronic conjunctival inflammation, Symblepharon, blepharitis , entropion, trichiasis, tear deficiency, corneal ulceration, infection, and other ocular scarring complications resulting from severe mucosal disease.

Please note that ALL of these conditions listed below affect the eye in ALL types of Bullous disease of the eye .
1) lacrimal glands:- (The glands which produce tears). In order for the eye to remain healthy, it must remain moist. The lacrimal gland is a specialized gland located under the outer one-third of the upper eyelid that produces tears. Each time you blink, the eyelid spreads the tears over the surface of the eye and pumps excess tears into the tear ducts that drain the tears into the nose.
2) Dry Eyes:- If the lacrimal gland fails to produce enough tears to properly wet the eye, the surface of the eye begins to dry out. An eye that is too dry, may burn, sting, or feel like there is sand in it. Dry eye is most often treated with lubricating drops and ointments that help to control the drying and irritation. Sometimes plugs need to be placed in the drainage ducts to increase lubrication.
3) Symblepharon:- (Adhesions of one or both eyelids to the eyeball, either partial or complete)
4) blepharitis:- Anterior blepharitis - affects the outside front of the eyelid, where the eyelashes are attached. Posterior blepharitis - affects the inner eyelid (the moist part that makes contact with the eye)
5) conjunctiva :-The thin clear mucous membrane that covers the white portion of the eye (sclera) and lines the eyelids, providing protection to the eyeball.
6) the occlusion of punctae :- (To close, and block the tear drainage tubes of the medial canthus (near the nose) in order to keep artificial tears in the eye) This can be recurrent, having to be done again and again.
7) Trichiasis:- A condition in which the hair adjacent to a natural opening turns inward and causes irritation, as in the inward turning of the eyelashes upon the eye.
All of the above results in.....
8) entropion:- a medical condition in which the eyelids fold inward. It is very uncomfortable,and painful as the eyelashes rub against the cornea constantly, This in turn can damage the cornea causing ulceration , which can result in blindness. Dry eyes are the usual cause of entropion. If the lacrimal glands are also affected with a bullous disease, no tears or diminished tears result. Another of the causes of entropion is of bullous disease affecting the conjunctiva , which apart from covering the eye ball lines the inside of the eye lids. This in turn scars , pulling the lids under. In combination, the situation is acute. A surgical operation called an ectropion, turns the lid margins back to the original position. This is done by cutting the margins away from the lid , turning them back out to the original position , and stitching them into place.In conjunction with all of the above......Epithelial swelling damages vision by changing the cornea's normal curvature, and causing a sight-impairing haze to appear in the tissue. Epithelial swelling and inflammation, will also produce tiny blisters on the corneal surface. When these blisters burst, it results in exposing the nerves that line the cornea, causing very severe pain. Even the involuntary act of blinking can be painful.
http://www.nei.nih.gov/health/cornealdisease/#3

Iatrogenic disease.
Disease or infection, which can be caused inadvertantly or without due care by a physician or other health carer. eg. cross infection due to lack of proper care in washing hands, or wearing of protective clothing.

From my own experience, having lost both my eyes and lacrimal glands to IgA mediated Bullous disease , it was discovered that Topical treatments to the eyes, either eye drops or ointments worked better and had a longer effect if applied in minimum strengths but more often. Many times, the normal dose or strength proved to actually cause a blister on the cornea. The ONLY really successful treatment (in my case) that had an immediate good result , ridding the corneas of blisters, was IV Methyl Prednisolone. I also became allergic to many of the topical treatments to my eyes, through regular use. Chloremphenocol drops Cefuroxane, Gentamycin, to name but a few. Even Atropin started to cause a reaction in time.

IgA Mediated Epidermolysis Bullosa Aquisita

2009-12-18T13:36:00.001Z

ImmunoGlobulin Antibody (IgA) Mediated Epidermolysis Bullosa Aquisita

The Presentation and symptoms of IgA Mediated Epidermolysis Bullosa Aquisita, is the same as LAD in the early stages, because it actually mimics LAD, but lesions become much deeper, and closer together, sometimes causing quite large areas to become devoid of epidermis. It is a much more severe, and rarer disease. (see abstract below)
J Am Acad Dermatol 2002 Dec ;47(6):919-25
Abstract quote:-We describe 2 adult patients with a subepidermal bullous dermatosis with exclusively linear IgA depositions along the epidermal basement membrane zone that were deposited in the sublamina densa zone as witnessed by direct immunoelectron microscopy.Indirect immunofluorescence microscopy of patients' sera revealed circulating IgA autoantibodies that bound exclusively to the dermal site of salt-split skin substrate. Immunoblot analysis using dermal and keratinocyte extracts were negative. Indirect immunofluorescence microscopy using type VII collagen-deficient skin ("knockout" substrate) showed no IgA binding, whereas linear IgA binding was seen at the epidermal basement membrane zone in normal human skin. The autoantigen in the patients was thus type VII collagen. A diagnosis of IgA-mediated epidermolysis bullosa acquisita (IgA-EBA) was made. We systematically reviewed the literature of this subset of patients with linear IgA dermatosis on the basis of the following criteria: exclusive binding of serum-IgA to the dermal side of salt-split skin or IgA depositions in the sublamina densa zone by indirect or direct immunoelectron microscopy. We learned that IgA-EBA is clinically indistinguishable from the classic "lamina-lucida type" linear IgA dermatosis or from the inflammatory type of IgG-mediated epidermolysis bullosa acquisita (IgG-EBA).

In the case of IgA mediated Epidermolysis Bullosa Aquisita, there is a defect in the genes that normally promote the formation of anchoring filaments, or Hemidesmosomes. An area directly below the Lamina Lucida Area of the BMZThese structures anchor the epidermis, to the dermis, and the gene defect leads to the tissues blistering, and seperating from one another. The pathogenic result of which, is equal to and treated as third degree burns.
The mechanobullous, noninflammatory form of epidermolysis bullosa acquisita,was defined in 1971 and is characterized by extreme skin fragility, trauma-induced blisters and erosions localized to the extensor skin surface, healing with scars and milia.
In addition to the mechanobullous variant, several inflammatory subtypes of epidermolysis bullosa acquisita were also defined, clinically mimicking bullous pemphigoid, linear IgA disease, or mucous membrane pemphigoid. Certain epidermolysis bullosa acquisita patients present with inflammatory phenotype at the onset of the disease with overlapping or later evolving mechanobullous features .
From The Brit.Assoc. Dermatol. (IMPORTANT! Please note in red)
Epidermolysis bullosa acquisita (EBA) IgG is an autoimmune bullous disease with frequent ocular involvement, but visual loss is rare.
In contrast, EBA patients with predominant IgA autoantibodies more frequently develop severe ocular involvement, which tends to be refractory to therapy.
NB. Proving yet again, that patients who have a bullous disease with predominant IgA autoantibodies are more difficult and less responsive to treatmant than Bullous disease with predominant IgG Autoantibodies, when affecting mucous membranes. The resulting scarring of these tissues is what creates permenant and potentially serious damage, such as blindness, deafness etc.
-----------------------------------------------------------------------------------------
(Personal note:- Which proves the point that Iga mediated bullous disease is more likely to affect the eyes and prove refractory to treatment.)
This is an article presented to the B.J.D UK concerning myself, written and presented by my own specialists. However it is copyrighted and must be paid for... (no direct link available)
British Journal of Dermatology 156 (4), 775–777. doi:10.1111/j.1365-2133.2006.07739.N.H. Cox, M.A. Bearn, J. Herold, G. Ainsworth, C. Liu (2007) Blindness due to the IgA variant of epidermolysis bullosa acquisita, and treatment with osteo-odonto-keratoprosthesis.
http://www.ingentaconnect.com/content/bsc/bjd/2007/00000156/00000004/art00040;jsessionid=3hc6044sxvoao.victoria
http://openurl.ingenta.com/content?genre=article&issn=0007-0963&volume=156&issue=4&spage=775&epage=777
http://dx.doi.org/10.1111/j.1365-2133.2006.07739.x

Br J Dermatol 1997 Aug;137(2):270-5 Abstract quote:-
Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal bullous disease characterized by IgG autoantibodies directed against type VII collagen, the major component of anchoring fibrils. The classical phenotype of EBA is a non-inflammatory, mechanobullous disease resembling the dystrophic forms of inherited epidermolysis bullosa.Mucous membrane involvement is frequent but usually mild. (personal note :-the above refers to the usual classic IgG (inherited) EBA)
We report a one-year-old girl suffering from IgA-EBA, who presented with an initial eruption of disseminated urticarial lesions and tense blisters of the skin but subsequently developed severe oral and ocular lesions reminiscent of cicatricial pemphigoid. Direct immunofluorescence of the skin and buccal mucosa revealed linear IgA and C3 at the basement membrane zone (BMZ). IgA anti-BMZ autoantibodies stained the dermal side of salt-split skin by indirect immunofluorescence and recognized a dermal protein of 290 kDa co-migrating with type VII collagen by immunoblotting.Direct and indirect immunoelectron microscopy revealed IgA deposits overlying the anchoring fibrils. The ocular involvement led to total blindness in spite of intense treatment. This case of childhood IgA-EBA is particularly striking because of the cicatricial pemphigoid phenotype with severe ocular involvement which resulted in blindness. It reinforces the necessity to use modern immunological methods to classify autoimmune bullous diseases in order to allow early and appropriate treatment.
http://www.ncbi.nlm.nih.gov/pubmed/9292080?dopt=abstractplus
We report two patients with 'IgA-EBA' with ocular involvement. Both initially presented with a generalized bullous disease, and direct immunofluorescence microscopy demonstrated IgA in the basement membrane zone of the skin, and in the conjunctiva and cornea of patient 1. On salt-split patient skin, IgA was found predominantly on the dermal side of the artificial split in both patients.Direct immunoelectron microscopy demonstrated IgA below the lamina densa in close association with the anchoring fibrils in both patients. In patient 1, who had a prolonged course of the disease, the skin disorder responded well to treatment with cyclosporin, but the ocular involvement ended in bilateral blindness despite repeated surgical treatment. In patient 2, the blister formation and scarring conjunctivitis was stopped by a combination of prednisolone and colchicine.These patients show that in subepithelial blistering diseases, early delineation of disease nosology is critical to detect subtypes with severe ocular involvement such as 'IgA-EBA'.

Diagnosis and Pathophysiology of IgA Mediated Bullous Dermatosis

2009-12-16T14:52:00.005Z

Diagnosis and Pathophysiology of IgA Mediated Bullous Dermatosis
Medical Terminology
1) Bullous (blistering)
2) Keratinocyte (An epidermal cell that produces keratin)
3) BMZ (Base Membrane Zone)
4) Epidermis.(the upper layer of the skin )
5) acantholysis (loss of cohesion between the epidermal cells, resulting in intraepidermal clefts, vesicles and bullae found in autoimmune skin diseases. )
6) anchoring filaments (thread-like fibres )
7) Hemidesmosomes (Hem-ee-DES-mo-so-m's. complex structures composed of many proteins)
8) Dermis (lower layer of the skin)
9) pruritis (itching)

Concerning Ocular Involvement in IgA Mediated Bullous Skin Disease
Please note that it is widely accepted that ANY bullous disease has the potential to affect the mucous membranes, in particular IgA mediated bullous diseases, as the IgA immunoglobulin antibody is the antibody most dominant found in the secretions of tears and saliva. About 80% of people with Linear IgA disease have mucosal involvement. It is untrue that Liga (LaD) or IgA mediated EBA does not affect the "inside" of the body. It CAN!! for the reasons stated above. It is also totally untrue that LigA does not affect the eyes. It CAN!!
Note too, it is published in many articles, that the resulting manifestations in mucosal involvement in Linear IgA disease and IgA mediated Epidermolysis Bullosa Aquisita, are indistinguishable from Cicatricial Pemphigoid when manifesting in mucous membranes. (therefore treatment and caution is the same!)

Following Extract from..... please note in bold
http://www.springerlink.com/content/j508q4l3580g4864/fulltext.pdf?page=1

Autoimmune diseases are extremely diverse in origin, pathogenesis and clinical ocular manifestations. As a group, these diseases are the ones that clinicians think of as the most destructive to the ocular surface. No matter whether the pathologic mechanism is neutrophilmediated, immune-complex-mediated, or T-cell-mediated, the end result is scarring or destruction of ocular tissues and interference with the physiologic processes necessary to maintaining ocular surface homeostasis.
Understanding the management of patients with this group of diseases requires a comprehensive understanding of how all of the components of the ocular surface work together. The clinician responsible for caring for patients who suffer from these diseases must simultaneously manage eyelid and meibomian gland disease, conjunctival and episcleral inflammatory disease, tear film disorders and keratitis, which may be exposure-related, infectious, inflammatory, toxic, or combinations of all these categories.

While the details of treating autoimmune diseases vary with each specific disease entity, it is critical that the treating clinician remain constantly aware of the interactions between all of the components of the ocular surface and direct appropriate treatment toward each abnormality simultaneously.
Just as it is impossible to provide comfort to the dry eye patient with blepharitis by using ocular lubricants alone, the severe pathologies involved in autoimmune diseases require a multi-armed therapeutic approach.

Bearing in mind that there is no clinical difference between Cicatricial pemphigoid and either of these two IgA mediated Bullous conditions, when affecting these tissues.....

Cicatricial pemphigoid is an autoimmune, cicatrizing disease of mucosal epithelium and, less often, skin. Cicatricial pemphigoid (CP) was first defined as a disease entity separate from pemphigus by Thost in 1911. It has been termed “chronic pemphigus,” “essential shrinkage of the conjunctiva,” “ocular pemphigus” and has been widely described as “benign mucous membrane pemphigoid” in dermatologic literature.
Since this disease is often anything but benign with regard to its ophthalmic consequences, the term cicatricial pemphigoid is suggested as the preferred terminology and will be used herein.
To the ophthalmologist, the usual presentation is chronic conjunctivitis with an insidious onset. The course of the disease is usually slow but may be punctuated by periods of explosive inflammatory activity. Ten to thirty years or more may be required for the disease to run its full course, with bilateral blindness as the result. Unilateral presentation is not rare, but eventually most patients develop bilateral ocular involvement; slowly progressive subconjunctival cicatrization is the hallmark of this disease.
Sixty-five to ninety percent of CP patients have ocular involvement, while approximately 25% have lesions on non-mucosal skin. Oral disease occurs in 70–90% of CP patients, and the mouth may be the sole site of involvement. Desquamative gingivitis is the most common oral manifestation, although nonhealing ulcers of buccal mucosa are not rare. Commonly, bullae develop after local trauma during chewing, and last several days. Once the bullae rupture, nonhealing erosions may last for weeks. Involvement of nasal, pharyngeal, laryngeal, esophageal, urethral, vaginal or anal mucosal surfaces may manifest as chronic ulcerations or strictures. (Bear in mind that 80% of patients with IgA mediated Bullous disease have mucosal involvement)

DIAGNOSIS
The diagnosis can be difficult, as linear IgA disease can mimic several other disorders. Confirmation of the diagnosis requires a skin biopsy in which a smooth line of IgA under the epidermis can be shown up by a special test (direct immunofluorescence) and by (indirect immunofluorescence) on blood serum which shows circulating antibodies.

Direct immunofluorescence
A study of both perilesional skin and healthy skin typically shows linear deposition of IgA at the BMZ. Linear deposition of C3 may also be seen. Direct immunofluorescence study of salt-split skin reveals IgA deposition on either the dermal side (blister floor) or the epidermal side (blister roof). Some patients demonstrate both linear IgA deposition and immunoglobulin G (IgG) deposition at the BMZ. Immunoglobulin M (IgM) deposition has rarely been reported.

Indirect immunofluorescence
Studies are taken from samples of Serum from blood. Patients with LAD have detectable circulating antibody that binds to the BMZ. Sensitivity is greater for immunofluorescence studies performed on salt-split healthy human skin. Circulating antibody titers are typically low (1:10 to 1:20). When present, linear deposition of antibody is observed at the BMZ or at the blister roof or floor in salt-split skin. Children with LAD may demonstrate circulating anti-BMZ antibodies more frequently than adults.

Definition: of C3 Complement:- is a blood test that measures the activity of certain proteins in the liquid portion of blood. The complement system is a group of proteins that move freely through the bloodstream. The proteins work with the immune system and play a role in the development of inflammation. There are nine major complement proteins. They are labeled C1 through C9.
(see Immunity- Complement System -under Cells of the Immune System : )
The result of this Direct immunofluorescence test in link below
http://www.ii.bham.ac.uk/clinicalimmunology/CISimagelibrary/images/EPI.jpg

NB:-Recent complicated methods of testing, to determine these target antigens, are set up in laboratories in some countries, in particular Japan, but due to the complexities of the set up, these tests are not readily available worldwide. However Proff.Neil Cox of Carlisle Cumbria has carried out part of these tests on the blood of myself, to establish an accurate diagnosis.

Histologic Findings in biopsy:
Early urticarial papules or plaques reveal neutrophils aligned along the BMZ accompanied by vacuolar change. Neutrophilic micro-abscesses may be seen in dermal papillae . Fully developed lesions reveal subepidermal blistering with a predominantly polymorphonuclear infiltrate, although mononuclear cells and eosinophils may be present.

Medical Terminology
See Definition of Vacuolar in link below
http://www.answers.com/topic/vacuole-1?cat=technology

Neutrophils (see Neutrophils under Cells of the Immune System- Phagocytes)
Polymorphonuclear-(Having a nuclei of varied forms; denoting a variety of leukocyte-see neutrophils)
Mononuclear- (Having only one nucleus; used especially in reference to blood cells.)
Eosinophils- (see Eosinophils under Cells of the Immune System)

Pathophysiology:
LAD is an autoimmune disease histopathologically characterized by the linear deposition of IgA at the basement membrane zone (BMZ). Antibody deposition leads to complement activation (see Complement System) and neutrophil chemotaxis, (see Chemotaxis ) which eventuates in loss of adhesion at the dermal-epidermal junction and in blister formation. Disease in children is immunologically identical to that of adults. The mechanism of loss of self-tolerance to target antigens is as yet uncertain.
Within the dermal-epidermal junction, different antigenic target sites, including the lamina lucida, the sublamina densa, or both locations simultaneously, have been identified.
The best-characterized antigen is a 97-kd protein extracted from human epidermis that binds IgA antibodies from sera of patients with LAD. Sera that binds the 97-kd antigen localizes to the lamina lucida of salt-split skin.
Originally thought to be a unique protein of the lamina lucida, recent work reveals that the 97-kd protein may represent a portion of the extracellular domain of the 180-kd bullous pemphigoid antigen (BPAg2).
The same patient sera have been shown to bind a 120-kd antigen in the BMZ. The 97- and 120-kd antigens may represent cleaved fragments of BPAg2, which exist as such in vivo or are produced by proteolytic digestion (The ability to break down protein molecules) in vitro. These smaller molecules could also be alternative splicing products of the same BPAg2 gene. Because antibodies that bind the 97- and 120-kd antigens do not recognize the 180-kd BPAg2, the former may express unique epitopes (see Epitopes) distinct from those of the parent protein.
A recent case series reported patients with sera not reactive against the 97-kd antigen but rather against both bullous pemphigoid antigens.
Of 11 patients, a 230-kd antigen (BPAg1) was recognized in 6 patients and BPAg2 was recognized in 5 patients.
The authors suggest that an IgA-specific immune response may occur against bullous pemphigoid antigens in LAD.
These results are provocative given that the 97-kd LAD antigen may represent a portion of the extracellular domain of BPAg2.
A 285-kd target antigen has been identified in the lamina lucida and the sublamina densa; this antigen is recognized by circulating antibodies in some patients with LAD, but it has not been further characterized.
A 250-kd dermal antigen corresponding to collagen VII of anchoring fibrils has also been reported as a target antigen in some patients.
LAD illustrates the importance of identifying the target antigen.
In cases where type VII collagen is the molecule against which the IgA antibody response is directed, patients are less likely to be responsive to treatment. Thus, viewing this condition as a subset of epidermolysis bullosa acquisita is better.
Similarly, patients with antibodies directed against the bullous pemphigoid antigens may be classified as having bullous pemphigoid but with an IgA response rather than an IgG response. Until more patients are reported whose antibody response is detailed to the molecular level and until this definition becomes clinically available, these heterogeneous patients will continue to be grouped into a single category, LAD. (see NB: above, under Diagnosis)
http://www.emedicine.com/derm/byname/Linear-IgA-Dermatosis.htm