Immunity, Autoimmunity, and IgA Mediated Autoimmune Bullous Disease

Please see my blogs on .....
Linear IgA Bullous Dermatosis and Iga Mediated Epidermolysis Bullosa Aquisita, here...
OOKP Surgery ( Tooth In Eye Surgery) here ....
Understand Autoimmunity here .....

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.
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 .....
Linear IgA Bullous Dermatosis & IgA Mediated Epidermolysis Bullosa Aquisita.......
The Immune System its Structure and Function ......

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)
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;
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.

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...

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)