(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
