Autoimmune Diseases
The autoimmunity is a mechanism that the immune system utilizes to destroy
extra cellular pathogens or host cells. The harbor intracellular foreign bodies such as mycobacterium or viruses must be appropriately targeted damage to normal host tissue is to be avoided.2 Under most inflammatory circumstances; some bystander tissue damage is unavoidable. In most circumstances, this damage is self limited. It is due to efficient clearance of exogenous nitrogen source and appropriate down modulation of immune response.2
Immune reactions against self antigens autoimmunity are an important cause of certain diseases in humans. Autoimmune disease occurs when a sustained, specific adaptive immune response is generated against self-components, and results in tissue damage or dysfunction.1 There are three requirements should be met before a disorder is categorized as truly due to autoimmunity.4
1) The presence of an autoimmunity reaction.
2) Evidence that such a reaction is not secondary to a tissue damaged. E.g. resulting from infection, but it is of primary pathogenic significances.
3) The absence of another well-defined cause of the disease.
Although a single immune effecter pathway may predominate in generating tissue dysfunction and damage in some autoimmune disease. It is much more frequent for multiple effectors pathways to participate in generating the final phenotype. Those pathways which generate tissue damage or dysfunction include autoantibody binding to target cells. There is immune complex –mediated activation of complement and Fc receptor pathways, cytokine pathways, and lymphocyte meditated cytotoxicity of target cells.4 The nature and sites of the tissue damage are what determine the pathological and clinical features of the specific diseases. Autoimmune disorders may results from tissue damage caused by T cells or antibodies that react against self antigens. The autoimmune disorders form a spectrum, on one end of which are conditions in which the immune response is directed against a single organ or tissue, resulting in organ-specific disease and on the other end are diseases in which the autoimmune reaction is against widespread antigens, resulting in generalized or systemic disease.4
Autoimmune diseases may affect individuals at all stage of life, in general diseases have a predilectation for beginning after the second decade with peak incidence in the third to sixth decades.5 In many instances female are predominate. The magnititudes of this sex difference varying among the different diseases. So for the systermic autoimmune disease such as systermic lupus erythomatosus, rheumatoid arthritis, sjogren’s syndrome, scleroderma, autoimmune myosities and autoimmune thyroid disease the female male ratio is 4:1 to9:1, whilst for insulin dependent diabetes mellitus, multiple sclerosis and myasthenia gravis the female predominance is much less prominent.5 The female: male ratio is les than 2:1. The extract mechanisms underlying this female predominance remain unknown.5 But this striking biological difference provides a major clue to pathway understanding susceptibility to autoimmunity.
It is obvious that autoimmunity results from the loss of self- tolerance. But there are mechanisms of immunological tolerance to self antigens.
Immunological tolerance
An immunological tolerance is a stage in which the individual is incapable of developing an immune response to a specific antigen.1 Self- tolerance refers to lack of responsiveness to an individuals own antigens, and it underlies our ability to live in our cells and tissues. The immunological tolerance can be broadly classified into 2 groups.1
1) Central tolerance
2) Peripheral tolerance
Central tolerance
This refers to death (deletion) of self reactive T and B lymphocyte clones during their maturation in the central lymphoid organs, the thymus for T cells and the bone marrow for B cells.6 This process is most active in fetal life, but continuous thought life as immature lymphocytes are generated.
There are several mechanisms of T cell tolerance. Once occurs in the thymus by means of a complicated, multistep selection mechanism. In the first stage of this process, immature T cells which do not bear either of the CD 4 and CD 8 molecules (double-negative) enter the sub capsular region of the thymus.8 And also divide and proliferate T cell receptors, CD 4 and CD8 molecules, are then co- expressed simultaneously; these cells are termed double-positive.8 Maturing cells are migrating towards the cortex of the thymus where the selection process occurs. T cells that can engage with MHC class I or 11 molecules on the thymus cortex are said to be positively selected and they undergo further processing. They will lose either the CD 4 or CD 8 co-receptor, depending on which particular MHC molecule they engage.8 Cells that do not interact with the MHC undergo programmed cell death (apoptosis).9 Thus after positive selection, only cells that can recognize MHC molecules (and thus antigenic peptides presented in association with these structures) remain.
However, another step is necessary to remove cells that can react with self-peptides, and this occurs through negative selection. This part of the selection process occurs in the corticomedulary junction, which is rich in dendrite cells and macrophages. If either CD 4 or CD 8 cells engage with cells bearing MHC class 1 or 2 molecules containing self-peptide (i.e. auto reactive T cells) they undergo apoptosis and are clonally deleted.7 The remaining cells pass through the thymus and become part of the mature T-cells pool. Negative selection is probably the most significant aspect of tolerance induction. The loss of thymocytes through the positive and negative selection process is high, with over 90% of cells undergoing apoptosis.4, 5
Peripheral tolerance
Those self reactive T-cells that escape intrathymic negative selection can inflict tissue injury unless they are deleted or muscles in the peripheral tissues.1 There is a prolonged or irreversible functional inactivation of lymphocytes induced by encounter with antigens under certain conditions. Apart from anergy there are also suppressions by regulatory T cells.3 Regulatory T cells may develop in the thymus as a result of recognition of self antigens, or they may be induced in the periphery. The best defined regulatory T cells are CD4+ cells that constitutively express CD 25, the chain of the IL-2 receptor, but some CD4+ cells lacking CD 25 may serve the same function.8
And also there is a colonel deletion by activation-induced cell death: CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis.7 This process has been called activation-induced cell death, because it is a consequence of T-cell activation.
In antigen sequestration some antigens are hidden from the immune system because the tissues in which these antigens are located do not communicate with the blood and lymph. This is believed to be the case for the testis, eye and brain all of which are also called immune – privileged sites. Because it is difficult to induce immune responses to antigen in this sites.4
Prevention of autoimmunity is so vital to survival that several mechanisms have evolved to protect us from our “protectors”. There is firm evidence in experimental animals for both central & peripheral mechanisms, but their relative importance in maintaining self-tolerance in humans is not established and may well very with the nature of the auto antigen.
Etiology of autoimmune disease
In autoimmune disease interactions between genetic and environmental factor are critically important.17
Genetic factors
Twin and family studies have confirmed a genetic contribution in all autoimmune diseases studied multiple autoimmune diseases may cluster within the same family.1 And sub clinical autoimmunity is common among family members. The genetic contribution to autoimmune disease usually involves multiple genes but some single gene defects involve defect in apoptosis.17
The strongest and best characterized associations involve alleles of the major histocompatibility com (MITC) as might be expected from the central role of the products of many of these genes in T-cell function, and in involvement of other MHCgenes in control of immunity and inflanmatic.7
Environmental factors.
Environmental triggers in autoimmunity include
• Hormones
• Infections
• Drugs
• Ultra violet radiation
Hormone
Female are more likely than males to develop autoimmune disease. While this has an obvious genetic basis. Hormonal factors must play a major role in this gender difference.
Most autoimmune diseases their peak age of onset within the reproductive years and evidence implicates estrogens as triggering factors. Removal of ovaries inhibits
the onset of spontaneous autoimmunity in animal models of SLE, while administration of estrogen accelerates the onset of disease. 17
Infection
The relationship between infection and autoimmunity is clearest in the situation of molecular mimicry.3 Autoimmune diseases tend to be less common in parts of the world that carry a high burden of parasitic diseases and other infections. In some animal models of autoimmunity, the development of disease can be dramatically inhibited by weeping the animals in a laboratory environment with high prevalence of infection.3 Keeping the same animals in germ free of conditions promotes the development of autoimmunity for reasons that are not clear. Attempts to identify hidden infections in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis have been unsuccessful.4
Drugs
Drug-induced autoimmunity may involve mechanisms comparable to molecular mimicry, whereby the drugs or a drug -self- molecule complex has a structural similarity to self and hence allows bypass of peripheral tolerance. Some drugs (e.g. penicillamine) have the ability to bind directly to the peptide-containing groove in MHC molecules and a direct capacity to induce abnormal T-cell responses. 17
Drug – mediated autoimmunity affects only as mall proportion of those treated and is probably genetically determined. For e.g., HLA- DR 2 is associated with penicillamine induced myasthenia graves, whereas DR3 is associated with nephritis. Genetic variation in drug metabolism is important. The best example is the relationship between drug-induced systermic lupus erythomatosus and the rate of acetylating of the triggering drug: slow acetylators are prone SLE. It seems likely that this partial defect in metabolism may allow the formation immunogenic conjugates between drug and self molecules. 17
Ultraviolet radiation
Exposure to ultra violet (UV) is a well defined trigger for skin inflammation and sometimes systemic involvement in systemic lupus erythematosus.4 UV radiation can modify self-antigens, so enhancing their immunogenicity, or lead to apoptotic death of cells within skin. Apoptosis is associated cell surface expression of auto- antigens usually found only within cells which are then able to bind related auto-antibodies and trigger tissue damage.5
Mechanisms of autoimmune diseases
The development of autoimmunity is related to the inheritance of susceptibility genes, which may influence the maintenance of self-tolerance, and environmental triggers, particularly infections, which promote the activation of self reactive lymphocytes.3
Most autoimmune diseases show a strong genetic predisposition among the genes known to be associated with autoimmunity, the best defined are HLA genes. It is postulated that the presence of particular MHC alleles affect the negative selection of T-cells in the thymus or the development of regulatory T-cells. Many normal individual inherit the MHC, alleles that are disease associated in patient populations, and normal molecules are capable of presenting self antigens.9 The presence of particular MHC alleles is not, by it self the cause of autoimmunity. In several autoimmune diseases such as systemic lupus erythomatosus and type I diabetes mellitus many non MHS genetic loci have been shown to be associated with autoimmunity.9
Many autoimmune diseases are associated with infections, and clinical flare-ups are often proceeding by infectious proteomes there are two mechanisms have been linked between infection and autoimmunity. First, infections may up regulate the explanations of costimulaters an antigen presenting cells. If these cells are presenting self antigens the result may be a brake down of colonel anergy and also there is an activation of T cells specific for the self antigens.9 Second, some microbes may express antigens that have same amino acids sequences as self antigens. Immune responses against the microbial antigens may result in the activations of self reactive lymphocytes. This phenomenon is called molecular mimicry. The clear example of such mimicry is rheumatic heart disease. In this case an antibody against streptococcal proteins cross-react with myocardial proteins and cause myocarditist.10
Once an autoimmune disease has been induced, it tends to be progressive. An important mechanism for the persistence and evolution of autoimmune disease in the phenomenon of epitope spreading. Infections and even the initial autoimmune response may release and damage self-antigens and expose epitopes of the antigens that are normally concealed from the immune system.4
Tissue-specific autoimmune diseases
These occur where immune-meditated is restricted to a particular tissue or organ that specifically expresses the targeted antigen. 2 Graves disease (where auto antibodies bind to and stimulate the thyroid-stimulating hormone receptor, resulting in thyrotoxicosis). Myasthenia gravis (where auto antibodies target the acetylcholine receptor at the neuromuscular junction, resulting in muscular weakness and fatigue due to the inefficient transmission of the acetylcholine signal), and insulin- dependent diabetes mellitus (where a cytotoxic T-cell response to the B-cells of the pancreatic islets results in destruction of the insulin producing cells.)

Systemic autoimmune diseases
These are frequently characterized by simultaneous damage in multiple tissues (such as kidney, lung, skeletal muscle, nervous system, and skin)4.Unlike tissue-specific autoimmune diseases are frequently directed against molecules expressed ubiquitously in multiple tissue examples include the RNA syntheses targeted in autoimmune myosities the small nuclear ribonucleoproteins targeted in systemic lupus erythomatosus, and topoisomerase -1 targeted in scleroderma, each of these molecules is expressed in all cells, where they play critical roles in essential cellular processes ( such as protein translation, m RNA splicing, and DNA replication and remodeling, respectively ).4 Recent studies have suggested that novel forms of these ubiquitously expressed antigens are generated when cells undergo some forms of apoptotic death, and that apoptotic cells may represent an important source of immunogens in this group of disorders. While tissue damage is frequently mediates by numerous mechanisms in systemic autoimmune diseases, deposition of immune complexes at sensitive sites (such as shin, joints, and kidney) represents a prominent mode of tissue damage.4
Systemic lupus erythomatosus (SLE)
It is a prototype of a multi-system disease of autoimmune origin. Virtually every other organ in the body however may also be affected. SLE is fairly common disease, with a prevalence that may be as high as in 2500 in certain populations. Similar too much autoimmune disease, SLE is predominantly a disease of women.5 The fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance. A variety of immunologic abnormalities affecting both T cells and B cells have been defected in patients with SLE. It had been thought that an intrinsic B cell hyperactivity is fundamental to the pathogenesis of SLE. 6 Polygonal B-cell activation can be readily demonstrated in patients with SLE and murine models of this disease.6
Sjogren’s syndrome
Is a chronic disease characterized by dry eyes and dry mouth resulting from immunological mediated destruction of the lacrimal and salivary glands.3 The characteristic decrees in tears and salivary is the result of lymphocytes infiltration and fibrosis of the lacrimal and salivary glands.3 The infiltrate contains predominantly activated CD helper T cells and some B cells. It is including plasma cells that secrete antibody locally. Sjogren’s syndrome is in all likelihood initiated by CD4 + T cells. Molecular analysis of the T- cell receptors of the T cells expands clonally, Suggesting antigen-driven stimulation.8
Occurs most commonly in older women, typically between ayes 50 and 60 as might be expected, symptoms results from inflammatory destructions of the exocrine glands.5
Systemic scleroderma
Systemic sclerosis is a chronic disease. It is characteristized by abnormal accumulation of fibrous tissue in the skin and multiple organs.11 And also kidneys heart, muscles and lungs are frequently involved.4 In some patients, the disease appears to remain confined to the skin for many years, but in the majority, it progresses to visceral involvement with death from renal failure, cardiac failure, pulmonary insufficiency or intestinal malabsoption.4
The likely trigger for excessive fibrosis is a combination of abnormal immune responses and vascular damage resulting in local accumulation of growth factors that act on fibroblast, and stimulation collagen production.11 There is abnormal immune responses play a role in the pathogenesis of systemic sclerosis.3 It is proposed that CD 4+T-cells responding to an as yet unidentified antigen accumulate in the skin and release cytokines that recruit and activate inflammatory cells, including mast cells and macrophages.
Molecular analysis of the antigen receptors of the infiltrating T cells suggests that the accumulated CD4+ cells are oligoclonal, and their expansion is antigen driven. In the skin and other affected tissues the accumulated T cells and other inflammatory cells release a variety of mediators, such as histamine, heparin, IL-1, IL-2, IL-3, TNF, several of these mediators can stimulate transcription of genes that encode collagen and other extracellulor metrics proteins in tibroblased.6 Fibroblasts from patients may also be hyper responsive to cytokines and may respond to excessive collagen production.6
Rheumatoid arthritis (RA)
Is a chronic systemic inflammatory disorder that may affect many tissues and organs such as skin blood vessels, heart, lungs and muscles.16 But it is principally attach to the joints. That producing a non supportive proliferactive and inflammatory synovites that offen progress to distraction of the auricular cartilage and ankylosis of the joints.16
About 1% of the world’s population is afflicted by RA. The women 2 to 3 times more often than men.16
RA is an autoimmune disease triggered by exposure of a genetically susceptible host to an unknown arthritogenic antigen. It is the continuing autoimmune reaction, with activation of CD4+cells and other lymphocytes and local release of inflammatory mediators and cytokines that ultimately destroys the joint.4
The autoimmune reaction in RA consists of activated CD4+ T cells, and probably B lymphocytes, as well.
The T cells apparently function mainly by stimulating other cells in the joint to produce cytokines that are central mediators of the synovial reaction.4
Wegener granulomatosis
Wegener granulomatosis is a necrotizing vacuities characterized by the triad of acute necrotizing granulomas of the upper respiratory tract, the lower respiratory tract or both. 4The glaucomatous vacuities affecting small to medium-sized vessels, most prominent in the lungs and upper airways but affecting other sites as well.4 The renal disease in the form of focal necrotizing often crescent, glomerulitis.4 The Wagener granulomatosis may represent some form of hypersensitivity, possibly to an inhaled infectious or other environmental agent. The presence of granulomas and dramatic response to immunosuppressive therapy also strongly support an immunologic mechanism, perhaps of the cell-mediated type, 4
Pernicious anemia
It is believed to result from immunological mediated, possibly autoimmune, detraction of gastric mucosa.3 The resultant chronic atrophic gastritis is marked by a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells. 3 types of antibodies are present in many but not all patients with pernicious anemia. About 75% of patients have a type 1 antibody that blocks binding of vitamin B12 to intrinsic factor.3 Type 1 antibodies are found in both plasma and gastric juice. Type 2 antibodies prevent binding of the intrinsic factor-Vitamin B12 complex to its ileal receptor.3 These immunoglobulin are also found in a large proportion of patients with pernicious anemia. Despite the presence of these auto antibodies it is not established that they are the primary cause of gastric changes. The auto reactive T cell response initiates gastric mucosal injury, triggering the formation of auto antibodies, which may exacerbate epithetical injury.3
Myasthenia gravis
Is a muscle disease caused by immune-mediated loss of ach receptors? And having characteristic temporal and anatomic patterns as well as chug responses the disease has a prevalence of about 3 in 100,000 persons.13
In most cases the auto antibodies against the AchR lead to loss of functional AchRs at the neuromuscular junction by fixing complement and causing direct injury to the post synaptic membrane. Increasing the internalization and degradation of the receptors and inhibiting binding and function of Ach.14 Electrophysiological studies are notable for decrement in motor responses with repeated stimulation. Nerve conduction studies findings are normal.13 Sensory as well as autonomic functions are not affected. Despite the evidence that anti-AchR antibodies play an artificial pathogenic role in the disease, there is not always a correlation between antibody levels and neurological deficit.12
Graves’ disease
Graves’ disease is peak incidence between the ages between ages of 20-40.women being affected up to 7 times more frequently than men. Graves’ disease is a disorder in which a variety of antibodies may be present in the serum.15
Long acting thyroid stimulator (LATS) so named because it stimulated thyroid function more slowly than TSH, LATS proved to be an IgG antibody that binds to the TSH receptor and mimics the action of TSH. It leads to stimulating adenyl cyclase, with resultant increased release of thyroid hormones.15 Almost all patients with Graves ’ disease in contrast to thyroglobuling and thyroid peroxides antibodies.15
Multiple sclerosis
Is an autoimmune demyelinating disorder characterized by distinct episodes of neurological deficits. It is the most common of the demyelinating disorders, having a prevalence of 1 per 1000 person.3 The disease becomes clinically apparent at any age. Although onset in childhood or after age 50 years is relatively rare.4
The lesions of multiple sclerosis are caused by a cellular immune response that is inappropriately directed against the components of the myelin sheath. The like hood of developing this autoimmune process is influenced by genetic and environmental factors.14 The available evidence indicate that the disease is initiated by CD4+T1+I T cells that react against self myelin antigens and secrete cytokines. These are IFN-R, which activates macrophage. 3
Treatments
Often, in organ specific Aug disorders the symptoms can be corrected by metabolic control. 2
E.g. hypothyroidism can be controlled by administration of thyroxin and thyrotoxicosis by antithyroid drugs.
In pernicious anemia metabolic correction is achieved by injection of VIT B and in myasthenia graves by administration of cholinesterase inhibiters.3. In the case of tissue grafts, protection from the immunological process, which necessitated the transplant may required.4
Conventional immunosuppressive therapy with ant mitotic drugs can be used to damp down the immune response but, because of the dangers involved, tends to be used only in life-threatening disorders such as SLE and dermatomyosities.17
The potential of cyclosporine and related drugs has get to be fully realized, but quite dramatic results have been reported in the treatment of type 1 diabetic mellitus.3,4
In particular, some experimental autoimmune diseases have been treated successfully with auto antigenic peptides and their analogues, and by vaccination with auto reactive T cells this suggests that stimulating normally suppressive functions.1

References
1) Kumar & Clark, Clinical immunology, 5th edition, (216-220)
2) John Stewars, Donald M, Weir Immunology7 th edition
3) D.P.Stites, J.D.Stobo, Basic & Clinical immunology.4th edition, (156-187)
4) Yoshisugi Hokama, Robert M., Immunology & Immunopathology
5) Roitt, Brostoff, Immunology, 4th edition, (chapter 27)
6) Wiesel f., Wellmann, Winkler, Auto reactive B cells get activated in cellular sites, Eur I Immune 2007 Nov. 29extra
7) Mackay IR, Autoimmunity since the clonal selection theory Immunal cell bio 11 2007 Nov. 27 Thewissen M., Somers, CD4+ CD28, null T cells in auto immune diseases
T immunol 2007 Nov. 15
9) Muller A., Lamprecht, Interleukin 17 in chronic Inflammatory and autoimmune disease, Z.Rheumatoid 2007 Nov. 16
10) Leyngold., Baughman. Kasper E., Comparison of survival among patients with connective tissue disease & cardiomyopathy, Am T. cardio 2007 Aug. 1-100
11) Williams HJ, Alarcon GS Early infiltration connective tissue J. Rheumatoid 1998 Feb
12) Ben David, H Sharan., The role of CD 8+, CD 28 regulatory cells
13) Apostaliski S, Larrinic D, Srp Arth Celok 2007 March, Apr. 135
14) Wakata N. Konno S., Interm Med 2007 46 (11) 747-750
15) Saiton O., Abiru N, Nakanara M, Nagayamoy, CD8+ CD 122 + T cells
16) T. Gibson, Rheumatic disease, an introduction for medical students
17) J. C. G. Underwood General & systemic Pathaphysiology4th edition
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