Some authors, in discussing a particular disease, refer to it as 'an autoimmune disorder of unknown etiology'! Others even question whether autoimmunity is a legitimate etiology for any disease, perhaps forgetting Harrington's experiment in the 1950s wherein plasma transferred from a donor with 'idiopathic' thrombocytopenic purpura caused, in volunteer recipients, an immediate fall in blood platelet levels due to pathogenic anti-platelet autoantibodies. Wit-ebsky in 1956 presented four 'postulates' to nominate a disease as autoimmune: 1) demonstration of free circulating antibodies that are active at room temperature, or of cell-bound antibodies detected using indirect means; 2) the recognition of the specific antigen against which these are directed; 3) the production of antibodies against the analogous antigen in actively immunized animals; and 4) pathological changes in the tissues of the actively sensitized animal resembling those of the corresponding human disease. However, the lack of models (components 3 and 4) precludes fulfillment of these postulates in many human autoimmune diseases.
Bayesian reasoning provides clinical and/or pathological features that can be factored in to presume an autoimmune basis for a given disease. These include: female gender; coassociation in the patient or family members of other diseases of autoimmune nature; histological evidence of 'organized' lymphoid infiltrates in the affected tissue including germinal centers, or deposition of immune complexes that contain autoantigen; association of the disease with particular alleles (usually class II) or the major histocompatibility complex (MHC), HLA in humans; and brisk responsiveness to corticosteroid drugs. As further evidence for an autoimmune basis for a given disease, there are models in animals, either spontaneous (lupus, hemolytic anemia or diabetes in particular strains of mice) or induced by immunization with the corresponding tissue in adjuvants (thyroiditis or encephalomyelitis in various species). Finally, in diseases designated as autoimmune, no other provocative causes should be demonstrable. Indeed, in chronic destructive diseases that are demonstrably due to a persisting microorganism, hallmarks of autoimmunity tend to be conspicuously absent, e.g. gastric mucosal destruction due to infection with Helicobacter pylori does not provoke the parietal cell antibody response characteristic of autoimmune (pernicious anemia-type) gastritis. But there are exceptions, including spirochetal infection (cardiolipin antibody), hepatitis C virus infection (liver microsomal antibody, occasionally) and others.
In the absence of firm nominative criteria, a listing of likely autoimmune diseases is necessarily provisional (Table 1). A somewhat imperfect classification is as follows:
1. Organ and autoantibody specific, i.e. diseases in the 'thyrogastric cluster'.
2. Tissue and autoantibody specific, i.e. diseases in which a 'disease-relevant' target autoantigen exists, but this is widely 'dispersed' throughout the body e.g. hemolytic anemia (erythrocytes), myasthenia gravis (acetylcholine receptor).
3. Diseases that are organ or tissue specific, and in which there is a disease-specific autoantigen(s), but this is distributed in all cells and thus not 'disease relevant', e.g. primary biliary cirrhosis and mitochondrial autoantigens, or Sjogren's syndrome and ribonucleoprotein autoantigens.
Table 1 A partial list of autoimmune diseases
Hashimoto's thyroiditis Primary myxedema Graves' disease Pernicious anemia
Autoimmune atrophic gastritis, pernicious anemia Addison's disease
Ovarian failure, premature menopause
Insulin-dependent diabetes mellitus
Myasthenia gravis, Lambert-Eaton syndrome
Male infertility (few cases)
Pemphigus, bullous pemphigoid
Crohn's disease (possibly)
Autoimmune hemolytic anemia
Autoimmune thrombocytopenic purpura
Primary biliary cirrhosis
Chronic active hepatitis, 'cryptogenic' cirrhosis
Ulcerative colitis (possibly)
Anti-phospholipid syndrome Mixed connective tissue disease Vasculitis
4. Diseases that are multisystem and 'nonfocused', with autoimmune reactivity against antigens associated with various non-tissue-specific intracellular organelles, e.g. systemic lupus erythematosus (SLE).
Etiology and pathogenesis
An important genetic component in autoimmune disease is female gender, with the female:male ratio ranging up to tenfold, although a notable exception is insulin-dependent diabetes mellitus (IDDM) that occurs at prepubertal ages with an equal gender incidence. The influence of female sex hormones on immune responsiveness, and perhaps an immuno-potentiating gene on the X chromosome, explains the female predisposition to autoimmunity. A strong genetic predisposition to autoimmunity is conferred by alleles of the MHC, in humans and in experimental models, particularly at the class II loci, HLA-DR, -DQ, -DP rather than the class I loci, HLA-A or -B. Class II alleles encode heterodimers that present antigenic epitopes to T cell receptors, and such MHC molecules may contain, in their hyper-variable regions, a sequence of amino acids that represents the disease susceptibility motif (DSM); this explains for example the HLA associations, DR1, DR4, with rheumatoid arthritis. The DSM may confer a high binding affinity for an autoepitope that can engage the T cell receptor, or may act to bias the thymic selection of the T cell repertoire.
Studies on genetic linkages in families with multiple members with an autoimmune disease e.g. IDDM, or in animals using backcrossing and chromosomal localization, e.g. lupus mice, indicate the existence of many other gene loci, encoding either 'immunologically relevant' genes or 'non-immunologic' (background) genes, that confer or alleviate risk for autoimmunity. Examples would be genes that govern expression of cytokines, chemo-kines or adhesion molecules, or genes that influence expression of molecules that promote or inhibit apoptosis, fas and bcl. Still further genetic effects on autoimmunity could relate to the antigenic composition of the target organ itself, or to autoantigenic molecules as products of alternatively spliced genes, isoforms of enzymes, or to other structural or functional polymorphisms of potential autoantigens.
Susceptibility to autoimmune disease may depend on somatic genetic effects (mutations) in postnatal life. The best example is antigenic stimulation of B lymphocytes in germinal centers of lymph nodes, with ensuring hypermutation of antibody V region genes to generate affinity maturation of antibodies. Thus B lymphocytes with reactivity with autoantigens may emerge as a 'byproduct' of affinity maturation of antibodies to bacterial antigens, and may persist if tolerogenic processes fail, with ensuing 'rescue' of such autoimmune B cells from apoptosis. Various other somatic genetic mutations in postnatal life could predispose to autoimmunity, e.g. those that influence patterns of cytokine secretion, or processes of apoptosis.
The environment can interact with genetic predisposition to induce autoimmune disease. Viewed most simply, any cause of tissue damage can result in release of cellular products which, if exposed to anti-gen-presenting cells of individuals with 'susceptibility-genotypes', in an appropriate microenvironment such as cytokine excess, could stimulate self-reactive T cells that normally circulate at low levels. In the case of infectious damage, there is the added possibility of antigenic (or epitope) mimicry. This idea is based on molecular homologies between a constituent protein antigen of a microorganism and host being sufficiently close that the 'protective' response to the organism becomes cross-reactive with 'self'. An example of a break in tolerance initiated by molecular mimicry is the provocation by streptococcal cell wall antigens of rheumatic endomyocarditis. Currently, molecular biological techniques for identifying sequences of autoantigenic epitopes have been combined with searches of gene and protein databanks to reveal potentially informative homologies; however, such comparisons often fail to acknowledge that B cell epitopes, including autoepitopes, are usually conformational rather than linear. Thus molecular mimicry may be more applicable to short linear T cell epitopes.
Other relevant environmental influences are ultraviolet radiation, chemicals including mercuric chloride that induce autoimmunity in rodent models, and medicinal drugs that induce various autoimmune syndromes including SLE, hepatitis and myasthenia gravis. Good explanations for the induction of autoimmunity by these influences are lacking: sunlight might act to create neoepitopes in skin cells, mercuric chloride may cause structural alterations in MHC molecules on antigen-presenting cells, and medicinal drugs may yield molecules that generate compound epitopes with cellular constituents.
Induction of autoimmune disease
The critical elements for the induction of autoimmune responses are: 1) the autoantigenic epitope;
2) processes that facilitate the presentation of the autoantigenic epitope to the immune system; and 3) recognition of the epitope by T and B lymphocytes that have evaded tolerogenic influences.
To serve as an autoantigen, a self molecule should activate both T and B lymphocytes. Autologous molecules will not be recognized as autoantigens if deletional processes have completely removed any cognate responsive T cells in the thymus, or B cells in the bone marrow. T cells can escape deletional tolerogenesis in the fetal thymus if the requisite self molecule is either not represented there, or is not adequately processed by antigen-presenting cells, or if its affinity for the antigen receptor on intrathymic T cells is too low. Thus some self-reactive T cells do exit from the thymus to the periphery: however, these are not necessarily dangerous as they may have only a low affinity for autoantigens and are not readily activated; or, being of a naive phenotype, will not express the surface adhesion molecules required for their transit into tissue parenchyma.
Autoreactive B cells can arise in two sites, the bone marrow during lymphogenesis, or lymph node germinal centers by affinity maturation during responses to extrinsic antigens (see above). B cells at both sites are subject to various tolerogenic influences, including antigen in excess, which induces cell death by apoptosis. Again, however, there is 'leakage' in health of self-reactive B cells from these sites into the periphery; evidence for this is the presence in the circulation, particularly in aging, of various autoantibodies, and also B cells capable of binding labeled autoantigens. A low degree of B cell autoimmunity may well be 'innocuous', if not beneficial (see above), provided that there is no source of potent contiguous T cell help.
Effector activities depend on the various functions of B or T lymphocytes or, probably, both sets of cells, in unison. B cells and circulating autoantibody are the clear cause of autoimmune pathology in hemocy-tolytic diseases, or SLE in which damage results from deposition of immune complexes, or diseases in which autoantibody binds to cell surface receptors, either to inhibit a neurotransmitter, e.g. acetylcholine receptor in myasthenia gravis, or to stimulate a hormone receptor, e.g. the thyrotropin receptor in Graves' disease. Another role for B cells is to act as antigen-presenting cells, in a focused way, as autoantigen can be specifically captured by the B cell immunoglobulin receptor for presentation to autoimmune T cells, thus sustaining the autoimmune reaction. CD4+ helper T cells are the likely effectors of damage in autoimmune disease of parenchymal tissues, thyroid gland, stomach, brain, synovium, pancreatic islets, etc., presumably by release of injurious cytokines, particularly tumor necrosis factor (TNF), or injurious enzymes (granzymes). CDS cytotoxic T lymphocytes (CTLs) are less easily studied functionally as effectors of autoimmune damage and data are scarce. As judged by the infrequency of MHC class I associations with autoimmune disease, CD8+ CTL-mediated damage might be relatively less important in autoimmunity. However, immuno-histochemical studies of tissue lesions often show a striking infiltration of CD8+ T cells in contiguity with damaged cells and, in animal models, cell transfer studies have implicated CD8+ CTLs as early effectors, e.g. in autoimmune islet cell damage in nonobese diabetic (NOD) mice.
Self tolerance and avoidance of autoimmunity are of such fundamental importance to the organism that several 'layers' of tolerogenesis are in place. The first and fundamental layer, 'central' tolerance, is deletion of lymphocytes in the primary lymphoid organs, thymus or bone marrow, consequent on high-affinity contact between autoantigen as ligand and antigen receptors on nascent T or B cells, i.e. negative selection. Deletional self tolerance has been elucidated by recent studies on transgenic mice in which cDNA for a marker antigen, e.g. hen-egg lysozyme, is introduced in embryonic life, and hence is treated as self; in 'double' transgenic mice there are additionally introduced genes that encode T cell or B cell antigen receptors for the transgenic molecule.
Processes of 'peripheral' tolerance operate to limit the activity of autoreactive cells that have escaped deletion in the thymus or bone marrow. Thus 1) thymic emigrant T cells have a 'naive' phenotype and lack activation molecules needed for extravasation through vascular endothelium into tissue parenchyma; 2) T cells that encounter autoantigens in the blood or on the surface of tissue cells do not receive a critical 'second signal' that is provided only by 'professional' antigen-presenting cells, and respond by anergy rather than activation; 3) particular cytokines may deflect a damaging autoreactive CD4 T helper cell response from the Tnl inflammatory type to the more benign TH2 antibody dominated type; 4) autoimmune B cells remain innocuous if they fail to obtain adequate helper signals from T cells that may be adequately tolerized; and, finally, 5) there are mechanisms of 'dominant' tolerogenesis, also called suppression, which can prevent autoimmunity or even override established self-reactive effector processes. Autoimmunity in states of natural and experimentally induced T cell lymphopenia is evidence for the existence of a regulatory/suppressive subset of T lymphocytes. Dominant tolerogenesis may also be mediated by anti-idiotype antibodies; such antibodies are directed against the combining site of the antibody molecule itself. Anti-idiotype antibodies to autoantibody molecules appear to exist in normal sera, and are considered to explain the beneficial therapeutic effect in certain autoimmune diseases of pooled normal human immunoglobulins given intravenously.
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