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Autoimmune Disease Introductory article Article Contents Robert Volpé, University of Toronto, Toronto, Ontario, Canada . Introduction The term autoimmunity describes the inappropriate reaction of the immune system against one or more of the organism’s own tissues. It does not necessarily imply any tissue damage or dysfunction. When there is tissue infiltration, damage and/or dysfunction, the condition is termed autoimmune disease. Introduction The term autoimmunity describes the inappropriate reaction of the immune system against one or more of the organism’s own tissues. It does not necessarily imply any tissue damage or dysfunction. When there is tissue infiltration, damage and/or dysfunction, the condition is termed autoimmune disease. The purpose of the body’s immune system is to fight off infection, such as viruses or bacteria, and normally the immune system can make a very fine distinction between exogenous antigens (as, for example, manifested by those microorganisms) and self antigens, against which it does not normally react (self-tolerance). Autoimmunity has traditionally been considered to represent a breakdown in self-tolerance, although the mechanisms of this breakdown may not be the same in each case and, in any event, are still not fully understood. The mechanisms of tolerance are considered in the next section. Autoimmunity is characterized by the inappropriate or excessive activity of immune effector cells directed to tissue(s) in the body of the organism. Thus, B lymphocytes may produce autoantibodies, and these may or may not have functional effects on the target tissue; immune complexes may be deposited in blood vessels; T lymphocytes may aggregate in tissues (or a tissue) with or without resultant destruction; and the complement system may activate phagocytic mononuclear cells. Generally speaking, in autoimmune disorders that are characterized by tissue damage, the damage is mediated by T lymphocytes. However, there are some conditions in which cellular function may be disturbed primarily by antibodies (e.g. Graves disease, myasthenia gravis). The development of these diseases, including the disturbances in target cell function, depends on a complex interplay between the antigen(s) on the target cells, the antigen-presenting cells (APCs), the helper or inducer T lymphocytes, T-effector lymphocytes, regulatory or cytotoxic T lymphocytes, B lymphocytes, antibodies and various cytokines (cytokines are soluble factors with various functional properties that are released by many cell types, including immune cells). In turn, these elements stimulate the target cell to express molecules of various types, such as intercellular adhesion molecules, heat-shock proteins, class I and class II . Self-tolerance . Possible Aetiologies for Autoimmune Diseases . Classification of Autoimmune Diseases . Major Autoimmune Diseases histocompatibility antigens, other autoantigens and so forth, that will further modify the immune process. Controversy abounds regarding the nature of the autoimmune process, the role of antigen and of antigen presentation, and the involvement of microorganisms in these mechanisms. At times, the immune response may be induced by a foreign antigen such as is carried by a virus, while on many other occasions no such foreign antigen can be identified (although there are many homologies between antigens of microorganismic origin and autoantigens). Where no exogenous antigen can be found, the abnormality may lie largely, if not entirely, in the regulation of the immune system: a breakdown in tolerance has occurred. The criteria involved in identifying human autoimmune disease are depicted in Table 1. Self-tolerance Four major mechanisms are responsible for tolerance to self: clonal deletion, clonal anergy, clonal ignorance and active regulation. Clonal deletion Clonal deletion occurs when immature lymphocytes first express their clonal receptors in primary lymphoid organs (T lymphocytes in the thymus, B lymphocytes in the bone marrow), and continues with lymphopoiesis throughout life. Antigen-specific receptors interact with self antigens, then delivering a signal that results in programmed cell death, or apoptosis. Clonal deletion depends on the presence of self antigens, which must be at tolerogenic concentrations, and also on the functioning of the apoptotic machinery within the lymphocyte. This process is regulated so as to ensure the timely death of the lymphocyte following encounters with self antigen. Selfreactive clones with high-affinity receptors are generally more likely to be clonally deleted than those expressing low affinity for self. While clonal deletion of autoreactive lymphocytes is clearly important in self-tolerance, there are many examples where autoreactive T and B lymphocytes survive in the periphery. ENCYCLOPEDIA OF LIFE SCIENCES © 2001, John Wiley & Sons, Ltd. www.els.net 1 Autoimmune Disease Table 1 Criteria for human autoimmune disease 1. Direct evidence (A) Circulating autoantibodies producing dysfunction (i) Damage to the target cell (ii) Stimulation or inhibition of a receptor (iii) Interaction with an enzyme or hormone (B) Antibodies localized to the lesion (i) Evidence of immunoglobulin and/or complement components at site of lesion (ii) Antibodies can be eluted from lesions (iii) Lesions may be represented by immunoglobulin eluates (C) Immune complexes localized to site of lesion (i) Elution of antigen–antibody complex (ii) Antigen identification (D) Passive transfer reproduction of disease (i) Maternal–fetal passive transfer (ii) Transfer to experimental animals (iii) In vitro injury to target cell demonstrable (E) T-cell mediated (i) T lymphocytes proliferate in vitro in response to self antigen (ii) Xenotransplantation of human target tissue plus sensitized T lymphocytes to immunodeficient mice. (iii) Target tissues cocultured in vitro with sensitized T cells – in vitro cytotoxicity 2. Indirect evidence (A) Reproduction by experimental immunization of autoimmune disease (i) Need to identify and utilize initiating antigen (ii) Immunization with appropriate susceptible syngeneic host with analogous antigen (iii) Characteristic lesions should be demonstrable (iv) Autoantibodies or T cells react with the same antigen or epitope (B) Spontaneous models in animals (i) Identification of disease in an animal species (ii) Selection and breeding to increase frequency of disease (iii) Production of self-reactive T lymphocytes and autoantibodies (iv) Passive transfer and adoptive transfer of condition to syngeneic recipients (C) Animal models produced by manipulation of immune system (i) Neonatal thymectomy, with or without radiation (ii) Homologous inbred animals deficient in cytokines (iii) Transgenic animals with altered antigen expression, cytokine production or costimulatory factor expression 3. Circumstantial evidence (A) Association with other autoimmune diseases (B) Presence of autoantibodies (C) Association with major histocompatibility complex haplotype (D) Infiltration of lymphocytes in target organ (i) Germinal centres in the lesions (ii) Infiltrating lymphocytes show restricted V gene usage (E) Favourable response to immunosuppression (specific, nonspecific) Adapted with permission from Rose NR (1996) Foreword – the use of autoantibodies. In: Shoenfeld Y and Peter JB (eds) Autoantibodies, p. xxiv. Amsterdam: Elsevier. Clonal anergy The second mechanism for maintaining tolerance is that of clonal anergy, which refers to a state of specific functional unresponsiveness. In contrast to clonal deletion, anergy does not lead to apoptosis, but rather results in a temporary dysfunction of reactivity to antigens. Anergy in both B and T lymphocytes contributes to self-tolerance. 2 In the case of helper T lymphocytes, the induction of anergy may be dependent on the signals they receive. Professional APCs activate T lymphocytes by providing two signals: (1) an antigen-specific signal through the interaction of major histocompatibility complex (MHC) class II molecule–peptide complexes and T-cell receptors (TCRs), and (2) an activating costimulatory signal which is also necessary for activation. Signalling through the TCR Autoimmune Disease alone induces a state of anergy, or unresponsiveness. Professional APCs such as macrophages, dendritic cells, B lymphocytes and Langerhans cells express costimulatory molecules such as CD80–CD86 on their surface, and can provide a costimulatory signal to T lymphocytes. In contrast, most nonhaematopoietic cells in the tissues, such as epithelial cells, do not express these molecules on their surfaces even when they are stimulated by interferon g (IFNg) to induce the expression of MHC class II molecules. These cells are termed nonprofessional APCs and cannot provide a costimulatory signal, thus inducing anergy on T lymphocytes. This two-signal model for Tlymphocyte activation may explain the observation that T lymphocytes are tolerant or unresponsive to self (or foreign) antigen presented on peripheral tissue. Another mechanism for inducing anergy in T lymphocytes is that of a lack of proliferation signals provided by interleukin (IL) 2, IL-4 and IL-7 when T lymphocytes are stimulated with both antigen-specific and costimulatory signals. Clonal ignorance The third mechanism, clonal ignorance, refers to the state in which certain autoantigens appear to be undetected by the immune system under normal circumstances. Neither clonal deletion nor anergy, nor stimulation of the lymphocytes, occurs in this situation. The explanation may be that the antigens are sparse, or normally sequestered from the immune system, or not presented with appropriate costimulation. Clonal ignorance may be overcome if these factors change. Active regulation The fourth mechanism, active regulation, represents a concept that has been revived and clarified. One recently developed theory approaches the problem of the control of self-reactivity from the angle of a balance between two mutually antagonistic T-helper (TH) subsets characterized by the cytokines they secrete (TH1 cells secrete IL-2 and IFNg, whereas TH2 cells secrete IL-4, IL-5 and IL-10). According to this theory, failure of a target organ should be viewed as caused predominantly by TH1-mediated pathways in which the target cells are destroyed by IFNgactivated scavenger macrophages; the macrophages are very important in this concept. The TH1–TH2 balance theory emphasizes the reciprocal relation between the TH1 and TH2 pathways, and suggests that if the TH1 pathway is diverted into the TH2 pathway the autoimmune reactivity is dampened. That is, tolerance to self is not restored, but the harmful reaction to self is diverted to a less harmful or benign one. However, this model may be too simplistic, since regulatory T-lymphocyte populations other than TH2 cells exist, including TH3 cells which secrete the inhibitory cytokine transforming growth factor b. Controversy surrounds the question as to whether antigen-specific suppressor T lymphocytes exist as a distinct subpopulation. Possible Aetiologies for Autoimmune Diseases It is now clear that autoimmune diseases result from the interaction of multiple factors which either determine susceptibility to disease or trigger autoimmune responses. Immunogenetics of Autoimmune Diseases There appears to be a genetic contribution in most, if not all, of the autoimmune diseases. The prevalence of a given autoimmune disease may vary widely between different ethnic groups (e.g. insulin-dependent diabetes mellitus (IDDM) is much more rare in Japanese people than in Caucasians), suggesting different genetic contributions. A family history of the disease in question may indicate a genetic element, but a common environmental factor could also be involved. If a given condition provides a family history suggestive of mendelian inheritance, a genome search might confirm a genetic contribution. Studies of identical (monozygotic) twins have demonstrated that many autoimmune diseases (e.g. IDDM, Graves disease) are present in both twins more often than the expected disease prevalence. Such studies are particularly useful when the twins have been separated, as environmental factors can thus be ruled out. Since the concordance rate in twins for an autoimmune disease does not approach 100% (usually about 50%), this indicates that the penetrance and expressivity of the gene will vary widely, assuming that there is no genetic heterogeneity. At a more fundamental level, human leucocyte antigen (HLA) haplotypes show clear associations with many of the autoimmune diseases. The genes that code for the restriction elements of the immune system are located in a cluster on the short arm of chromosome 6, designated the MHC; this encompasses the HLA system in humans. Distinction should be made between the three major classes of MHC factors: class I antigens are membranebound surface molecules present on most cells of the body; class II antigens are biochemically different cell surface molecules found only on certain cell types; and class III factors comprise some of the components of the complement cascade. MHC expression is essential for antigen presentation and immune responses. Both class I and II molecules bind processed antigenic peptides and present them to T lymphocytes. Class II factors have had the closest correlation with many of the autoimmune disorders (see Table 2). Persons possessing certain class II HLA haplotypes have an increased risk of developing certain autoimmune diseases, probably via abnormal antigen 3 Autoimmune Disease Table 2 Associations between human leucocyte antigen (HLA) haplotypes and some autoimmune disorders Frequency (%) Condition Autoimmune Addison disease Graves disease Insulin-dependent diabetes Myasthenia gravis Sjögren syndrome Atrophic thyroiditis Goitrous thyroiditis Pernicious anaemia Ankylosing spondylitis Reiter syndrome Disseminated lupus erythematosus Rheumatoid arthritis * HLA D/DR3 D/DR3 D/DR3 D/DR4 D/DR2 D/DR3 D/DR3 DR3 DR5 Dw5 B27 B27 DR3 Dw4 Patients 69 56 56 75 10 50 78 64 53 25 79–100 65–100 56 38–65 Controls 26.3 26.3 28.2 32.2 30.5 28.2 26.3 23.8 26.3 5.8 4–13 4–14 28.2 18–31 Relative risk* 6.3 3.7 3.3 6.4 0.2 2.5 9.7 5.7 3.1 5.4 90 36 3.7 4.4 Indicates how many times more frequently the disease develops in individuals carrying the HLA antigen, compared with the frequency of the disease in individuals lacking the antigen. The data refer exclusively to Caucasians. Adapted with permission from Svegaard et al. (1996). In: Volpé R (ed.) Autoimmunity in Endocrine Disease, p.93. New York: Marcel Dekker. presentation. However, in most instances these genes confer only weak susceptibility, making it evident that other genes must be involved. The two approaches used to study susceptibility genes of complex diseases are association and linkage analyses. Association studies are performed most simply by comparing the frequency of the specific phenotype of the marker studied (e.g. HLA DR3) in patients having the disease in question, with the frequency of that marker in an ethnically similar disease-free population. However, linkage studies are more effective in analysing disease-related genes because they are capable of detecting genes that are required (but not necessarily sufficient) for the development of the disease. Linkage analysis relates to the observation that, if two genes are close together on a chromosome, they will tend to segregate together. Thus, if a marker is near to a disease-related gene, it will cosegregate with the disease in families. The value of linkage analysis is that it identifies genes that are necessary for disease expression. Linkage analysis is expressed as a lod score (i.e. the measure of the probability of linkage between a disease and a genetic marker). Still another approach comes from the Human Genome Program, which has been extremely useful for identifying genes for diseases that have a simple mendelian genetic basis. Individuals in suitable families are ‘typed’ using a ‘genome screen’ of genetic markers (microsatellites) covering the entire genome, and it is then determined which markers segregate with the disease. However, autoimmune diseases do not follow simple mendelian rules, and represent more complex inherited conditions; only recently have microsatellites proved also to be useful in studying such disorders as these. Practically, microsatellites are 4 regions in the genome that are composed of repetitive sequences. Microsatellites are abundant and uniformly distributed throughout the genome at distances of less than one million base pairs. Thus, microsatellites can act as markers in linkage studies in the search for unknown disease susceptibility genes. The suspected gene region can then be further defined and refined by means of denser markers and cloning techniques, with the ultimate objective of identifying the appropriate gene. Using these techniques, it has been demonstrated that the HLA-related gene region provides an important contribution to the genetic susceptibility of many but not all of the autoimmune diseases, but this varies from disease to disease; in some conditions, the contribution is minimal, and these genes may confer only a modulating effect on disease development in such cases. Non-HLA genes may also be important, exemplified by the association between inherited defects in complement proteins and particular autoimmune diseases. Other candidate genes for the various autoimmune diseases are currently being sought, primarily through whole genome screening using microsatellites. Data from such studies suggest that the genetic susceptibility to many of the autoimmune diseases is probably influenced by shared alleles at several unlinked loci across the genome. The identification of the responsible genes at these foci remains to be accomplished. Other predisposing factors The increased prevalence of many autoimmune diseases often observed in women suggests that female hormones predispose to autoimmunity, and this view is supported by Autoimmune Disease experimental evidence in animal models that oestrogens can exacerbate disease, while testosterone is protective. The question of whether immune dysregulation is the primary abnormality in autoimmune disease remains unanswered. Ageing in humans and in animals is often associated with autoimmune phenomena such as increased autoantibody levels, and some autoimmune diseases show increased clinical expression with ageing (e.g. Hashimoto thyroiditis); in other instances, the presence of autoantibodies alone may not reflect clinical disease. A number of autoimmune diseases are also associated with concurrent neoplastic conditions, but it is unclear whether neoplasia may cause immune dysregulation and so predispose to autoimmunity, or whether both diseases may have a common aetiology. Factors that induce autoimmune disease It is clear that, even in individuals with the appropriate predisposition to autoimmunity, environmental factors are necessary to trigger disease. The importance of such factors is demonstrated by the finding that the concordance rate for autoimmune conditions in human monozygotic twins, although high, does not approach 100%. A variety of hypotheses have been put forward to explain the onset of autoimmune disease, but most of the proposed mechanisms are dependent on the activation of autoreactive T and/or B lymphocytes that have escaped deletion and are normally clonally ignorant or anergic. Infectious agents are commonly implicated. The possible mechanisms by which infectious agents may provoke autoimmunity are diverse and include antigenic cross-reactivity between the microorganisms and the host tissues, the production of microbial superantigens that stimulate T lymphocytes expressing particular receptor genes, direct infection of immune cells, deviation of the balance between T-helper subsets towards TH1, exposure of autoreactive lymphocytes to costimulatory signals or inflammatory cytokines, and presentation of previously hidden autoantigenic epitopes. Particular drugs are also associated with autoimmune disease. Other environmental factors include stress, trauma, smoking and nutritional factors which tend to downregulate the immune system. antibodies or specifically sensitized T lymphocytes are directed against components of different organs of a given host. Examples of this type of autoimmune disease would be disseminated lupus erythematosus (DLE) and rheumatoid arthritis. In such cases, it is unclear whether the immune system is responding to several antigens or whether the immune response is more restricted, responding to common antigenic determinants present in the different organs. The autoimmune polyglandular endocrine failure group of diseases should be considered, not as examples of nonorgan-specific autoimmune disease, but rather as examples of multiple organ-specific disease, as it is clear that the target-cell antigens involved are quite different from one another, hence the antibodies are likewise separate. Major Autoimmune Diseases Organ-specific autoimmune diseases A brief description will follow for a few of the main examples of this group, categorized by organ or system. Endocrine system The autoimmune diseases of the endocrine system include Graves disease (autoimmune hyperthyroidism), Hashimoto (autoimmune) thyroiditis, IDDM, autoimmune Addison disease (adrenocortical failure), hypoparathyroidism, autoimmune hypophysitis and autoimmune gonadal failure. These entities may occur singly, or more than one condition may appear in one individual or one family. This appears to be due to genetic overlap, as it cannot be accounted for by antigenic overlap in most instances; indeed the antigens in the different glands are not homologous. These disorders may also be associated with organ-specific autoimmune diseases outside the endocrine system, such as myasthenia gravis, pernicious anaemia, vitiligo, alopecia areata, autoimmune hepatitis, primary biliary cirrhosis, idiopathic thrombocytopenic purpura and others. Some of the major autoimmune endocrinopathies will be more fully described below. Graves disease Classification of Autoimmune Diseases Autoimmune diseases may arise spontaneously in animals and humans, and several experimental models have been induced in animals. This account focuses on spontaneous disorders in humans, which may be divided into organspecific and nonorgan-specific autoimmune diseases. In the former, antibodies or specifically sensitized T lymphocytes are directed against a component or components of one organ of a given host. In nonorgan-specific conditions, Graves disease is the commonest form of hyperthyroidism (overactive thyroid). It is mediated by an antibody directed against the thyroid-stimulating hormone (TSH) receptor on the thyroid cells, which acts as an agonist for TSH, thus stimulating the thyroid cells to hyperactivity. Mild to moderate lymphocytic infiltration is seen in the hyperplastic thyroid gland. The eyes are frequently involved with an autoimmune inflammatory reaction as well (Graves ophthalmopathy), the nature of which is still not understood. Patients are very nervous, lose weight, have a rapid 5 Autoimmune Disease heart beat, sweating, weakness and tremor. Graves disease can be treated with medication that suppresses the thyroid, or with thyroid ablation with radioactive iodine or surgery. Hashimoto (autoimmune) thyroiditis This condition is characterized by marked lymphocytic infiltration of the thyroid gland, often with lymphoid follicles and variable fibrosis. Thyroid enlargement (goitre) is common. Thyroid cell damage is largely due to the action of T lymphocytes (possibly directed against thyroperoxidase and thyroglobulin), and is the commonest form of spontaneous hypothyroidism. Antibodies to thyroperoxidase and thyroglobulin are usually found in the circulation, and correlate with, but do not cause, the thyroid cell damage. Antibodies to the TSH receptor which interfere with TSH binding and action may be associated with hypothyroidism in some cases of atrophic thyroiditis. Insulin-dependent diabetes mellitus IDDM is secondary to lymphocytic infiltration of pancreatic islets, with T lymphocyte-mediated damage directed specifically to b cells (which produce insulin). Several candidate antigens are present within the b cells, with glutamic acid decarboxylase (GAD) most strongly suspected. Destruction of over 80% of the b cells (which may take years) is necessary before the production of insulin becomes inadequate, blood glucose rises, and diabetes is initiated. Antibodies to GAD and other islet cell antigens act as markers for IDDM. Autoimmune adrenocortical failure (Addison disease) Autoimmune destruction of the adrenal cortices is mediated by T lymphocytes, probably directed against 17-a and 21-hydroxylase. Antibodies against these enzymes act as markers for this condition, which is frequently associated with other autoimmune diseases in the syndrome of autoimmune polyendocrine failure. When damage is severe, inadequate cortisol and aldosterone concentrations are produced, with dire consequences of sodium loss, hypotension, hypoglycaemia and weight loss. Haematopoietic disorders Autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura and autoimmune neutropenia are caused by autoantibody binding to erythrocytes, platelets and neutrophils, respectively. The target cells are destroyed by phagocytic macrophages and/or by complement-mediated lysis. Gastrointestinal disorders Pernicious anaemia is due to an immune reaction directed against gastric parietal cells, resulting in reduced absorption of vitamin B12, in turn leading to macrocytic anaemia and a neurological condition (i.e. subacute combined degeneration of the spinal cord). Antibodies to the parietal 6 cells act as a marker for the disease. Other probable autoimmune conditions of the gastrointestinal tract (e.g. autoimmune sprue, Crohn disease, ulcerative colitis, autoimmune hepatitis and primary biliary cirrhosis) are not discussed further here. Neuromuscular diseases Myasthenia gravis is an uncommon neuromuscular disease, characterized by progressive muscular weakness with muscular activity. This is another antibody-mediated disease, in which the antibody is directed against acetylcholine receptors at the neuromuscular junction, blocking the reception of impulses normally initiated at the acetylcholine receptor by acetylcholine. Several patients with this disorder also have thymic hyperplasia or even thymomas. Neurological disease Multiple sclerosis involves demyelinization of central nervous tissue, leading to a relapsing–remitting or a chronic progressive paralytic course. While the pathogenesis is incompletely understood, available evidence indicates that it is a T-cell disease, with an association with HLA-DR2. Eye Diseases specific to the eye which are considered to be of autoimmune origin include various forms of uveitis, sympathetic ophthalmia and Sjögren syndrome (keratoconjunctivitis sicca). The eye may also be involved in systemic (nonorgan-specific) autoimmune disease, such as rheumatoid arthritis, DLE, ankylosing spondylitis and Reiter syndrome. Sjögren syndrome is most common with rheumatoid arthritis. Involvement of the lachrymal and salivary glands leads to dryness of the eyes and mouth. Heart Rheumatic heart disease, with valvular damage, can be considered an autoimmune disease, although the inciting antigen clearly appears to be of bacterial origin, namely Streptococcus haemolyticus. Cross-reactivity with multiple cardiac antigens appears to explain the involvement of the heart. Other conditions with a probable autoimmune basis include idiopathic cardiomyopathy and endomyocardial fibrosis. The heart can also be affected in nonorgan-specific systemic autoimmune diseases, such as DLE and rheumatoid arthritis. Skin Bullous pemphigus and dermatitis herpetiformis are serious skin eruptions, the former with bullae and the latter with vesicular rashes, both due to autoimmune processes. The skin, like the heart, can also be involved in systemic autoimmune disorders, such as DLE, rheumatoid arthritis, polyarteritis nodosa and scleroderma. Vitiligo, an autoimmune disorder of the skin in which the melanocytes Autoimmune Disease are the immune target, causes patches of skin depigmentation and is associated with autoimmune thyroid disease in 20% of cases. Kidney Goodpasture disease is caused by autoantibodies specific for type IV collagen in the kidney glomerular basement membrane. Nonorgan-specific autoimmune disease Examples of nonorgan-specific autoimmune diseases include DLE, rheumatoid arthritis, polyarteritis nodosa, ankylosing spondylitis and, possibly, scleroderma. Only the first two are discussed here. Disseminated lupus erythematosus DLE attacks many organs of the body, causing a butterfly rash across the bridge of the nose, with fever, joint pains, central nervous system damage, heart damage, thrombocytopenia and kidney damage. The latter can be the most serious complication of this disease. In this condition, antibodies are produced against several nuclear components of cells, most notably against native double-stranded deoxyribonucleic acid (DNA). Occasionally, antibodies are also produced against denatured, single-stranded DNA, and against nucleohistones. These various antibodies are believed to form circulating soluble complexes with DNA derived from the breakdown of normal tissue such as skin. These soluble complexes are filtered from the blood by the kidneys, and thus become trapped against the basement membrane of the glomeruli where they may form characteristic irregular deposits, leading to inflammation (glomerulonephritis) and loss of protein from the kidneys (proteinuria). Similar deposits may also be seen in arteriolar walls and synovial spaces of the joints. Many other tissues can be affected in this condition, as noted above, and may lead to very serious complications and death. Several possible inciting factors have been suspected, including bacteria and drugs. The disease may run a course of remissions and exacerbations over years. Rheumatoid arthritis This is a chronic systemic disease in which joint manifestations are most dominant, although the condition may also involve the eyes, skin, heart and intestinal tract. The joint synovium is inflamed and densely infiltrated with lymphocytes, plasma cells, dendritic cells and macrophages. Lymphoid follicles may also be seen. Various immune elements participate in this disorder, including T lymphocytes, complement, antigen–antibody complexes, cytokines, enzymes and mediators, leading to the destruction of joint cartilage, with further exposure of the cartilagenous cells to the immune system, leading to perpetuation of the disease. The inflammation is characterized by rheumatoid factor, an abnormally produced IgM antibody, which is directed against a determinant on the Fc portion of the patient IgG molecules. Rheumatoid factor–IgG complexes may deposit in the joint synovia, contributing to the activation of the complement cascade, which releases chemotactic factors, in turn attracting inflammatory neutrophils. It is also thought that autoreactive T lymphocytes may have an important role in driving the inflammation. The joints may ultimately be destroyed by this process. Generally, other tissues are not as seriously involved. Further Reading Gill RG and Haskins K (1993) Molecular mechanisms underlying diabetes and other autoimmune diseases. Immunology Today 14(2): 49–51. Iwatani Y, Amino N and Miyai K (1989) Peripheral self-tolerance and autoimmunity: the protective role of expression of class II histocompatibility antigens on non-lymphoid cells. Biomedicine Pharmacotherapy 43: 593–605. Nepom GT and Erlich H (1991) MHC class II molecules and autoimmunity. Annual Review of Immunology 9: 493–525. Ott J (1996) Analysis of Human Genetic Linkage. Baltimore: Johns Hopkins University Press. Shoenfeld Y and Peters JB (1996) Autoantibodies. Amsterdam: Elsevier. Theofilopoulos AN (1995) The basis of autoimmunity. Immunology Today 16: 90–98 (Part I), 150–159 (Part II). Tomer Y, Barbesino G, Greenberg D and Davies TF (1997) The immunogenetics of autoimmune diabetes and autoimmune thyroid disease. Trends in Endocrinology and Metabolism 8: 63–70. Volpé R (1999) Autoimmune Endocrinopathies. Contemporary Endocrinology Series. New Jersey: Totowa, Humana Press. Weber JL (1990) Human DNA polymorphisms based on length variations in single sequence tandem repeats. Genome Analysis 1: 159–181. Zouali M, Kalsi J and Isenberg D (1993) Autoimmune diseases – at the molecular level. Immunology Today 14(10): 473–476. 7