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Dr. Yong-Sun Kim Oct. 31, 2001 Autoimmune Diseases The adult host usually exhibits tolerance to tissue antigens present during fetal life that are recognized as “self”. However, in certain circumstances tolerance may be lost and immune reactions may develop to host antigens, resulting in autoimmune diseases. Various bacteria, viruses, and drugs are implicated as the source of cross-reacting antigens that trigger the activation of autoreactive T cells or B cells. For example, Reiter’s syndrome is associated with outbreaks of Shigella dysentery, and systemic lupus erythematosus is associated with the use of the drug procainamide. The concept of “molecular mimicry” is used to explain these phenomena; ie, the environmental trigger resembles (mimics) a component of the body sufficiently that an immune attack is directed against the cross-reacting body component. One of the best-characterized examples of molecular mimicry is the relationship between the M protein of Streptococcus pyogenes and the myosin of cardiac muscle. Antibodies against certain M proteins cross-reactions can be involved, but most are antibody-mediated. Many autoimmune diseases exhibit a marked familial incidence, which suggests a genetic predisposition to these disorders. There is a strong association of some diseases with certain human leukocyte antigen (HLA) specificities, especially the class II genes. For example, rheumatoid arthritis occurs predominantly in individuals carrying the HLADR4 gene. It should be noted, however, that whether a person develops an autoimmune disease or not is clearly multifactorial, because people with HLA genes known to predispose to certain autoimmune diseases nevertheless do not develop the rheumatoid arthritis. That is to say, HLA genes appear to be necessary but not sufficient to cause autoimmune diseases. In general, class II MHC-related diseases occur more commonly in women, eg, rheumatoid arthritis, Graves’s disease (hyperthyroidism), and systemic lupus erythematosus, whereas class I MHC-related diseases occur more commonly in men, eg, ankylosing spondylitis and Reither’s syndrome. In summary, the current model is that autoimmune diseases occur in people (1) with a genetic predisposition that is determined by their MHC genes and (2) who are exposed to an environmental agent which triggers a cross-reacting immune response against some component of normal tissue. 1 Dr. Yong-Sun Kim Oct. 31, 2001 Mechanisms The following mechanisms for autoimmunity have been proposed. A. Release of Sequestered Antigens : Certain tissues, eg, sperm, central nervous system, and the lens and uveal tract of the eye, are sequestered so that their antigens are not exposed to the immune system. When such antigens enter the circulation accidentally, eg, after damage, they elicit both humoral and cellular reponses, producing aspermatogenesis, encephalitis, or endophathalmitis, respectively. Sperm, in particular, must be in a sequestered, immunologically privileged site, because they develop after immunologic maturity has been reached. B. Escape of Tolerance at the T Cell Level : Unresponsiveness to a self antigen may be maintained by tolerance at the T cell level. Such tolerance may be terminated by cross-reactions, ie, when the host responds to antigens that crossreact with tolerated self antigens. For example, in rheumatic fever, antibodies against streptococcal antigens cross-react with heart tissue antigens. C. Diminished Suppressor T cell Function: In normal immune regulation, suppressor T cells may limit an immune response to self antigens. If suppressor T cell functions decrease, antibodies to self antigens, eg, an antibody to normal IgG, may be formed. Such antibody (IgM or IgG) occurs in rheumatoid arthritis, in which antigen-antibody complexes form in joints. Diseases Some examples of diseases that involve autoimmune reactions are described below. A. Allergic Encephalitis : This is due to cell-mediated response to the basic protein of brain myelin. For example, when animal brain substance mixed with adjuvant is injected into an animal of the same species, a demyelinating encephalitis develops. It resembles postvaccinal encephalitis seen in persons injected with older rabies vaccines made in rabbit brains. Rarely, it occurs following certain viral infections, eg, measles or influenza, or following immunizations against these viral infections. 2 Dr. Yong-Sun Kim Oct. 31, 2001 B. Chronic Thyroiditis : When animals are injected with thyroid gland material, they develop humoral and cellmediated immunity against thyroid antigens and a chronic thyroiditis. Humans with Hashimoto’s chronic thyroiditis have antibodies to thyroglobulin, suggesting that these antibodies may provoke an inflammatory process that leads to fibrosis of the gland. C. Rheumatic Fever : Group A streptococcal infections regularly precede the development of rheumatic fever. Cross-reactions occur between cell membrane antigens of streptococci and human heart muscle sarcolemma, which may play a causative role in disease. D. Hemolytic Anemias, Thrombocytopenias, and Granulocytopenias : Various forms of these disorders have been attributed to the attachment of autoantibodies to cell surfaces and subsequent cell destruction. Pernicious anemia is caused by an autoimmune reaction to intrinsic factor, a protein secreted by parietal cells of the stomach that facilitates the absorption of vitamin B12. Idiopathic thrombocytopenic purpura is due to antibody directed against platelets. E. Diabetes, Myasthenia Gravis, and Hyperthyroidism (Graves’ Disease) : In these diseases, antibodies to receptors play a pathogenic role. In extreme insulin resistance in diabetes, antibodies to insulin receptors have been demonstrated that interfere with insulin binding. In myasthemia gravis (a nervous system disease), antibodies to acetylcholine receptors of neuromuscular junctions are found in the serum. Some patients with Graves’ disease have circulation antibodies to thyrotropic receptors, which, when they bind to the receptor, resemble thyrotropin in activity and stimulate the thyroid to produce more thyroxine. F. Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, and Other Collage Vascular Disease : These disorders feature vasculitis and collagen degeneration plus a variety of focal inflammatory lesions and the presence of autoantibodies against many different self antigens. For example, antibodies to DNA are found in SLE and antibodies to IgG (rheumatoid factor) occur in rheumatoid arthritis. Complement levels are low, and the nephritis associated with these disorders is an immune-complex disease. Although the causes of these disorders are unknown, typical cases have followed sensitization by drugs, foreign proteins, and other immune stimuli. 3 Dr. Yong-Sun Kim Oct. 31, 2001 Other diseases in this category include ankylosing spondylitis, which is very common in people carrying the HLA-B27 gene; polymyositis-dermatomyositis; Sjögren’s syndrome; and Reiter’s syndrome. G. Reiter’s Syndrome : This syndrome is characterized by the triad of arthritis, conjunctivitis, and urethritis. Cultures of the affected areas do not reveal a causative agent. Infection by one of the intestinal pathogens, eg, Shigella, Salmonella, Yershinia, and Campylobacter, as well as other organisms such as Chlamydia, predisposes to the disease. Most patients are men who are HLA-B27-positive. The pathogenesis of the disease is unclear, but immune complexes may play a role. 4 Dr. Yong-Sun Kim Oct. 31, 2001 Table 1. Inducers of Autoimmune Diseases Inducer Mechanism Viral infection Virus integrates into host genome; Causes expression of altered cell-surface markers, polyclonal activation of B lymphocytes, etc. Drugs Binding of drug alters Ags and elicits immune response Antigen crossreaction Abs directed against infective agent (e.g., Treponema pallidum [in syphilis]), also react with normally expressed Ags on healthy cells (e.g., erythrocytes, causing their unintended autoimmune destruction) Expression of novel Antigenic determinants Newly exposed determinants in Fc region of Abs (IgG) can evoke immunological attack (e.g., attack by rheumatoid factor [IgM and IgG] against portions of certain IgGs) Table 2. Means Through Which the Immune Network Might Break Down in Autoimmune Diseases 5 Dr. Yong-Sun Kim Oct. 31, 2001 Production defects Modified expression Somatic mutation or alteration progenitor cells Thymus and bone marrow defects of lymphoid Contrasuppression of T cell function Enhanced TH activity Polyclonal B cell activation Breakdown in idiotype network Defects in macrophage function Breakdown in lymphokine release Abnormal gene expression Table 3. Mechanisms of Tissue Damage in Autoimmune Diseases Mechanism How Damage is induced Complement-fixing Abs Binding of complement to Ab attached to cell-surface Ag; causes cytolysis Ab binding to cell receptor* Binding of Ab to cell-surface receptor impairs normal function by blocking access of normal ligand to its receptor Immune-complex formation Formation of immune complexes between self-Ags and self-Abs trigger inflammatory reaction, which can damage local tissues TC cells Activation of TC cells against normal surface Ags leads to their destruction *This is considered a form of hypersensitivity (Type V) by some; see chapter 14 for further discussion. Table 4. Autoimmune Diseases Associated with Histocompatibility Antigens 6 Dr. Yong-Sun Kim Oct. 31, 2001 Antigen Disease Disease Risk* DR2 Goodpasture’s syndrome Multiple sclerosis 5 5 DR3 Juvenile-onset diabetes Graves’ disease Myasthenia gravis SLE 5 5 10 5 DR4 RA 10 DR5 Hashimoto’s thyroiditis 5 *Disease risk defines likehood of disease occurring when particular histocompatibility Ag is expressed, as compared with the general population at large, whose risk factor is assigned a value of 1. Table 5. Tests Used to Diagnose Autoimmune Diseases Test Autoantibody Detected Autoimmune Disease Coombs test Immunoprecipitation IF Antierythrocyte Ab Abs to Ach receptors Abs to islet cells Abs to myelin Abs to TSH receptors Anti-basal lamina Abs Abs to thyroglobulin Anti--globulin Ab Antinuclear Ab Autoimmune hemolytic anemia Myasthenia gravis Diabetes mellitus (juvenile) Multiple sclerosis Graves’ disease Goodpasture’s syndrome Hashimoto’s thyroiditis RA SLE RIA IF and RIA 7