Bachelor of Chinese Medicine ( ) AUTOIMMUNE DISEASES

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1 Bachelor of Chinese Medicine ( ) BCM II Dr. EYT Chan February 6, :30 am 1:00 pm Rm 134 UPB AUTOIMMUNE DISEASES 1. Introduction Diseases may be the consequence of an aberrant immune response, directed against self antigens. This was foreseen by Ehrlich at the beginning of this century, who put forward the concept of horror autotoxicus. Autoimmune response, however, does not always result in disease manifestation. The occurrence of autoantibodies (pathogenetic or non-pathogenetic) in perfectly healthy individuals is one example. Moreover, when autoimmune response and manifestations of a given disease occur together they do not necessarily imply a causal relationship. For example, a virus might independently provoke an autoimmune response and the lesions of a disease. Alternatively, the disease process itself may release self molecules which provoke an autoantibody response secondarily. It is only when the autoimmune process itself appears to be primarily responsible for producing the disease, that we speak of an autoimmune disease as such. 2. Self tolerance and autoimmunity The mechanisms of self tolerance include Clonal deletion: auto-reactive cells deleted early in development within the primary organs Clonal anergy: mature lymphocytes leave the primary organs but become functionally unresponsive (tolerized) to self molecules Sequestrated antigen: anatomically isolated and precluded from contact with lymphocytes T suppressor cells: nature and existence of these cells now becomes controversial, although suppressive activity is quite Autoimmunity is a result of breakdown of these normal control mechanisms. For example, a defect in the generation of non-specific Ts cells is found in unaffected relatives of SLE patients. Many cell types can be induced to express MHC class II molecules following stimulation with interferon-?. MHC class II is essential for antigen presentation to CD4 + T cells. Release of sequestrated antigens may occur after trauma (e.g. to the eye). Self-reactive lymphocytes may be stimulated by crossreacting microbial antigen which has peptide sequences in common with the autoantigen. 1

2 3. Th1 and Th2 CD4 + T cells in the Pathogenesis of Autoimmune Diseases Functional subsets of Th (CD4 + ) cells are first identified by in vitro analysis of murine T cell clones. There is now strong evidence for similar subsets in vivo in mice, rats and human. Three subsets are identified according to the profile of cytokines each produces - Th1, Th2, Th0. Th1 cells secrete IL-2, IFN?, TNF which are found to support macrophage activation, DTH response. Th2 cells secrete IL-4, IL-5, IL-6, IL-10 and IL-13 which provide efficient help for B cell activation, antibody production and switch to IgG1 and IgE isotypes. Th0 cells produce cytokines of both Th1 and Th2 types and are the precursors of Th1 and Th2 cells. Factors influencing differentiation of naive Th cells into specific subsets include cytokines (most important), type of antigen-presenting cell, MHC class II haplotype. For example IFNgamma inhibits differentiation and effector functions of Th2, lead to dominant Th1 response. IL-12 (produced by APC) drives differentiation of Th1 cells, partly through its induction of IFNgamma. IL-4 directs development of Th2 cells. IL- 4, Il-10 and IL-13 inhibit Th1 proliferation and oppose the effects of IFNgamma on macrophages. Therefore, reciprocal regulation occurs between Th1 and Th2 subsets. It is postulated that Th1 cells have a pathogenic role in autoimmune disease and Th2 cells a protective role. This refers mainly to T cell mediated autoimmune diseases e.g. experimental autoimmune encephalo-myelitis (EAE), insulin-dependent diabetes mellitus (IDDM). EAE is an inflammatory autoimmune disease of the CNS and is an animal model of multiple sclerosis. There is strong evidence that Th1 cells are important in the initiation of the disease process and data also (e.g. in situ expression of cytokine mrna during recovery) suggested that Th2 inhibit encephalitogenic CD4 cells 4. Autoimmune diseases are multifactorial The factors which lead to the development of autoimmune disease are varied, and include (1) familial and genetic factors, in particular those concerned with the genetic control of the immune response, and (2) hormonal and environmental factors, e.g. trauma, infections, drugs. Genetic: There is a close association between susceptibility to autoimmune disease and certain HLA allotypes, especially among the class II antigens. Family members of patients with certain autoimmune diseases have a definitely higher incidence of the same or a related disease. Hormonal: Many autoimmune diseases are more common in females, and in experimental animal models of autoimmunity the administration of male sex hormones to females retards the development of the disease process. Some autoimmune diseases are preceded by infection or exacerbated following infections. In a few, the relationship is well established, e.g. rheumatic heart disease 2

3 and streptococcal infection. In others there is an association of the disease with high titres of antibodies to a particular organism, implying a recent infection, eg. increased antibodies to ECHO virus have been described in insulin-dependent diabetes mellitus. Some drugs (penicillamine, hydrallazine, methyldopa, etc.) can induce states of autoimmunity in some patients. All the contributory factors act to break the tolerance of the individual s immune system to self-antigens. 5. The spectrum of autoimmune disease Autoimmune disorders are classified broadly as organ specific and non-organ specific. In the former, a particular organ is the site of the autoimmune process and of the disease. These involve most endocrine organs and a number of other organs or tissues. In non-organ specific diseases, the autoimmune process is directed against widely distributed antigens, eg. nuclei and mitochondria, and the mechanisms by which the disease occurs and affects the tissues and organs concerned are not always clear. Most non-organ specific autoimmune diseases are systemic but commonly involve skin, kidney, joint and muscles. Examples of primarily organ-specific diseases: haematological: autoimmune haemolytic anaemia autoimmune thrombocytopenia dermatological: pemphigus vulgaris bullous pemphigoid endocrine: autoimmune thyroiditis (Hashimoto's, Grave's, primary myxoedema) type I diabetes primary Addison's disease neurological: myasthenia gravis Examples of non-organ specific diseases: rheumatoid arthritis systemic lupus erythematosus Wegener's granulomatosus Overlap syndromes are not uncommon in both groups of diseases. For example, thyroid antibodies occur with a high frequency in patients with pernicious anaemia, and these patients have a higher incidence of thyroid autoimmune disease than the normal population. Features of rheumatoid arthritis are often associated with the clinical picture of SLE. 6. Pathogenesis There are 3 general mechanisms in pathogenesis of autoimmune diseases: 3

4 a. interaction of antibodies with cell surface components (eg. in myasthenia gravis, antibodies bind to and destroy acetylcholine receptors). This mechanism operates more often in organ specific autoimmune diseases. b. formation of autoantigen-autoantibody complexes in fluids with deposition and hence inflammation in tissue (eg. immune complex mediated glomerulonephritis in SLE). Immune complexes deposition is more often in non-organ specific autoimmune diseases. c. sensitisation of T cells which damage tissue (eg. the lymphocyte infiltrate associated with Hashimoto s thyroiditis). 7. Clinical features The clinical consequences of autoimmunity are varied. In autoimmune thyroiditis, the thyroid gland may undergo infiltration and hypertrophy without significantly affecting overall thyroid function (euthyroid stage of Hashimoto's thyroiditis) or it may be stimulated to overactivity as a consequence of antibodies directed against the TSH receptor on the surface of thyrocytes, which mimic the action of TSH (producing Grave's disease). Alternatively, the gland may become atrophic due to the cytotoxic action of the immune response, leading to myxoedema. In fact, autoimmune processes leading to specific damage and loss of function of the organ or tissue concerned occur in most organ-specific diseases. In autoimmune haemolytic anaemia and thrombocytopenia, autoantibodies to the cell surface antigens lead to damage and sequestration of the cells. In Goodpasture's syndrome, autoantibodies to the basement membrane antigens of the renal glomeruli and lung alveoli lead to damage, with nephritis and pulmonary haemorrhage. In myasthenia gravis, antibodies to acetylcholine receptors impair neuromuscular transmission, causing the weakness and fatiguability characteristic of the disease. In non-organ specific disease, the way in which the autoimmune process results in disease is often unclear. Autoantibodies formed may not be pathogenic but often are useful as a diagnostic marker of the disease concerned. In some instances (although in most cases not) they can be used to monitor progress or treatment. Such diseases include rheumatoid arthritis, systemic lupus erythematosus and many of the so-called connective tissue diseases, as well as some vasculitic disorders. They are characterised by particular patterns of autoantibodies to antigens widely dispersed throughout the body. 8. Laboratory investigations With very few exceptions, laboratory investigations should be based on clinical suspicions. Routine screenings without any specific indications are usually fruitless. No laboratory test can give an absolute answer. The person who requests a test has to know how far the test result can help in clinical management. Most laboratory tests are used in diagnosis of diesases. A laboratory test is said to be sensitive in the diagnosis of a certain disease if it is positive in most cases of the 4

5 disease. A test is said to be specific if it is positive only that particular disease. Some laboratory tests are useful in monitoring disease. For example, the anti-dsdna antibody level increases with SLE disease activity while C3 and C4 levels decrease with SLE disease activity. Autoantibodies may also have a predictive value. For example, siblings of a child with insulin dependent diabetes who share an HLA haplotype should be monitored by antiislet cell antibody. Presence of this antibody in the unaffected sibs is an indication to later development of diabetes. 9. Therapy For autoimmune endocrine disorders, the immunological process is seldom apparent until sufficient damage has occurred to impair the function of the gland, hence most patients present with glandular dysfunction. By this time the immune process is usually burnt out and treatment is largely by pharmacological agents which reduce the function of the gland (in overactivity states) or replacement hormones in states of hypofunction (myxoedema, diabetes, Addison's disease...) Most other autoimmune disorders wax and wane and are subject to natural remissions and exacerbations. Treatment is mainly aimed at ameliorating the effects of the immunological reactions by anti-inflammatory agents, usually corticosteroids, until a period of natural remission occurs. In severe cases, immunosuppressive therapy to dampen down the aberrant immune response is needed, although it brings the attendant hazards of secondary immunodeficiency. 5