Effector mechanisms

As to effector mechanisms, autoimmune diseases are no different from any other pathogenic immune response against foreign antigens involving reactions of types II (cytotoxic antibodies), III (immune complexes), IV (cellular-mediated immunity) and V (stimulating antibodies) according to the Gell/ Coombs nomenclature. Furthermore, antigen nonspecific mechanisms secondarily activated by auto-antigen-activated lymphocytes play an important pathogenetic role.

The role of autoantibodies

The detection of circulating and/or tissue-bound autoantibodies is undoubtedly one of the most consistent findings in autoimmune diseases in human and animal models. Although low levels of autoantibodies can be detected in healthy individuals, and, on the other hand, autoimmune diseases can exist without detectable autoantibodies, there is in general a good correlation between peripheral levels of autoantibody and activity of an autoimmune disease, whereby the spectrum of specificities may be characteristic, sometimes even diagnostic, for a particular autoimmune disease. There are several ways by which autoantibodies can be involved in the pathogenesis of autoimmune diseases:

• Tissue-specific autoantibodies may activate complement and lead to cytolysis of the target cell (type II), as is observed for example in spontaneous or drug-induced autoimmune lysis of red or white blood cells. In organ-specific diseases cytotoxic autoantibodies are thought to contribute to tissue destruction, e.g. in autoimmune diseases of endocrine glands, in Goodpasture's syndrome and in myasthenia gravis.

• The binding of autoantibodies to tissues leads to triggering of the natural immune system by attracting and activating Fc receptor and complement receptor bearing cells to phagocytosis, cytotoxicity and antibody-dependent cellular cytotoxicity. Furthermore, the amplification system of inflammatory mediators involving the clotting fibrinolysis and kallikerin-kinin systems can be induced by autoantibodies and complement via activation of factor XII.

• Autoantibodies specific for cell surface structures, e.g. hormone receptors, can stimulate or block the growth and functions of target cells. Stimulatory autoantibodies were first recognized in autoimmune disease of the thyroid gland being directed against the thyroid-stimulating hormone (TSH) receptor, blocking autoantibodies are found for example in myasthenia gravis, and bind specifically to the motor end-plate.

• Autoantibodies specific for soluble cell products can give rise to high levels of circulating immune complexes (type III reactions) causing inflammatory tissue damage at the sites of deposition as seen in both systemic and organ-restricted autoimmune diseases. The localization of immune complexes is dependent on hemorheological factors, Fc binding, and on nonspecific binding characteristics of certain tissues. Hence, an enhanced binding of DNA to basement membranes appears to be responsible for the characteristic deposition of DNA-anti-DNA complexes.

• Autoantibodies with specificity for the idiotype of autoantibodies have been detected in several auto immune diseases. Treatment with such autoanti-idiotypes has been shown to suppress spontaneous autoimmune disease in animal models, which points to the potential of these autoantibodies to control the course of an autoimmune disease. On the other hand, as anti-idiotype antibodies can mimic the primary antigen (i.e. autoantigen) auto-anti-idiotypes could enhance autoimmune disease by eliciting and/or perpetuating an autoimmune response.

The role of T cells

For a long time autoantibodies were thought to play the major role in autoimmune effector mechanisms. Results in both experimental and spontaneous animal models, however, revealed that autoreactive T lymphocytes are both necessary and often sufficient to cause autoimmune disease. This was shown for example in the obese strain of chickens afflicted with spontaneous Hashimoto-like thyroiditis, where eradication of the T cell system by neonatal thymectomy plus treatment with T cell-specific antibodies resulted in prevention of disease. On the other hand, it was shown that the disease could be effectively transferred to healthy recipients of the same genetic background by injection of autospecific thymocytes, or purified T cells derived from infiltrated thyroid glands of B cell-deprived (bursectomized) obese strain chickens. The dominance of the autoreactive T effector cell also emerged from the work on experimentally induced autoimmune diseases in rats and mice, where autoantigen-specific T cell lines could be developed that were instrumental in the study of the pathogenetic role of T cell immunity. Transfer of low numbers of viable autoreactive T cells induces vigorous autoimmune disease in several models. If such cells are growth arrested by irradiation prior to transfer, the recipient becomes protected against induction of the disease by immunization with the autoantigen. Taken together, these data clearly point to the fact that both the induction and effector phases of an autoimmune disease can primarily involve autoantigen-specific T lymphocytes. The appearance of autoantibody may often be secondary and have only a modulatory role in the disease.

As to the effector mechanisms by which autoreactive T cells mediate tissue damage, the evidence obtained suggests that it is mainly the CD44 Tnl phenotype (Tdth) that upon activation by autoantigen in the context of MHC class II molecules releases cytokines, such as IL-2, IFNy, TNFa/0 and others, and which by themselves or by activation of other specific (autoreactive CD8+ cells) and nonspecific (NK cells, macrophages) inflammatory cells destroy the target tissue. TH2 cells, as mentioned above, supposedly suppress TH1 effector cells, but, on the other hand, may exert helper functions to autoreactive B cells via IL-4, IL-5, IL-6, and may keep autoreactive T cells alive by IL-10, which - besides its immunosuppressive effects - prevents apoptosis.

Nonspecific mechanisms

Pathogenetic mechanisms of natural immunity were long ago recognized as important in autoimmune disease. This is confirmed by a number of more recent investigations showing the crucial roles of inflammatory monokines IL-ip, IL-6, and particularly of TNFa, as well as several chemokines in autoimmune tissue destruction. Furthermore, IL-12 produced by several professional antigen-presenting cells has been shown to be critical in the development of autoimmune disease, as it promotes the differentiation of Th1 cells. The essential role of the monocyte/macrophage series is further underscored by more recent findings in certain animal models, where autoimmune diseases were effectively controlled by antioxidants or by inhibition of nitric oxide synthesis. Until recently, it was thought that nonspecific effector cells were secondarily activated by autoantibodies, autoimmune complexes with or without activation of complement, and cytokines derived from activated T helper cells. The newer concepts of how autotolerance can get lost in the periphery (see above), however, make it likely that a primary abnormal activation of monocytes/macrophages may lead to loss of autotolerance and thereby initiate an autoimmune disease. This view is supported by recent data in the obese strain of chickens with spontaneous autoimmune thyroid disease, and by the induction of lupus-associated autoantibodies in BALB/c mice by i.p. injection of pristane.

It should be stressed that the tissue destruction process in autoimmune diseases with few exceptions has to be regarded as the result of a combination of several humoral and cellular pathogenetic mechanisms.

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