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There is a large body of circumstantial evidence highlighting a primary role of the thymus in the pathogenesis of MG. Nevertheless, the etiologic link remains to be forged. We are reexamining the hypothesis that AChR expressed in the thymus drives the pathogenic autoimmune response. To this end, we have established a model of intrathymic inflammation that is localized to the thymic medulla and demonstrated that this inflammatory process promotes the nonspecific entry of peripheral CD4^+ T cells into the thymus. Using this model, we are in the process of determining whether (a) AChR-reactive CD4^+ T cell homing to the thymus is augmented by a concurrent intrathymic inflammatory response to an unrelated antigen, and (b) AChR-reactive T cell immigrants undergo activation following their engagement of autoantigen in this inflammatory milieu, provide help for the production of anti-AChR antibodies by immigrant autoreactive B cells, and thereby promote the development of a myasthenic syndrome.

Our understanding of antibody-mediated renal damage has not changed drastically in recent years. However, within this framework a lot of new data emerged to change our way of looking at “old” diseases. For example, APSGN, which in the past has been regarded as a typical CIC-mediated disease, may also show ICs formed in situ . In Goodpasture’s syndrome, once considered to be the classical model of autoantibody-mediated disease, it is now realized that nephritogenic T cells play an important role. Complement, formerly thought to be a pathogenic factor in nephritis, is now believed to be crucial for the protection of immune-mediated renal injury. At the same time, components of the fibrinolytic system play a role as autoantibody targets in renal damage, and a disregulation of this pathway may be a mechanism in different renal diseases. Furthermore, new hypotheses are emerging to explain how the immune system interacts with the external world. One of them suggests that a great deal more is involved than the mere discrimination between self and nonself: the immune system is able to handle all elements, even endogenous ones, that pose a potential danger to the host (Matzinger, 1994). Thus, tissues themselves play a central role: when healthy, they may induce tolerance and when distressed, they may stimulate immunity. In this view, autoimmunity can be regarded as a defect in the “cross-talk” between the immune system and the body tissues, a perspective that opens up fascinating new avenues for research on the mechanisms that regulate the expression of renal antigens in health and disease.

Studies of B cells in systemic autoimmune diseases have provided important clues. Their role in autoimmunity is more important than previously thought. Only recently was it realized that B cells can be subject to positive selection generated and maintained on the basis of their autoreactivity and that B cells are essential in promoting systemic autoimmunity. Their depletion has been used in treating a number of autoimmune conditions, including autoimmune thrombocytopenic, rheumatoid arthritis, lupus, autoimmune hemolytic anemia, cold agglutinin disease, mixed cryoglobulinemia, autoimmune neuropathies, myasthenia gravis, Wegener’s granulomatosis, and dermatomyositis. In many of these conditions major improvement is seen in a good proportion of cases, particularly in rheumatoid arthritis, lupus, dermatomyositis, autoimmune neuropathies, immune thrombocytopenic purpura, and hemolytic anemia (Patel, 2002). While it seems clear that immune receptor signaling checkpoints are involved in the progression of systemic autoimmunity, their origin remains unclear. Even though genetic factors are important for disease development, the environmental contribution to clinical expression cannot be ignored, and it is likely that different mechanisms could lead to loss of self-tolerance characteristic of SLE. The observation that different SLE patients produce different spectra of autoantibodies suggests that more than one factor could play a role in a single patient and it is conceivable that the combination of factors varies throughout the disease. Environmental factors include infectious agents, endogenous retroviruses, pollutants, and hormones (Hasler and Zouali, 2003; Zouali, 2005). While immune receptor signaling checkpoints may not prove to be the single key to elucidating all aspects of autoimmunity, it is likely that further studies of these and related pathways may lead to novel approaches of more specific therapeutic intervention in human systemic autoimmunity.