Epidemiological studies indicate that host immunogenetics and history of
infection, particularly by viruses, may be a necessary cofactor for the induction of a variety of
autoimmune diseases. To date, however, there is no clear-cut evidence, either in experimental animal models or in human
autoimmune disease, that supports either molecular mimicry (Wucherpfennig and Strominger, 1995; Fujinami and Oldstone, 1985) or a role for
superantigens (Scherer et al., 1993) in the initiation of T cell-mediated autoimmunity. In contrast, the current data provide compelling evidence in support of a major role for
epitope spreading in the induction of myelin-specific autoimmunity in mice persistently infected with TMEV. It is significant that two picornaviruses closely related to TMEV, coxsackievirus (Rose and Hill, 1996) and encephalomyocarditis virus (EMCV) (Kyu et al., 1992), have been similarly shown to persist (either the
viral RNA or the infectious virus) in their target organs and have been associated with the development of chronic
autoimmune diseases, including
myocarditis and diabetes. Thus, inflammatory responses induced by viruses that trigger proinflammatory Th1 responses, and have the ability to persist in genetically susceptible hosts, may lead to chronic organ-specific
autoimmune disease via
epitope spreading.
Epitope spreading has important implications for the design of
antigen-specific
therapies for the potential treatment of MS and other
autoimmune diseases. This process indicates that
autoimmune diseases are evolving entities and that the specificity of the effector
autoantigen-specific T cells varies during the
chronic disease process. Our experiments employing tolerance in R-EAE clearly indicate that
antigen-specific treatment of ongoing disease is possible for preventing disease relapses, provided the proper relapse-associated
epitope is targeted (Vanderlugt et al., 1999). However, the ability to identify relapse-associated
epitopes in humans will be a difficult task because immunodominance will vary in every individual. The use of costimulatory antagonists that can induce anergy without requiring prior knowledge of the exact
epitopes (Miller et al., 1995b), or the use of
therapies that induce bystander suppression (Nicholson et al., 1997; Brocke et al., 1996), may thus be more practical current
alternative therapies for the treatment of human
autoimmune disease.