Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical signs in susceptible mice. The TMEV system is considered to be a relevant animal model, an alternative to the experimental autoimmune encephalomyelitis (EAE) system, for studying human multiple sclerosis (MS) in light of the potential viral etiology and similarities in the progression of chronic demyelination. In the previous grant period, we have characterized the major conformation-independent antibody epitopes of viral capsid proteins and the potential role for the protection from and/or pathogenicity of virally induced demyelination. Two additional major Th epitopes (VP1233-250 and VP324-37) have also been identified and these epitopes together with VP274-86 account for greater than 85 percent of the Th response to TMEV. In addition, we have identified the Th epitopes (VP1233-250 and VP274-86, but not VP324-37) involved in the pathogenicity of demyelination and their association to induce relatively high levels of Th1 responses. Furthermore, we have recently characterized spontaneously arising variant viruses that do not cause demyelination but induce strong protective immunity to subsequent infection with pathogenic TMEV. This variant virus contains a single amino acid substitution of arginine from lysine at position 244 within the major Th1 epitope, VP1233-250, resulting in conversion to a Th2 response. Moreover, our recent findings have indicated that the initial demyelination induced by TMEV infection can lead to the development of autoimmune Th response to a major myelin component. Based on these provocative results, we propose to further investigate the mechanisms involved in the pathogenesis of immune-mediated demyelination.
The specific aims of our proposed studies include: 1). Delineation of the T cell responses involved in TMEV-induced demyelination using modified Th epitopes. 2). Investigation of the role of viral epitope expression in the development of demyelination. 3). Examination of the potential molecular mimicry in the development of immune- mediated demyelination. 4). Assessment of the function of antibodies specific for the major antibody and Th epitopes during the course of demyelination. We believe that our proposed studies will yield important information on the underlying mechanism(s) involved in virus-induced, immune-mediated demyelination, leading to the development of autoimmunity to CNS autoantigens.
Showing the most recent 10 out of 61 publications