Autoimmune CNSnDisease Induced by Virus Infection

La Jolla Institute For Immunology, La Jolla CA

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Abstract

Numerous reports indicate the important role infections play in multiple sclerosis (MS) and other autoimmune diseases of humans such as diabetes. Viral infections appear to be associated with attacks and/or exacerbations of MS and are thought to be involved at the initial priming stage by expanding autoreactive T cells in certain individuals with a susceptible genetic phenotype. More than a dozen viruses have been isolated from MS patients in the past 50 years, but no single virus has been identified as the causative agent. We propose that infections having molecular mimicry with self central nervous system (CNS) proteins can prime genetically susceptible individuals; once priming has occurred, an immunologic challenge could result in disease, through bystander activation and/or molecular mimicry. It is hypothesized that myelin specific Th1 CD4 + T cells mediate MS. In the experimental animal model for MS, experimental allergic encephalomyelitis (EAE), myelin specific CD4 + and more recently CD8 + T cells can adoptively transfer disease to naive animals. In conventional forms of EAE, mice are sensitized to myelin antigens by injection of myelin proteins or encephalitogenic peptides in powerful adjuvants eliciting these myelin specific Th1 CD4 + T cells. This results in an inflammatory demyelinating disease of the CNS. Lesions seen in EAE are very similar to early lesions present in MS patients. Mice with EAE also will develop a relapsing-remitting clinical course seen in about 80% of MS patients. In this proposal we will test the hypothesis that viral infections having molecular mimicry with self-CNS proteins can prime animals for EAE. Once this "fertile field" is sown an infection favoring proinflammatory cytokines such as IL-12 will initiate an exacerbation. Preliminary data shows that cDNAs or recombinant viruses encoding self-CNS proteins when used to inoculate or infect mice can prime for EAE creating the fertile field. These primed mice do not show any clinical or pathological changes indicative of EAE. However, at a later time when these mice are challenged by a viral infection, mice develop an acute attack of EAE. This application proposes to understand the immunological basis for the initiation of disease and investigate the mechanisms involved in the priming and challenge phases. This proposal will provide insight into how infectious agents cause autoimmune disease.