Our research is aimed at elucidating the pathogenesis of autoimmune disorders and virus infections in the central nervous system (CNS), using autoimmune and viral models for multiple sclerosis (MS): experimental autoimmune (or allergic) encephalomyelitis (EAE) and Theiler’s murine encephalomyelitis virus (TMEV) infection. We have studied both host immune responses and pathogens (viruses), in vivo and in vitro, using immunological, virological, and neuropathological methods. Although axonal degeneration has been described in MS, it was believed to occur only secondarily to demyelination. We have demonstrated that 1) axonal damage precedes demyelination in TMEV infection (Inside-Out model) and 2) axonal degeneration plays a detrimental role in EAE, while it plays a beneficial role in TMEV infection, and 3) axonal degeneration recruits inflammatory cells to sites of Wallerian degeneration. We hypothesize that axonal degeneration can be a self-destructive defense mechanism that limits the spread of neurotropic viruses. We have also investigated the roles of helper T (Th) 1, Th2, Th17, and regulatory T (Treg) cells and natural killer T (NKT) cells in TMEV infection. We have established EAE models for primary progressive (PP)- and secondary progressive (SP)-MS. This established model system will be used to elucidate the roles for cytokines, natural antibody, and apoptosis in lymphoid organs in deciphering how these factors interact and contribute to switching a disease course of autoimmune diseases from relapsing-remitting to a progressive type. We are also investigating a model for myocarditis induced by TMEV, using bioinformatics (Systems Biology) analyses with microarray, immunological and histological assays.