Pathogenesis of autoimmune-mediated inflammatory CNS disease. to why epitope spreading does not occur in other forms of CNS inflammation such as stroke, where there is massive tissue destruction and inflammation by macrophages upon activation of microglial cells. The explanation for this may relate to a series of observations made by Miller et al., who demonstrated that expression of B7-1 on local APCs is critical for the induction of epitope spreading in the relapsing SJL EAE model (11). In patients with MS, perhaps similar to what is observed in EAE, there is significant B7-1 expression in the CNS inflammation found in MS plaques (12–14). In marked contrast, the inflammation associated with stroke consists almost entirely of B7-2 expression (14). In addition, with chronic viral infection such as subacute sclerosing panencephalitis, there is also B7-1 expression in the CNS white matter (14). Thus, either viral infection or infiltration of activated myelin-reactive Th1 T cells in the CNS is accompanied by B7-1 expression, leading to myelin breakdown that may then lead to epitope spreading and chronic CNS inflammation. MS can be broadly divided into 2 forms of disease: the early relapsingremitting type, where there is an average of 1.5 attacks per year clinically and 10 new lesions a year by magnetic resonance imaging (MRI); and chronic progressive disease, where, in marked contrast to patients with relapsingremitting disease, there is a slowly progressive, downhill course without clinical exacerbations. Patients with chronicprogressive MS tend to have fewer new MRI lesions, as measured by dye leaking through the blood vessels (gadolinium enhancement), an indication of acute inflammation (15). Approximately one third of patients with relapsing-remitting disease go on to progressive disease, and approximately 10% of MS patients begin with progressive disease without any previous relapsing-remitting events (primary-progressive MS). What are the implications of these findings in TMEV CNS infection with MS? The animal models can perhaps provide insight into the group of syndromes that we call MS. Specifically, these experimental models lead us to hypothesize that early relapsing-remitting MS may be similar to the EAE model where there is activation of autoreactive T cells mediated by peripheral immune system stimulation by microbial antigens cross-reactive with CNS myelin antigens (Figure 1). This is consistent with the only known trigger associated with MS: antecedent viral infections (16). Thus, the myriad clinical and subclinical viral and bacterial infections we experience every year result in the specific and nonspecific activation of the immune system that can induce the activation of autoreactive T cells (17). In contrast, it can be hypothesized that in the transition to chronic-progressive MS, as seen in the TMEV model, the inflammation is driven by chronic CNS presentation of self antigen (Figures 1 and 2). In this model, the environmental influences of repeated microbial infections are not necessary for the peripheral activation of the immune system; instead, the CNS becomes a depot of myelin antigens presented by activated APCs expressing B7-1. This steady state is predicted to be associated with the slow, insidious progression of disease. The results presented by Katz-Levy et al. now tie together the autoimmune and viral models of T cell–mediated CNS damage, by demonstrating that viral infection of the CNS can directly lead to epitope spreading by microglia presentation of self antigen in chronic autoimmune disease (Figure 2). This might explain why the insidious, secondary-progressive MS that follows repeated exacerbations …