Temporal development of autoreactive Th1 responses and endogenous presentation of self myelin epitopes by central nervous system-resident APCs in Theiler's virus-infected mice

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disea se is a chronic-progressive, immune-mediated CNS demyelinating disease and a relevant model of multiple sclerosis, Myelin destruction is initiated by TMEV-specific CD4(+) T cells targeting persistently infected CNS-resident A PCs leading to activation of myelin epitope-specific CD4(+) T cells via epi tope spreading. We examined the temporal development of virus- and myelin-s pecific T fell responses and acquisition of virus and myelin epitopes by CN S-resident APCs during the chronic disease course, CD4(+) T cell responses to virus epitopes arise within 1 wk after infection and persist over a >300 -day period. in contrast, myelin-specific T cell responses are first appare nt similar to 50-60 days postinfection, appear in an ordered progression as sociated with their relative encephalitogenic dominance, and also persist, Consistent with disease initiation by virus-specific CD4(+) T cells, CNS mo nonuclear cells from TMEV-infected SJL mice endogenously process and presen t virus epitopes throughout the disease course, while myelin epitopes are p resented only after initiation of myelin damage (>50-60 days postinfection) , Activated F4/80(+) APCs expressing high levels of MHC class II and B7 cos timulatory molecules and ingested myelin debris chronically accumulate in t he CNS, These results suggest a process of autoimmune induction in which vi rus-specific T cell-mediated bystander myelin destruction leads to the recr uitment and activation of infiltrating and CNS-resident APCs that process a nd present endogenous myelin epitopes to autoreactive T cells in a hierarch ical order.