期刊
JOURNAL OF IMMUNOLOGY
卷 165, 期 9, 页码 5304-5314出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.165.9.5304
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资金
- NINDS NIH HHS [NS26543, NS34819, NS23349] Funding Source: Medline
Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease 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 APCs leading to activation of myelin epitope-specific CD4(+) T cells via epitope spreading. We examined the temporal development of virus- and myelin-specific T fell responses and acquisition of virus and myelin epitopes by CNS-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 apparent similar to 50-60 days postinfection, appear in an ordered progression associated with their relative encephalitogenic dominance, and also persist, Consistent with disease initiation by virus-specific CD4(+) T cells, CNS mononuclear cells from TMEV-infected SJL mice endogenously process and present virus epitopes throughout the disease course, while myelin epitopes are presented only after initiation of myelin damage (>50-60 days postinfection), Activated F4/80(+) APCs expressing high levels of MHC class II and B7 costimulatory molecules and ingested myelin debris chronically accumulate in the CNS, These results suggest a process of autoimmune induction in which virus-specific T cell-mediated bystander myelin destruction leads to the recruitment and activation of infiltrating and CNS-resident APCs that process and present endogenous myelin epitopes to autoreactive T cells in a hierarchical order.
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