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

Y. Katz-Levy, K. L. Neville, J. Padilla, S. Rahbe, W. S. Begolka, A. M. Girvin, J. K. Olson, C. L. Vanderlugt, S. D. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

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 cell 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 ~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.

Original languageEnglish (US)
Pages (from-to)5304-5314
Number of pages11
JournalJournal of Immunology
Volume165
Issue number9
DOIs
StatePublished - Nov 1 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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