Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus–infected mice

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Abstract

The mechanisms underlying the initiation of virus-induced autoimmune disease are not well understood. Theiler’s murine encephalomyelitis virus–induced demyelinating disease (TMEV-IDD), a mouse model of multiple sclerosis, is initiated by TMEV-specific CD4+ T cells targeting virally infected central nervous system–resident (CNS-resident) antigen-presenting cells (APCs), leading to chronic activation of myelin epitope–specific CD4+ T cells via epitope spreading. Here we show that F4/80+, I-As+, CD45+ macrophages/microglia isolated from the CNS of TMEV-infected SJL mice have the ability to endogenously process and present virus epitopes at both acute and chronic stages of the disease. Relevant to the initiation of virus-induced autoimmune disease, only CNS APCs isolated from TMEV-infected mice with preexisting myelin damage, not those isolated from naive mice or mice with acute disease, were able to endogenously present a variety of proteolipid protein epitopes to specific Th1 lines. These results offer a mechanism by which localized virus-induced, T cell–mediated inflammatory myelin destruction leads to the recruitment/activation of CNS-resident APCs that can process and present endogenous self epitopes to autoantigen-specific T cells, and thus provide a mechanistic basis by which epitope spreading occurs.

Authors

Yael Katz-Levy, Katherine L. Neville, Ann M. Girvin, Carol L. Vanderlugt, Jonathan G. Pope, Lit Jen Tan, Stephen D. Miller