Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus–infected mice
Yael Katz-Levy, … , Lit Jen Tan, Stephen D. Miller
Yael Katz-Levy, … , Lit Jen Tan, Stephen D. Miller
Published September 1, 1999
Citation Information: J Clin Invest. 1999;104(5):599-610. https://doi.org/10.1172/JCI7292.
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Article

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

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

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Figure 4

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Myelin epitopes are not generated during the isolation of CNS-resident A...
Myelin epitopes are not generated during the isolation of CNS-resident APCs. Spinal cords from naive SJL mice and a group of SJL mice infected with TMEV 85 days previously were dissociated and treated with collagenase. The spinal cord suspension from the naive mice was split and mixed with either naive splenocytes or LPS-preactivated splenocytes at the ratio of 1 spleen equivalent per spinal cord. All 3 suspensions were separated on discontinuous Percoll gradients. The cells were incubated in plastic dishes for 1.5 hours, and the plastic-adherent cells were irradiated (30 Gy). A total of 2.8 × 104 cells from a PLP56-70–specific T-cell line were cultured with the following: 3 × 104 irradiated naive SJL splenocytes in the absence of added peptide (group A); 3 × 104 irradiated naive SJL splenocytes + 50 μM PLP56-70 (group B–positive control); 3 × 104 irradiated, plastic-adherent CNS APCs from TMEV-infected mice (group C); 3 × 104 irradiated naive splenocytes recovered from Percoll gradients after admixture with the naive spinal cord suspension (group D); 3 × 104 irradiated, LPS-preactivated splenocytes (group E); and 3 × 104 irradiated, LPS-preactivated splenocytes recovered from Percoll gradients after admixture with the naive spinal cord suspension (group F). Cultures were pulsed with 1 μCi of [3H]TdR at 48 hours, and were harvested 16 hours thereafter. Values represent the mean cpm ± SEM of triplicate cultures. Stimulation indices are indicated above each bar, and were calculated using the cpm of the PLP56-70–specific T-cell line cultured with irradiated naive splenic APCs in the absence of peptide. *Naive and LPS-preactivated splenocytes in these groups were processed similarly to the CNS APCs.