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

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.

A Longitudinal Study of Abnormalities on MRI and Disability from Multiple Sclerosis

“…First, acute inflammation is associated with axonal damage, including transection 37,38 ; widespread axonal loss will diminish the amount of axonal reserve, and a threshold may be reached at an early point when continuing axonal loss -by whatever mechanism -begins to manifest as disability. Second, widespread inflammation could expose a range of potential autoantigens to immune surveillance, resulting in complex immunopathogenic events due to epitope spreading 39 ; such a process may be less regulated and may be likely to cause axonal damage. Third, widespread early demyelination itself may create an environment that is not conducive to long-term axonal survival.…”

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 + Foxp3 + regulatory T cells

“…Mice were assigned clinical scores daily as described (51). CNS mononuclear cells were isolated as described (52).…”

Antigen-Based Immunotherapy Drives the Precocious Development of Autoimmunity

“…Peptides from other key ␤ cell autoantigens included the immunodominant peptide of the 65-kDa HSP, termed HSPp277 (VLGGGCALL RCIPALDSLTPANED) (33) and insulin ␤-chain (Sigma-Aldrich, St. Louis, MO). Control peptides included GAD(157-176) (EEILMHCQT TLKYAIKTGHP, also known as GADp11), which does not contain a determinant, and an immunogenic hen egg lysozyme (HEL) peptide (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) (AMKRHGLDNYRGYSL) (36). With the exception of the insulin ␤-chain, all peptides were synthesized by Multiple Peptide Systems (San Diego, CA) and were Ն95% purity.…”

“…Although the initial autoimmune response is limited in its recognition of self-Ags, it subsequently expands to involve other Ags within the target tissue (2,(5)(6)(7)(8)(9)(10)(11)(12)(13). This spreading of T cell autoimmunity often follows a defined chronological pattern during disease progression.…”