Epitope spreading in a viral model of multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) characterized by destruction of the myelin sheaths surrounding axons in the CNS by specific T cells eventually leading to paralysis of the affected individual. The direct cause of MS is unknown yet both genetic and environmental factors (e.g. viruses) are being investigated. Theiler's murine encephalomyelitis virus (TMEV)is a natural mouse pathogen. Infection with TMEV results in a chronic, progressive, paralytic CNS demyelinating disorder that is a highly relevant animal model for human MS. We have recently shown that TMEV-induced demyelination is initiated by virus specific Th1 cells targeting virus persisting in the CNS. The chronic stages of the disease however, are mediated in part by myelin-specific autoimmune responses which arise via epitope spreading. We have examined the temporal development of delayed-type hypersensitivity (DTH) responses to both viral and myelin epitopes throughout disease course. Anti-viral responses appear early in disease while myelin specific responses appear in an ordered progression in the later stages of the disease. We have also shown that plastic adherent mononuclear cells isolated from the CNS of mice with ongoing demyleinating disease can directly activate T cell lines specific for both virus and myelin epitopes. The activation is MHC Class II-restricted and dependant on B7 costimulatory molecules. This is the first demonstration that APC's from the target organ of an autoimmune disease constitutively process and present self epitopes which may contribute to chronic disease pathology.