title: Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases.
abstract: Fig. 6 depicts a model for epitope spreading in T cell-mediated demyelination. The acute phase of disease is due to T cells specific for the initiating epitope, which can be either a determinant on the CNS target organ of the autoimmune response or a determinant on a persisting, CNS-tropic virus. The primary T cell response is responsible for the initial tissue damage by the production of proinflammatory Th1 cytokines which can affect myelination directly (Selmaj et al. 1991) and indirectly by their ability to recruit and activate macrophages to phagocytize myelin (Cammer et al. 1978). As a result of myelin damage and opening of the blood-brain-barrier during acute disease, T cells specific for endogenous epitopes on the same and/or different myelin proteins are primed and expand either in the periphery or locally in the CNS. These secondary T cells initiate an additional round of myelin destruction, leading to a clinical relapse by production of additional pro-inflammatory cytokines, similar to the bystander demyelination operative during acute disease. It will be of great interest to determine the relative contributions of local and systemic immune responses to these endogenous neuroepitopes. It is possible that local CNS presentation of endogenous neuroepitopes following acute CNS damage could be mediated by infiltrating inflammatory macrophages, activated microglial cells, endothelial cells and/or astrocytes. These tissue resident antigen presenting cells have been shown to upregulate expression of MHC class II (Sakai et al. 1986, Traugott & Lebon 1988), certain adhesion molecules (Cannella et al. 1990), and B7 costimulatory molecules (K. M. Nikcevich, J. A. Bluestone, and S. D. Miller, in preparation) in response to pro-inflammatory cytokines. The data on epitope spreading provided by the murine demyelinating disease models clearly illustrate the dynamic nature of the T cell repertoire during chronic inflammation in a specific target organ. The contribution of epitope spreading to chronic CNS demyelination could be considered to be a special case since tolerance to myelin epitopes would be expected to be inefficient due to their sequestration behind the blood-brain-barrier. However, the recent description of epitope spreading in response to pancreatic antigens in spontaneous diabetes in the NOD mouse may indicate that this phenomenon is operative in a variety of organ-specific experimental and spontaneous autoimmune diseases.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Miller
authors.forename: B L
authors.initials: BL
authors.lastname: McRae
authors.forename: C L
authors.initials: CL
authors.lastname: Vanderlugt
authors.forename: K M
authors.initials: KM
authors.lastname: Nikcevich
authors.forename: J G
authors.initials: JG
authors.lastname: Pope
authors.forename: L
authors.initials: L
authors.lastname: Pope
authors.forename: W J
authors.initials: WJ
authors.lastname: Karpus
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology*; D006801:Humans; D009103:Multiple Sclerosis / Q000276:immunology*; D011051:Poliomyelitis / Q000209:etiology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D017945:Theilovirus / Q000276:immunology*