Immune tolerance in multiple sclerosis.
ABSTRACT Multiple sclerosis is believed to be mediated by T cells specific for myelin antigens that circulate harmlessly in the periphery of healthy individuals until they are erroneously activated by an environmental stimulus. Upon activation, the T cells enter the central nervous system and orchestrate an immune response against myelin. To understand the initial steps in the pathogenesis of multiple sclerosis, it is important to identify the mechanisms that maintain T-cell tolerance to myelin antigens and to understand how some myelin-specific T cells escape tolerance and what conditions lead to their activation. Central tolerance strongly shapes the peripheral repertoire of myelin-specific T cells, as most myelin-specific T cells are eliminated by clonal deletion in the thymus. Self-reactive T cells that escape central tolerance are generally capable only of low-avidity interactions with antigen-presenting cells. Despite the low avidity of these interactions, peripheral tolerance mechanisms are required to prevent spontaneous autoimmunity. Multiple peripheral tolerance mechanisms for myelin-specific T cells have been identified, the most important of which appears to be regulatory T cells. While most studies have focused on CD4(+) myelin-specific T cells, interesting differences in tolerance mechanisms and the conditions that abrogate these mechanisms have recently been described for CD8(+) myelin-specific T cells.
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ABSTRACT: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4(+) and CD8(+) T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4(+) myelin-specific T cells. The role of CD8(+) myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8(+) T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8(+) T cell-mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4(+) T cell-mediated EAE. These data suggest that myelin-specific CD8(+) T cells could function as effector cells in the pathogenesis of MS.Journal of Experimental Medicine 10/2001; 194(5):669-76. · 13.85 Impact Factor
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ABSTRACT: Myelin basic protein-specific CD8(+) T cells can induce central nervous system autoimmunity; however, immune tolerance prevents these autoreactive cells from causing disease. To define the mechanisms that mediate tolerance, we developed two T cell receptor-transgenic mouse lines with different affinities for the H-2K(k)-restricted myelin basic protein epitope consisting of amino acids 79-87 (MBP(79-87)). We observed both thymic deletion and peripheral tolerance in the lower-affinity T cells. The higher-affinity T cells, however, showed no evidence of tolerance induction and were able to prevent tolerance of the lower-affinity T cells by removing H-2K(k)-MBP(79-87) complexes from antigen-presenting cells without proliferating. This form of immune regulation could limit responses of self-reactive T cells that escape other tolerance mechanisms.Nature Immunology 07/2004; 5(6):606-14. · 26.01 Impact Factor