title: Self-tolerance in multiple sclerosis.
abstract: During the last decade, several defects in self-tolerance have been identified in multiple sclerosis. Dysfunction in central tolerance leads to the thymic output of antigen-specific T cells with T cell receptor alterations favouring autoimmune reactions. In addition, premature thymic involution results in a reduced export of naïve regulatory T cells, the fully suppressive clone. Alterations in peripheral tolerance concern costimulatory molecules as well as transcriptional and epigenetic mechanisms. Recent data underline the key role of regulatory T cells that suppress Th1 and Th17 effector cell responses and whose immunosuppressive activity is impaired in patients with multiple sclerosis. Those recent observations suggest that a defect in self-tolerance homeostasis might be the primary mover of multiple sclerosis leading to subsequent immune attacks, inflammation and neurodegeneration. The concept of multiple sclerosis as a consequence of the failure of central and peripheral tolerance mechanisms to maintain a self-tolerance state, particularly of regulatory T cells, may have therapeutic implications. Restoring normal thymic output and suppressive functions of regulatory T cells appears an appealing approach. Regulatory T cells suppress the general local immune response via bystander effects rather than through individual antigen-specific responses. Interestingly, the beneficial effects of currently approved immunomodulators (interferons β and glatiramer acetate) are associated with a restored regulatory T cell homeostasis. However, the feedback regulation between Th1 and Th17 effector cells and regulatory T cells is not so simple and tolerogenic mechanisms also involve other regulatory cells such as B cells, dendritic cells and CD56(bright) natural killer cells.
authors.affiliation: Fondation-Charcot-Stichting, Avenue Huart Hamoir 48, 1030 Brussels, Belgium. r.gonsette@skynet.be
authors.forename: R E
authors.initials: RE
authors.lastname: Gonsette
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D007107:Immune System / Q000503:physiopathology*; D009103:Multiple Sclerosis / Q000276:immunology* / Q000503:physiopathology*; D017634:Self Tolerance / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015703:Antigens, CD