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  • Title: Do microbes with peptides mimicking myelin cause multiple sclerosis if the T cell response to their unique peptides is limited?
    Author: Kaufman MD.
    Journal: J Theor Biol; 1998 Aug 21; 193(4):691-708. PubMed ID: 9745761.
    Abstract:
    This hypothesis for the pathogenesis of multiple sclerosis is based upon assumptions about the response of the T cell repertoire to pathogens. Immunologic and epidemiologic observations of several conditions suggest that activation of T cells formed in early life mediate injury to the central nervous system. Early in life, selection of lymphocytes by the thymus produces a weakly autoreactive T cell repertoire which, with the help of transient maternally-derived defenses, recognizes pathogens. These responses later are supplemented by pathogen-specific responses, acquired as microbes are encountered. As the thymus involutes, the diversity of pathogen-specific responses to microbial epitopes is progressively fixed. Reduced and delayed pathogen exposure, common in developed societies, limits the repertoire of memory T cells, which can efficiently eliminate pathogens. Due to their small number, pathogen-specific lymphocytes which mature extrathymically may not be able to rapidly eliminate most pathogens, and without the editing of the thymus, they may be autoreactive. In this setting, novel pathogens with epitopes mimicking myelin may elicit a T cell response which is autoreactive. Peptides of common microbes are known to activate T cells recognizing dominant antigens of myelin. It is postulated that at the equator, intense, non-seasonal encounters with microbes elicit an immune repertoire that produces resistance to autoimmunity, while, in temperate climates, moderate, seasonal exposures increase susceptibility to it. The differences in responses to microbes between populations with a low or high prevalence of multiple sclerosis suggests that T cell repertoires are divergent in these groups. An exuberant innate response, postulated to diminish as the load of enteric microbes falls and sanitation improves in relation to the distance from the equator, may increase resistance to multiple sclerosis by eliminating the need for T cell activation. Human herpesvirus-6 and respiratory syncytial virus are possible prototypes of microbes which activate myelin-directed T cells.
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