Autoimmunity and infection : experimental approachs of the mechanisms of B cell tolerance breakdown
Autoimmunity and infection : experimental approachs of the mechanisms of B cell tolerance breakdown.
Thèses de doctorat,
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Autoimmune diseases are associated with genetic and environmental factors. Among the latter, infections have been particularly implicated. However, the mecanisms of such an association between infections and autoimmune diseases are still unknown. We have tried to understand those mecanisms by using transgenic mouse models expressing chimeric rheumatoid factors (RF) in the presence or in the absence of their autoantigen (human IgG). In these models, RF B cells are ignorant towards their autoantigen. However, infection of RF trangenic mice with Borrelia burgdorferi (Bb) breaks this state of tolerance thanks to the formation of Bb/anti-Bb human IgG immune complexes that induce a synergic signal between the BCR and a receptor recognising Bb antigens (probably a Toll-like receptor, TLR). This tolerance breakdown needs T cell help.On the other hand, infection with influenza virus does not break RF B cell tolerance in our tg model although this infection is able to induce type I IFN production, otherwise often associated with autoimmune diseases, and even when the transgene is expressend on an autoimmune background, NZBxNZW(F1).Bb infection induces a polyclonal B cell activation. Ce phenomenon is not well known, it has consequences on the immune response against infections and on the production of potentially harmfull autoantibodies. The infection of MyD88 deficient mice (considered at first to understand the role of TLR in the RF B cell tolerance breakdown) showed that this protein is important for polyclonal B cell activation. MyD88 inhibits the development of a Th2 immune response, thus probably preventing an increased production of IL-4 that can directly and excessively activate B cells.
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