Résumé :
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Communication n° 576 Thymus-derived CD4+CD25hi T regulatory cells play a decisive role in the generation and maintenance of peripheral tolerance. These cells are naturally hyporesponsive in vitro and can inhibit the proliferation of co-cultured CD4+CD25- conventional T cells in a contact-dependent manner. Although regulatory T cells have been largely involved in the prevention of autoimmune diseases in animals, only limited information is available on their role in the pathogenesis of human autoimmune diseases. We first analyzed the frequency of CD4+CD25hi in peripheral blood and in the thymus/thymomas of patients with myasthenia gravis (MG), a prototype autoimmune disease mediated by autoantibodies against the acetylcholine receptor at the neuromuscular junction. The frequency of regulatory cells was not altered in the peripheral compartment, but we found a marked decrease in the number of CD4+CD25+ thymocytes in MG-associated thymoma, suggesting that the thymic development of regulatory T cells is impaired in these patients. By contrast, patients with myasthenia-associated thymic hyperplasia showed nearly normal levels of CD4+CD25+ cells. We hypothesized that altered functions of peripheral CD4+CD25 hi regulatory T cells in the periphery play a role in the breakdown of immunologic self-tolerance in patients with MG. Suppression assays were thus conducted to analyze the functionality of these regulatory cells in vitro. We report a highly significant decrease in the suppressive function of the CD4+CD25hi cells from peripheral blood of patients with myasthenia gravis in comparison to healthy donors. The maximum defect in the suppressive function was observed in untreated patients, while patients that were under cytostatic or immunosuppressive drugs showed only a mild decrease in function. One important question that arises now is why the regulatory T cells in patients with autoimmune disease are not functional. Our current investigations aim to establish the role of steroid hormones in the control of the regulatory function by these cells.
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