Résumé :
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Communication n° 590 Myasthenia gravis (MG) is an autoimmune disease associated with thymic pathologies, including hyperplasia. In this study we investigated the processes that may lead to thymic overexpression of the triggering antigen, the acetylcholine receptor (AChR). Using microarray technology, we found that IFN-regulated genes are more highly expressed in these pathological thymic tissues compared to age- and sex-matched normal thymus controls. We therefore investigated whether pro-inflammatory cytokines could locally modify acetylcholine receptor (AChR) expression in myoid and thymic epithelial cells (TEC). We found that AChR transcripts are upregulated by IFN-gamma, and even more so by IFN-gamma and TNF-alpha, as assessed by real-time RT-PCR, with the alpha-AChR subunit being the most sensitive to this regulation. The expression of AChR protein was increased at the cytoplasmic level in TEC and at the membrane in myoid cells. To examine whether IFN-gamma could influence AChR expression in vivo, we analyzed AChR transcripts in IFN-gamma gene knock-out mice, and found a significant decrease in AChR transcript levels in the thymus but not in the muscle, compared to wild type mice. However, upregulation of AChR protein expression was found in the muscles of animals with myasthenic symptoms treated with TNF-alpha. Altogether these results indicate that pro-inflammatory cytokines influence the expression of AChR in vitro and in vivo. Since pro-inflammatory cytokine activity is evidenced in the thymus of MG patients, it could influence AChR expression and thereby contribute to the initiation of the autoimmune anti-AChR response.
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