Résumé :
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Communication n° 471 Myasthenia Gravis (MG) is caused by autoantibodies against the acetylcholine receptor (AChR) and is often associated with thymic abnormalities. The hyperplastic thymus contains germinal centres (GCs), with B cells producing anti-AChR antibodies, and is therefore considered to be the effector organ of the disease. Although progress has been made in developing treatments for MG, this disease is still incapacitating. Glucocorticoids are efficient in most patients but their use is limited by their severe side effects. Objective : The aim of this study was to identify glucocorticoid targets that could explain the beneficial effects of corticosteroids in MG pathophysiology. Strategy : Our strategy was to identify genes dysregulated in MG thymic hyperplasia and normalized in thymuses from corticosteroid treated patients, using DNA microarray. Results : We found 36 genes fulfilling these criteria, including 15 genes associated with B cell functions. CXCL13, a chemokine highly chemoattractive for B cells is the gene on which glucocorticoids exert the most important normalization. We then investigated the expression of this gene during the MG disease process. We found a striking dysregulation of CXCL13 in MG patients including: 1) increased concentration in both sera and thymuses of almost all MG patients; 2) a decrease after in-vivo treatment by both corticosteroid therapy and thymectomy in correlation with the clinical improvement. Furthermore, we demonstrated that CXCL13 is normally produced by thymic epithelial cells, at higher amount during MG, and is downregulated in-vitro by corticosteroids. Conclusion : Our findings implicate CXCL13 in the pathogenesis of MG and demonstrate that it is a major glucocorticoid target. Thus, novel therapies that specifically inhibit CXCL13 should be of interest for MG disease and are expected to have fewer side effects than glucocorticoids.
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