Résumé :
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Communication n° 506 Myasthenia Gravis (MG) is an autoimmune disease due to autoantibodies directed against components of the neuromuscular junction and leading to disabling fatigability of muscles. Our objective, using microarrays, was to identify genes differentially expressed in the effector organ of MG, the thymus. We compared thymuses from baby girls (control) to thymuses from age-matched adult females from healthy donors, seronegative MG patients, seropositive MG patients with and without thymic hyperplasia. Microarray experiments were carried on using the human cDNA arrays from Agilent (G4100A). Raw data were corrected by two normalization steps and statistically analyzed using the SAM software to define a set of significantly up- and down-regulated genes in different MG patients compared to healthy donors. With a global approach, we analyzed the main chromosomal locations of dysregulated genes. Most of the up-regulated genes could be localized in specific regions such as the three clusters encoding immunoglobulins (Ig K, Ig H and Ig L, respectively 2p12, 14q32 and 22q11). Moreover, the 6p21.3 region with the MHC cluster is also over-represented and the 3 regions corresponding to the MHC paralogous clusters. Analysing specifically the dysregulated genes, we observed an up-regulation of MHC class II, immunoglobulins and interferon-induced genes in all MG thymuses, but particularly in hyperplastic thymuses, substantiating the pro-inflammatory environment of MG thymuses. We also observed an up-regulation of chemokines known to orchestrate germinal center formation, such as CCL21 and CXCL13. CCL21 is especially overexpressed in patients with thymic hyperplasia suggesting its crucial role in ectopic germinal center formation. We confirmed by real-time RT-PCR and ELISA the specific over-expression of CCL21 in hyperplastic thymuses from MG patients. However, we did not detect any variation in the expression of its receptor CCR7 on peripheral blood lymphocytes of MG patients. Altogether, microarray analyses on thymic tissues evidence the role of chemokines in the remodelling of the thymus in MG patients.
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