Résumé :
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Communication n° 312 Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG) are autoimmune disorders in which the acetylcholine receptor (AChR) is the major autoantigen. Microarray technology was used to identify new potential drug targets for treatment of myasthenia which would reduce the need for the currently used nonspecific immunosuppression. Quantitative Methods for RNA and protein analysis were used in this study. The chemokine IFN-gamma inducible protein 10 (IP-10, CXCL10), a CXC chemokine and its receptor CXCR3 were found to be overexpressed in lymph node cells (LNC) of EAMG rats. Real time PCR confirmed these findings and revealed upregulated mRNA levels of another chemoattractant that activates CXCR3, monokine induced by IFN-gamma (Mig, CXCL9). TNF alpha and IL-1 beta that act synergistically with IFN-gamma to induce IP-10 were also upregulated. These upregulations were observed in immune response effector cells - namely LNC and in the target organ of the autoimmune attack - the muscle of myasthenic rats, and were significantly reduced after suppression of EAMG by mucosal tolerance induction with an AChR fragment. The relevance of IP-10/CXCR3 signaling in myasthenia was validated by similar observations in MG patients. A significant increase in IP-10 and CXCR3 mRNA levels in both thymus and muscle was observed in myasthenic patients compared to age-matched controls. CXCR3 expression in PBMC of MG patients was markedly increased in CD4+ but not in CD8+ T cells or CD19+ B cells. Our results demonstrate the involvement of IP-10/CXCR3 signaling in the pathogenesis of myasthenia and suggest that CXCR3 and IP-10 may be suitable new drug targets for treatment of MG and other autoimmune diseases.
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