INTERLEUKIN-6 OVERPRODUCTION BY CULTURED THYMIC EPITHELIAL-CELLS FROMPATIENTS WITH MYASTHENIA-GRAVIS IS POTENTIALLY INVOLVED IN THYMIC HYPERPLASIA

Most patients with Myasthenia Gravis (MG) present a thymic hyperplasia characterized by the presence of lymphoid follicles. The acetylcholin e receptor autoantigen, as well as autoantigen specific activated T an d B cells round in the thymus, strongly suggest that auto-sensitizatio n could take place in this organ. Since IL-6 is involved in T and B ce ll growth and differentiation, we thought that abnormal IL-6 expressio n by thymic epithelial cells (TEC) could be related to thymic hyperpla sia in MG. In this paper, IL-6 protein and gene expression by cultured TEC from patients with MG were examined. TEC from patients presented a dramatic IL-6 hyperproduction phenotype as compared to controls when stimulated by exogeneous signals such as LPS and cytokines (IL-1beta, TNF-alpha) alone or in combination. Moreover, we observed a similar e ffect with a physiological signal such as the syngeneic lympho-epithel ial cell contact. Autologous thymocytes stimulated normal and MG TEC I L-6 production in a time- and dose- dependent way, and with a higher m agnitude in MG TEC compared to controls. In all stimulation conditions , induction of IL-6 production required protein synthesis and was asso ciated with increased IL-6 mRNA level expression as assessed by comput er-aided quantification after in situ mRNA hybridization. In addition, recombinant IL-6 induced in vitro growth or TEC, demonstrating that I L-6 is a possible autocrine growth factor for these celts. This deregu lated IL-6 production as well as the ability of TEC to use it as a gro wth factor may be or pathophysiological relevance in MG. It provides a n explanation for morphological changes of the thymus and may have a k ey role in initiation, exacerbation and ongoing of the autoimmune resp onse in MG. Therefore this study extends our current understanding of the molecular pathophysiology of MG.