Central role of interferon-beta in thymic events leading to myasthenia gravis

The thymus plays a primary role in early-onset Myasthenia Gravis (MG) mediated by anti-acetylcholine receptor (AChR) antibodies. As we recently showed an inflammatory and anti-viral signature in MG thymuses, we investigated in detail the contribution of interferon (IFN)-I and IFN-III subtypes in thymic changes associated with MG. We showed that IFN-I and IFN-III subtypes, but especially IFN-beta, induced specifically alpha-AChR expression in thymic epithelial cells (TECs). We also demonstrated that IFN-beta increased TEC death and the uptake of TEC proteins by dendritic cells. In parallel, we showed that IFN-beta increased the expression of the chemokines CXCL13 and CCL21 by TECs and lymphatic endothelial cells, respectively. These two chemokines are involved in germinal center (GC) development and overexpressed in MG thymus with follicular hyperplasia. We also demonstrated that the B-cell activating factor (BAFF), which favors autoreactive B-cells, was overexpressed by TECs in MG thymus and was also induced by IFN-beta in TEC cultures. Some of IFN-beta effects were down-regulated when cell cultures were treated with glucocorticoids, a treatment widely used in MG patients that decreases the number of thymic GCs. Similar changes were observed in vivo. The injections of Poly(I:C) to C57BL/6 mice triggered a thymic overexpression of IFN-beta and IFN-alpha 2 associated with increased expressions of CXCL13, CCL21, BAFF, and favored the recruitment of B cells. These changes were not observed in the thymus of IFN-1 receptor KO mice injected with Poly(I:C), even if IFN-beta and IFN-alpha 2 were overexpressed. Altogether, these results demonstrate that IFN-beta could play a central role in thymic events leading to MG by triggering the overexpression of alpha-AChR probably leading to thymic DC autosensitization, the abnormal recruitment of peripheral cells and GC formation. (C) 2013 Elsevier Ltd. All rights reserved.