Inovarion, Paris, France.
Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
Sci Rep. 2017 Aug 11;7(1):7970. doi: 10.1038/s41598-017-08631-5.
The early-onset form of Myasthenia Gravis (MG) is prevalent in women and associates with ectopic germinal centers (GCs) development and inflammation in the thymus. we aimed to investigate the contribution of estrogens in the molecular processes involved in thymic GCs formation. We examined expression of genes involved in anti-acetylcholine receptor (AChR) response in MG, MHC class II and α-AChR subunit as well as chemokines involved in GC development (CXCL13, CCL21and CXCL12). In resting conditions, estrogens have strong regulatory effects on thymic epithelial cells (TECs), inducing a decreased protein expression of the above molecules. In knockout mouse models for estrogen receptor or aromatase, we observed that perturbation in estrogen transduction pathway altered MHC Class II, α-AChR, and CXCL13 expression. However, in inflammatory conditions, estrogen effects were partially overwhelmed by pro-inflammatory cytokines. Interestingly, estrogens were able to control production of type I interferon and therefore play dual roles during inflammatory events. In conclusion, we showed that estrogens inhibited expression of α-AChR and HLA-DR in TECs, suggesting that estrogens may alter the tolerization process and favor environment for an autoimmune response. By contrast, under inflammatory conditions, estrogen effects depend upon strength of the partner molecules with which it is confronted to.
重症肌无力（MG）的早发型在女性中更为常见，与胸腺中异位生发中心（GC）的发展和炎症有关。我们旨在研究雌激素在涉及胸腺 GC 形成的分子过程中的作用。我们检查了 MG 中与抗乙酰胆碱受体（AChR）反应、MHC Ⅱ类和α-AChR 亚基以及参与 GC 发育的趋化因子（CXCL13、CCL21 和 CXCL12）相关的基因表达。在静息状态下，雌激素对胸腺上皮细胞（TEC）有很强的调节作用，导致上述分子的蛋白表达降低。在雌激素受体或芳香酶敲除小鼠模型中，我们观察到雌激素转导途径的干扰改变了 MHC Ⅱ类、α-AChR 和 CXCL13 的表达。然而，在炎症条件下，雌激素的作用部分被促炎细胞因子所掩盖。有趣的是，雌激素能够控制 I 型干扰素的产生，因此在炎症事件中发挥双重作用。总之，我们表明雌激素抑制了 TEC 中 α-AChR 和 HLA-DR 的表达，这表明雌激素可能改变耐受过程并有利于自身免疫反应的环境。相比之下，在炎症条件下，雌激素的作用取决于其与之对抗的伙伴分子的强度。
