Autoimmune myasthenia gravis (MG) is a neurological disease caused by antibodies directed against proteins of the neuromuscular junction. In 85% of patients, these antibodies target the acetylcholine receptor (AChR) and are associated with thymic abnormalities, including follicular hyperplasia. Its early-onset form predominantly affects women, with a four-to-one ratio, during their childbearing years. The thymus of these patients displays ectopic germinal centers—structures that provide the activated, differentiated B cells producing anti-AChR antibodies—as well as dysregulation of chemokines involved in lymphocyte trafficking (CXCL13, CCL21, and CXCL12/SDF-1) and signs of inflammation. This long-unexplained female predominance prompted the authors to investigate the role of estrogens, the main female sex hormone, in the molecular processes leading to the formation of these thymic germinal centers.
To this end, the researchers studied the expression of genes involved in the anti-AChR response—major histocompatibility complex class II molecules (notably HLA-DR) and the α subunit of the AChR—as well as that of the chemokines CXCL13, CCL21, and CXCL12 in cultured thymic epithelial cells. They complemented this approach with mouse models knocked out for the estrogen receptor or for aromatase, an enzyme involved in the estrogen signal transduction pathway.
Under basal conditions, estrogens exert a strong regulatory effect on thymic epithelial cells, decreasing the protein expression of the molecules examined. In the deficient murine models, disruption of the estrogen pathway alters the expression of MHC class II, the α-AChR subunit, and CXCL13. By contrast, when cells are placed under inflammatory conditions, the effect of estrogens is partially overridden by pro-inflammatory cytokines. The authors further show that estrogens are able to control the production of type I interferon, thereby playing a dual role during inflammatory events.
In conclusion, estrogens inhibit the expression of α-AChR and HLA-DR in thymic epithelial cells, suggesting that they could impair the tolerization process and promote an environment conducive to an autoimmune response. However, in an inflammatory context, their effects depend on the strength of the molecules they encounter. This work thus sheds light on a mechanism by which the balance between estrogens and pro-inflammatory cytokines modulates the production of chemokines involved in the formation of thymic germinal centers, and helps explain the particular female susceptibility to this form of myasthenia gravis.