Differential Estrogen Receptor Expression in Autoimmune Myasthenia Gravis

Abstract

Myasthenia gravis (MG) is an autoimmune disease associated with thymic hyperplasia and is much more prevalent in women than men. In this study we investigated potential changes in estrogen receptor (ER) expression in thymic hyperplasia. We first quantified by real-time PCR the relative expression of ER alpha and ER beta in normal thymus and found that the ER beta to ER alpha ratio was inverted in thymocytes (8.6 +/- 1.2), compared with thymic epithelial cells (0.18 +/- 0.05). The ER transcript number gradually decreased in thymic epithelial cells during culture, indicating that the thymic environment influences ER expression. CD4+ helper T cells expressed higher level of ERs, compared with CD8+ cells, as assessed by flow cytometry in thymocytes and peripheral blood mononuclear cells. In MG patients, we found an increased expression of ER alpha on thymocytes and both ERs on T cells from peripheral blood mononuclear cells, indicating that the signals provided by thymic and peripheral microenvironments are distinct. Finally, activation of normal thymocytes by proinflammatory cytokines induced increased expression of ERs especially in the CD4+ subset, suggesting that an excess of proinflammatory cytokines could explain the increase of ERs expression on MG lymphocytes. The dysregulation of ER expression in MG lymphocytes could affect the maintenance of the homeostatic conditions and might influence the progression of the autoimmune response.

Impact of the Neuroendocrine System on Thymus and Bone Marrow Function

“…Conversely, male androgens have been shown to relieve SLE in female patients [88] . Myasthenia gravis is another predominantly female autoimmune disease which has been shown to involve increased ER ␣ and ER ␤ on T cells and ER ␣ on thymocytes, indicating a potential role of estrogen in the pathogenesis of myasthenia gravis patients [89] . Reduced levels of androgens and increased estrogen have also been associated with inflammation in rheumatoid arthritis; however, changes in these hormones do not initiate flares as readily as in SLE [90] .…”

Sex-based differences in regulatory T cells.

“…An * indicates a significant difference at p <0.05. In our studies, we also observed that Foxp3, which is a specific marker for regulatory activity (78) (192,193 (127,195). However, studies have…”

Expression of estrogen and progesterone receptors and Ki-67 antigen in Graves’ disease and nodular goiter

“…They may act as immunosuppressors as well as immunostimulators, and the balance between these two processes seems to be dependent upon steroid hormones levels. The higher incidence of AID in women seems to be linked to influence of sex steroid hormones on autoimmunity, as ER and PR were reported to be expressed also on some types of immune cells [5,25,26]. This may partly explain the higher incidence of AID noted in woman.…”