Polymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases

Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors probably controls the sex discrepancy in the immune response, but the underlying mechanisms are unclear. Here we positionally identify a polymorphic estrogen receptor binding site that regulates Cd2 expression, leading to female-specific differences in T cell-dependent mouse models of autoimmunity. Female mice with reduced Cd2 expression have impaired autoreactive T cell responses. T cells lacking Cd2 costimulation upregulate inhibitory Lag-3. These findings help explain sexual dimorphism in human autoimmunity, as we find that CD2 polymorphisms are associated with rheumatoid arthritis and 17-β-estradiol-regulation of CD2 is conserved in human T cells. Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice. These results demonstrate the relevance of sex-genotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.

Polymorphic estrogen receptor binding site causes CD2-dependent sex bias in the susceptibility to autoimmune diseases

Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors likely determines the sex discrepancy in the immune response, but conclusive evidence is lacking regarding the underlying molecular mechanisms. Using forward genetics, we positionally identified a polymorphic estrogen receptor binding site that regulates CD2 expression, leading to female-specific differences in mouse models of T cell-dependent autoimmunity. Female mice with reduced CD2 levels displayed diminished expansion of autoreactive T cells. Mechanistically, CD2 affected T cell activation by inhibiting LAG-3 expression. Our findings explain the sexual dimorphism in human autoimmunity, as CD2 associated with rheumatoid arthritis and its regulation through 17-β-estradiol was conserved in human T cells. Hormonal regulation of CD2 has implications for CD2-targeted therapy. Indeed, anti-CD2 treatment was more potent in female mice. In conclusion, our results demonstrate the relevance of sex-genotype interactions and provide strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.

Hibiscus Anthocyanins Can Selectively Modulate Estrogen Receptor Activity with Favorable Toxicology: a Computational Analysis

The estrogen hormone receptor (ER) mediated gene expression mainly regulate the development and physiology of primary and secondary reproductive system alongside bone-forming, metabolism and behaviour. Over-expressed ER is associated with several pathological conditions and play a key role in breast cancer occurrence, progression and metastasis. Hibiscus sabdariffa L. or roselle is a rich source of naturally occurring polyphenolic compounds including anthocyanins and reportedly have strong estrogenic activity. To validate these findings, we have investigated the estrogen receptor binding affinity and safety of some previously recorded polyphenols using a suite of computational methods. Our investigation showed the estrogen-receptor binding potential of Pelargonidin, Delphinidin, Cyanidin, and Hibiscetin are more efficient than popular breast cancer drugs, Tamoxifen and Raloxifene, with favourable toxicological parameters and low half maximal inhibitory concentration. This is the first report to investigate the phytochemical basis of estrogenic activity of Hibiscus sabdariffa L.

Estrogen Receptor–Binding Fragment–Associated Antigen 9 Is a Tumor-Promoting and Prognostic Factor for Renal Cell Carcinoma

The estrogen receptor–binding fragment–associated antigen9 (EBAG9) has been identified as a primary estrogenresponsivegene in human breast cancer MCF7 cells. A highexpression of EBAG9 has been observed in invasive breastcancer and advanced prostate cancer, suggesting a tumorpromotingrole of the protein in malignancies. Here we showthat intratumoral (i.t.) administration of small interferingRNA against EBAG9 exerted overt regression of tumorsfollowing s.c. implantation of murine renal cell carcinoma(RCC) Renca cells. Overexpression of EBAG9 did not promotethe proliferation of culture Renca cells; however, theinoculated Renca cells harboring EBAG9 (Renca-EBAG9) inBALB/c mice grew faster and developed larger tumorscompared with Renca cells expressing vector alone (Rencavector).After renal subcapsular implantation, Renca-EBAG9tumors significantly enlarged compared with Renca-vectortumors in BALB/c mice, whereas both Renca-EBAG9 andRenca-vector tumors were developed with similar volumes inBALB/c nude mice. No apparent difference was observed inspecific cytotoxic T-cell responses against Renca-EBAG9 andRenca-vector cells; nonetheless, the number of infiltratingCD8+ T lymphocytes was decreased in Renca-EBAG9 subcapsulartumors. Furthermore, immunohistochemical study ofEBAG9 in 78 human RCC specimens showed that intense anddiffuse cytoplasmic immunostaining was observed in 87% ofthe cases and positive EBAG9 immunoreactivity was closelycorrelated with poor prognosis of the patients. Multivariateanalysis revealed that high EBAG9 expression was anindependent prognostic predictor for disease-specific survival(P = 0.0485). Our results suggest that EBAG9 is a crucialregulator of tumor progression and a potential prognosticmarker for RCC.