Jci.Org Volume 126 Number 4 April 2016 1239 Commentary the Journal of Clinical Investigation

The Journal of Clinical Investigation COMMENTARY Estrogen turns down “the AIRE” Pearl Bakhru and Maureen A. Su Department of Pediatrics, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Early clues that sex hormones may Genetic alterations are known drivers of autoimmune disease; however, also modulate thymic stromal populations, there is a much higher incidence of autoimmunity in women, implicating such as mTECs, came from elegant studies sex-specific factors in disease development. The autoimmune regulator that utilized bone marrow chimeras (5, 6). (AIRE) gene contributes to the maintenance of central tolerance, and These studies showed that thymic epitheli- complete loss of AIRE function results in the development of autoimmune al cells express estrogen receptor (ER) and polyendocrinopathy syndrome type 1. In this issue of the JCI, Dragin and androgen receptor (AR) and that expres- colleagues demonstrate that AIRE expression is downregulated in females sion of these hormone receptors in the stromal compartment is required for alter- as the result of estrogen-mediated alterations at the AIRE promoter. The ing bone marrow–derived T cell subsets association between estrogen and reduction of AIRE may at least partially in the thymus (5, 6). In this issue, Dragin account for the elevated incidence of autoimmune disease in women and et al. confirm that sex hormones indeed has potential implications for sex hormone therapy. act on receptors on thymic stromal cells to impinge upon T cell development within the thymus. Furthermore, this study dem- onstrates that sex hormones regulate AIRE Autoimmune disease: autoimmune disease autoimmune poly- expression in mTECs and, in particular, sex-dependent differences endocrinopathy syndrome type 1 (APS1, estrogen decreases AIRE to predispose The incidence of autoimmune disease is which is also known as autoimmune poly- females to autoimmunity (7). increasing worldwide; therefore, the need endocrinopathy-candidiasis-ectodermal to understand the basis of autoimmunity dystrophy [APECED]). Estrogen-mediated AIRE has taken on a new urgency. Progress in While genetics are a major factor that downregulation identifying genetic contributors to autoim- determines autoimmune disease predispo- Transcriptional control of AIRE is com- munity has been made through the study of sition, it is clear that sex also plays a defining plex and involves cis-regulatory elements monogenic autoimmune diseases. Such an role in disease development. The incidence and epigenetic modifications (Figure 1A). approach has identified critical immune- of autoimmunity is skewed toward females Identified regulators include enhancer regulatory genes, such as the autoimmune for many autoimmune diseases, including elements that contain NF-κB response ele- regulator (AIRE), which encodes a nuclear Sjögren’s disease, systemic lupus erythe- ments (8, 9); transcription factors, includ- protein that functions as a key regulator matosus (SLE), and autoimmune thyroid ing activator protein-1 (AP-1), specificity of thymic central tolerance (reviewed in disease (reviewed in ref. 2). Remarkably, protein 1 (Sp1), nuclear factor Y (NF-Y), ref. 1). AIRE enforces self tolerance by pro- over 80% of those affected with these con- and ETS family transcription factors (10); moting the promiscuous expression of tis- ditions are female, illustrating the strong histone modifications (9); and DNA meth- sue self-antigens (TSAs) within medullary influence of sex in disease predisposition. ylation (11). Dragin et al. report that direct thymic epithelial cells (mTECs), a nonhe- Multiple factors likely underlie this sex bias, binding of estrogen/ER complexes to the matopoietic, stromal cell population (Fig- including the distinct sex hormone pro- AIRE promoter is unlikely, as predicted ure 1A). Presentation of these TSAs within files in females versus males. Accumulat- estrogen response elements are lacking the thymus results in negative selection of ing evidence suggests that male androgen at this site. Instead, estrogen-dependent bone marrow–derived T cells, which rec- hormones are immune suppressive, while downregulation of AIRE transcription ognize these TSAs with high affinity. In female estrogen hormones are immune was determined to be dependent on DNA addition to eliminating autoreactive T cell activating. For instance, androgen increas- methylation, an epigenetic mark of gene clones within the thymus, AIRE also main- es the differentiation of immunoregulatory silencing (Figure 1B). An inhibitor of DNA tains self tolerance by diverting autoreac- CD4+CD25+FOXP3+ T cells (3), whereas methyltransferases (DNMTs), 5-aza-2′- tive T cells into the Treg lineage. AIRE is estrogen enhances survival of T cells in deoxycytidine, blocked estrogen-medi- important for preventing autoimmune dis- patients with autoimmunity (4). Thus, there ated modulation of AIRE, and addition ease, as individuals with a complete loss is a plethora of evidence that sex hormones of estrogen to primary human mTEC cul- of AIRE function develop the multiorgan directly modulate T cells in the periphery. tures increased DNA methylation at the AIRE promoter. Notably, it remains to be clarified exactly how estrogen promotes Related Article: p. 1525 DNA methylation. One could speculate Conflict of interest: The authors have declared that no conflict of interest exists. that estrogen/ER complexes may promote Reference information: J Clin Invest. 2016;126(4):1239–1241. doi:10.1172/JCI86800. DNMT function to increase DNA methyla- jci.org Volume 126 Number 4 April 2016 1239 COMMENTARY The Journal of Clinical Investigation Figure 1. Estrogen downregulates AIRE-mediated central (thymic) tolerance. (A) AIRE in mTECs plays a major role in protection against autoimmunity. AIRE upregulates expression of TSAs, so that high-affinity T cells (Teff) that recognize these TSAs are triggered to undergo negative selection. Addition- ally, AIRE induces Treg development. AIRE expression is regulated by NF-κB responsive enhancer elements (~3 kB upstream of AIRE), transcription factors (Sp1, AP-1, NF-Y, ETS family transcription factors [ETS/TF], and AR [not shown]), and DNA methylation of the AIRE promoter region. (B) Estrogen (E)/ER complexes downregulate AIRE through DNA methylation. Although the mechanism is not known, ER may potentially facilitate DNMT activity or bind to other transcription factors to induce DNA methylation. DNA methylation results in AIRE gene silencing with decreased AIRE-dependent TSA expression, escape of self-reactive T cells from negative selection, and decreased Treg development. These estrogen effects contribute to increased susceptibility to autoimmunity. tion or that the estrogen/ER complex may instance, patients and mice with a single also stifle an effective immune response indirectly inhibit DNA demethylation. Evi- copy of a dominant AIRE mutation have against the cancer cells. Thus, therapies dence in support of the former comes from a quantitative decrease in AIRE function that alter estrogen production/effects may studies in breast cancer that suggest that and develop autoimmune manifestations have a deleterious effect on the anticancer ER may indeed positively regulate DNMTs (14, 15). Thus, “dialing down” AIRE func- immune response, a possibility that war- (12). It is also possible that estrogen/ER tion to intermediate levels also elevates rants further study. may bind to other transcription factors to the incidence of autoimmunity. Given enhance transcription. Indeed, ER bind- this, the effects of estrogen on reducing Conclusions and future ing to AP1, which is predicted to bind to AIRE expression could account for the directions the AIRE promoter region (13), has been increased autoimmune predisposition The findings in the study by Dragin and described in other cell types. noted in females. Estrogen downregula- colleagues provoke a number of follow-up tion of AIRE may be particularly relevant questions. First, the authors show that, in Clinical implications to autoimmune thyroiditis, which mostly addition to estrogen, other sex hormones of estrogen-mediated affects females, as Dragin et al. show that (progesterone and the androgen dihy- AIRE regulation estradiol treatment exacerbates autoan- drotestosterone [DHT]) also affect AIRE The finding that estrogen downregulates tibody production in a mouse model of mRNA levels. Progesterone, similarly to AIRE has substantial clinical implica- autoimmune thyroiditis through a thymus- estrogen, decreased AIRE expression, tions. Estrogen downregulation of AIRE dependent mechanism (7). while the androgen DHT increased AIRE. may account, in part, for the increased Estrogen downregulation of AIRE may What are the mechanisms by which these risk of autoimmunity in females. Dragin be relevant, not only to autoimmunity, hormones regulate AIRE transcription? et al. demonstrated that AIRE expression but also to cancer. Therapies that block Our data indicate that DHT/AR complexes is lower in females than males, and this estrogen production or estrogen-mediated bind directly to androgen response ele- difference was only seen after the onset of effects (such as selective ER modulators ments (AREs) in the AIRE promoter to puberty, a time when females have higher [SERMs]) are commonly used to treat upregulate AIRE transcription (18). Does circulating levels of estrogen than males. In breast cancer. These therapies are utilized progesterone act through

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