Autoimmune Polyendocrinopathy Syndrome Type Research Articles

Human autoantibodies neutralizing type I IFNs: From 1981 to 2023.

Human autoantibodies (auto-Abs) neutralizing type I IFNs were first discovered in a woman with disseminated shingles and were described by Ion Gresser from 1981 to 1984. They have since been found in patients with diverse conditions and are even used as a diagnostic criterion in patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1). However, their apparent lack of association with viral diseases, including shingles, led to wide acceptance of the conclusion that they had no pathological consequences. This perception began to change in 2020, when they were found to underlie about 15% of cases of critical COVID-19 pneumonia. They have since been shown to underlie other severe viral diseases, including 5%, 20%, and 40% of cases of critical influenza pneumonia, critical MERS pneumonia, and West Nile virus encephalitis, respectively. They also seem to be associated with shingles in various settings. These auto-Abs are present in all age groups of the general population, but their frequency increases with age to reach at least 5% in the elderly. We estimate that at least 100 million people worldwide carry auto-Abs neutralizing type I IFNs. Here, we briefly review the history of the study of these auto-Abs, focusing particularly on their known causes and consequences.

Recurrent venous thrombosis - an unusual first presentation of autoimmune polyendocrinopathy syndrome type 3B.

A 45-year-old female presented with unprovoked recurrent venous thromboembolism (VTE), in unusual sites, and pancytopenia, posing a complex diagnostic challenge. Work-up for inherited thrombophilia, antiphospholipid syndrome (APLS) and paroxysmal nocturnal haemoglobinuria were unremarkable. Investigations revealed autoimmune thyroid disease, and a mixed iron/vitamin B12 deficiency due to pernicious anaemia and resultant atrophic gastritis. Hyperhomocysteinaemia due to vitamin B12 deficiency was identified as a potential contributor to her recurrent VTE. This case highlights the unusual initial presentation of autoimmune polyendocrinopathy syndrome type 3B (APS-3B) with recurrent thromboembolism, and emphasises the importance of considering hyperhomocysteinaemia in unprovoked and atypical VTE cases.

Early-onset Chronic Keratitis as the First Presenting Component of Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1): A Case Report and Review of the Literature

Early-onset Chronic Keratitis as the First Presenting Component of Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1): A Case Report and Review of the Literature

Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

Initiation of Continuous rhPTH Infusion With Insulin Pump in an Inpatient Setting

Abstract Hypoparathyroidism is one of the few remaining hormonal insufficiencies not treated with replacement of its missing hormone. Conventional therapy involves multiple daily oral doses of calcium, active vitamin D, and magnesium, which is not only cumbersome for patients, but carries risk of nephrocalcinosis and is inadequate in patients with enteral malabsorption. Subcutaneous parathyroid hormone 1-34 (PTH[1-34]) has been tested as a hormonal replacement therapy for treatment of hypoparathyroidism. PTH(1-34) delivered by continuous infusion via insulin pump decreases or eliminates the need for oral medications, stabilizes serum and urine calcium at normal levels with minimal fluctuation, and significantly reduces PTH doses. In this case report, we describe the clinical application of PTH(1-34) via insulin pump in an adolescent with autoimmune polyendocrinopathy syndrome type 1 (APS1). Transition to a PTH pump reduced hospital admissions for calcium abnormalities and allowed our patient to discontinue all scheduled daily conventional therapy.

Impaired thymic AIRE expression underlies autoantibodies against type I IFNs in humans with inborn errors of the alternative NF-κB pathway

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency display autoantibodies (auto-Abs) neutralizing type I IFNs, conferring a predisposition to life-threatening COVID-19 pneumonia. We report that patients with autosomal recessive NIK or RelB deficiency, or a specific type of autosomal dominant (AD) NF-κB2 deficiency also display neutralizing auto-Abs against type I IFNs. They are prone to severe viral disease, including life-threatening COVID-19 pneumonia, influenza pneumonia, and severe form of varicella. Among patients with AD NF-κB2 deficiency, these auto-Abs are found only in heterozygotes with variants that are both transcriptionally loss-of-function (p52 activity), due to impaired p100 processing into p52, and regulatory gain-of-function (IκBδ activity), due to accumulation of unprocessed p100, thus increasing the inhibitory IκBδ activity (p52LOF/IκBδGOF). Conversely, neutralizing auto-Abs against type I IFNs are not found in individuals heterozygous for NFKB2 variants causing either p100 and p52 haploinsufficiency (p52LOF/IκBδLOF), or p52 gain-of-function (p52GOF/IκBδLOF). Unlike patients with APS-1, patients with disorders of NIK, RelB, or NF-κB2 harbor very few other auto-Abs. Their thymuses are however abnormally structured, and their medullary thymic epithelial cells (mTECs) have defective AIRE expression. Human inborn errors of the alternative NF-κB pathway impair thymic AIRE expression in mTECs, thereby underlying the production of auto-Ab against type I IFNs and predisposition to viral diseases.

Tip 1 Diabetes Mellitus Tanılı Çocuklarda Otoimmün Poliendokrinopati Tip 3b Sıklığı

Amaç: Tip 3 otoimmün poliendokrinopati sendromu (OPS), Addison hastalığı olmaksızın otoimmün tiroid hastalığı ile diğer bir otoimmün hastalık birlikteliği olarak tanımlanmaktadır. Hastada otoimmün bir gastrointestinal hastalık olursa klinik tablo tip 3b OPS olarak tanımlanır. Bu incelemede çocukluk çağında tip 1 diyabet (T1D) tanısı almış hastalarda tip 3b OPS sıklığı araştırılması amaçlandı. Gereç ve Yöntemler: Çalışmaya 01.06.2013-31.08.2019 tarihleri arasında takibi yapılmış 232’si erkek 446 T1D’li çocuk çalışmaya alındı. Hashimoto tiroiditi (HT), pozitif anti TPO ve/veya anti-Tg pozitifliği ile otoimmün enteropati ise anti-doku transglutaminaz Ig A pozitifliğini takiben yapılmış ince bağırsak biyopsisinde çölyak hastalığı (ÇH) ile uyumlu histoloji varlığı ile tanımlandı. Bulgular: Hastaların 61’inde (%13,7) HT ve 34’ünde (%7,6) ÇH tespit edildi. Hastaların 87’sinde (%19,5) HT veya ÇH varken, aynı hastada hem HT hem de ÇH varlığı (tip 3b OPS) sadece 3’ü kız 4 hastada (%0,9) tespit edildi. Tip 3b OPS’li hastaların T1D tanı yaşı sadece HT veya sadece ÇH olanlar ve her iki hastalığı olmayanlar ile karşılaştırıldığında daha düşük olmakla birlikte istatistiksel bir farksaptanmadı (p=0,087). Sonuç: Çocukluk çağında tanı almış T1D’li çocukların yaklaşık beşte birinde HT veya ÇH tespit edilirken tip 3b OPS sıklığının oldukça nadir olduğu tespit edilmiştir.

Chronic cutaneous candidiasis in children: should we stop there? Report of two cases associated with auto-immune polyendocrinopathy syndrome type I

BackgroundAuto-immune polyendocrinopathy syndrome type I is a rare genetic disease, usually revealed by chronic superficial candidiasis and autoimmune endocrine dysfunction in childhood.Cases presentationWe report the cases of 2 children, a 4 years-11 months old boy and 13 years old adolescent, admitted and followed up in the endocrinology unit of the Mother and Child Centre of Chantal Biya’s Foundation for auto-immune polyendocrine syndrome type 1.ConclusionThe occurrence of chronic cutaneous candidiasis in a child should always imply endocrine screening, to exclude auto-immune polyendocrine syndrome type I.

Autoimmune polyendocrinopathy syndrome type 1: new conceptions on pathogenesis and extended clinical symptoms

The objective was to present the caseof autoimmune polyendocrinopathy syndrome type 1 (APS1) and new clinical aspects and current knowledge of its pathogenesis.Materials and methods. This article includes clinical data, laboratory parameters, treatment and follow­updata of the patient with APS1. Also, a review of the latest data in world literature was made.Results and discussion. The described patient has two main criteria for APS1: hypoparathyroidism and chronic mucosal candidiasis, as well as some additional ones such as: autoimmune thyroiditis with hypothyroidism, type 1 diabetes, malabsorption syndrome. Periodic seizures and gait abnormality may be due to a chronic inflammatory demyelinating polyneuropathy. The diagnosis of APS1 is to detect the genetic anomaly underlying the syndrome: mutations in the AIRE gene and identification of organspecific antibodies. International studies have shown that 100 % of patients with APS1have autoantibodies that interact with interferon omega, so tests for such autoantibodies can help to get quick diagnosis. The treatment consists of correction of endocrine insufficiency with hormone replacement therapy, and specific treatment of other diseases common to APS1.Conclusions. APS1 is extremely diverse in its symptoms and the progression of the disease causes the expanding of clinical spectrum of its components. Therefore this syndrome must be diagnosed in the early stages, taking into account high morbidity and mortality. The main purpose of treatment is to preserve the patient’s life and maintain its quality good. Awareness of this rare autoimmune polyendocrine disorder can help a doctor to recognize it and treat timely, preventing potential death­related illnesses.

MON-364 Autoimmune Polyendocrinopathy Syndrome Type I Presented with Adrenal Insuffiency and Nail Fungal Infection Confirmed by Homozygous Pathogenic Variant in the AIRE Gene

Autoimmune polyglandular syndrome type 1 (APS-1) is a rare and complex recessively inherited disorder. APS-1 diagnosed when patient have at least two of the three major conditions that result from this syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency. APS-1 is caused by changes (mutations) in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis (CMC), a condition of recurrent candidiasis infections that may involve the skin, nails, oral, anal and genital mucosa, is a hallmark of APS-1. We report a7 years old boy with history of fungal infections since early childhood affecting nails and skin. Also he has alopecia . recurrent abdominal pain,lethargy and vomiting. At diagnosis his skin was hyper pigmented at gums and palms and nail dystrophy. His laboratory shows high ACTH 1251 pmol/l and low aldosterone 57 pg/ml. he has positive candida culture in the nail. We send genetic study Whole Exome Sequencing and came to be positive for A homozygous pathogenic variant in the AIRE gene. c.205_208dup p.(Asp70Alafs*148). The child was treated with hydrocortisone and fludrocortisone. We report a rare case of a homozygous pathogenic variant in the AIRE gene that illustrate the typical presentation of APS type 1

Transfer Factor Revisited: Treatment of Chronic Mucocutaneous Candidiasis in a Child with Autoimmune Polyendocrinopathy Syndrome Type-1

A 5-year-old boy was diagnosed as having chronic mucocutaneous candidiasis at the age of three months. He showed no improvement despite treatment with two courses of intravenous amphotericin B, 2½ years of oral 5-fluorocytosine, and daily treatment with topical Mycostatin. An immune assessment revealed that he was anergic and had low levels of circulating FCγR+ monocytes. Buccal smears revealed numerous candida and no inflammatory response. On treatment with transfer factor his FCγR+ monocyte count increased from 10 to 429 cells/cumm.

Development and Validation of an Ultrasensitive Single Molecule Array Digital Enzyme-linked Immunosorbent Assay for Human Interferon-α.

The main aim of this protocol is to describe the development and validation of an interferon (IFN)-α single molecule array digital Enzyme-Linked ImmunoSorbent Assay (ELISA) assay. This system enables the quantification of human IFN-α protein with unprecedented sensitivity, and with no cross-reactivity for other species of IFN.The first key step of the protocol is the choice of the antibody pair, followed by the conjugation of the capture antibody to paramagnetic beads, and biotinylation of the detection antibody. Following this step, different parameters such as assay configuration, detector antibody concentration, and buffer composition can be modified until optimum sensitivity is achieved. Finally, specificity and reproducibility of the method are assessed to ensure confidence in the results. Here, we developed an IFN-α single molecule array assay with a limit of detection of 0.69 fg/mL using high-affinity autoantibodies isolated from patients with biallelic mutations in the autoimmune regulator (AIRE) protein causing autoimmune polyendocrinopathy syndrome type 1/autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APS1/APECED). Importantly, these antibodies enabled detection of all 13 IFN-α subtypes.This new methodology allows the detection and quantification of IFN-α protein in human biological samples at attomolar concentrations for the first time. Such a tool will be highly useful in monitoring the levels of this cytokine in human health and disease states, most particularly infection, autoimmunity, and autoinflammation.

Development and Validation of an Ultrasensitive Single Molecule Array Digital Enzyme-linked Immunosorbent Assay for Human Interferon-α

The main aim of this protocol is to describe the development and validation of an interferon (IFN)-α single molecule array digital Enzyme-Linked ImmunoSorbent Assay (ELISA) assay. This system enables the quantification of human IFN-α protein with unprecedented sensitivity, and with no cross-reactivity for other species of IFN. The first key step of the protocol is the choice of the antibody pair, followed by the conjugation of the capture antibody to paramagnetic beads, and biotinylation of the detection antibody. Following this step, different parameters such as assay configuration, detector antibody concentration, and buffer composition can be modified until optimum sensitivity is achieved. Finally, specificity and reproducibility of the method are assessed to ensure confidence in the results. Here, we developed an IFN-α single molecule array assay with a limit of detection of 0.69 fg/mL using high-affinity autoantibodies isolated from patients with biallelic mutations in the autoimmune regulator (AIRE) protein causing autoimmune polyendocrinopathy syndrome type 1/autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APS1/APECED). Importantly, these antibodies enabled detection of all 13 IFN-α subtypes. This new methodology allows the detection and quantification of IFN-α protein in human biological samples at attomolar concentrations for the first time. Such a tool will be highly useful in monitoring the levels of this cytokine in human health and disease states, most particularly infection, autoimmunity, and autoinflammation.

Aire is not essential for regulating neuroinflammatory disease in mice transgenic for human autoimmune-diseases associated MHC class II genes HLA-DR2b and HLA-DR4

The human autoimmune disease-associated HLA alleles HLA-DR2b (DRB1*1501) and HLA-DR4 (DRB1*0401) are strongly linked to increased susceptibility for multiple sclerosis (MS) and rheumatoid arthritis (RA), respectively. The underlying mechanisms are not fully understood, but these MHC alleles may shape the repertoire of pathogenic T cells via central tolerance. The transcription factor autoimmune regulator (AIRE) promotes central T cell tolerance via ectopic expression of tissue-specific antigens (TSAs). Aire deficiency in humans causes autoimmune polyendocrinopathy syndrome type 1 (APS1), and Aire knockout mice (Aire−/−) develop spontaneous autoimmune pathology characterized by multi-organ lymphocytic infiltrates.Here, we asked whether impaired TSAs gene expression in the absence of Aire promoted spontaneous MS- or RA-like autoimmune pathology in the context of human HLA alleles in HLA-DR2b or HLA-DR4 transgenic (tg) mice.The results show that reduced TSAs gene expression in the thymus of Aire-deficient HLA-DR2b or HLA-DR4 tg mice corresponded to mild spontaneous inflammatory infiltrates in salivary glands, liver, and pancreas. Moreover, Aire-deficiency modestly enhanced experimental autoimmune encephalomyelitis (EAE) in HLA-DR tg mice, but the animals did not show signs of spontaneous neuroinflammation or arthritis. No significant changes were observed in CD4+ T cell numbers, T cell receptor (TCR) distribution, regulatory T cells (Treg), or antigen-induced cytokine production. Abrogating Treg function by treatment with anti-CTLA-4 or anti-CD25 mAb in Aire-deficient HLA-DR tg mice did not trigger EAE or other autoimmune pathology. Our results suggest a redundant role for Aire in maintaining immune tolerance in the context of autoimmune disease-associated human HLA alleles.

Aire is not essential for regulating autoimmune pathology in mice transgenic for human autoimmune-disease associated MHC class II genes HLA-DR2b and HLA-DR4.

Abstract The human MHC class II molecules HLA-DR2b (DRB1*1501) and HLA-DR4 (DRB1*0401) are strongly linked to increased susceptibility to autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (RA). However, their contribution to disease pathogenesis is not completely understood. Conceivably, autoimmune disease-associated HLA alleles could shape the repertoire of pathogenic T cells via central or peripheral tolerance. The ectopic expression of tissue-specific antigens promoted by the autoimmune regulator (AIRE) is thought to play a critical role in central tolerance. Aire knockout mice (Aire−/−) develop spontaneous autoimmune pathology characterized by multi-organ lymphocytic infiltrates. Aire deficiency in humans causes multi-organ autoimmune conditions observed in autoimmune polyendocrinopathy syndrome type 1 (APS I). We wanted to investigate whether lack of Aire expression promoted spontaneous MS- or RA-like autoimmune pathology in HLA-DR2b or HLA-DR4 transgenic (tg) mice. We observed that Aire-deficiency modestly enhanced experimental autoimmune encephalomyelitis (EAE) in HLA-DR tg mice, but did not lead to spontaneous neuroinflammation or arthritis. Our results suggest that Aire has a mild and non-essential effect in restraining the autoimmune response in the context of autoimmune disease-associated human HLA alleles.

A Case of Pediatric Adrenal Crisis, Not Just a Condition of Infancy

Pediatric adrenal insufficiency is often thought to mainly affect patients with congenital adrenal hyperplasia (CAH) in the newborn period. However, many cases occur outside of infancy and are not related to CAH. They often present in an insidious nature with symptoms attributed to more common and often benign etiologies. Unfortunately, if not diagnosed early, adrenal insufficiency can lead to acute adrenal crisis with hemodynamic collapse. We present the case of a 15-year-old young man with a history of hypothyroidism who presented to an ED and developed hypotension and wide complex tachycardia due to hyperkalemia. After initial fluid resuscitation and treatment for his arrhythmia, he was then emergently transported to our hospital for further work up and care. Laboratory studies ultimately diagnosed him with Autoimmune Polyendocrinopathy Syndrome Type II leading to adrenal crisis.

Group 6. Modalities and frequency of monitoring of patients with adrenal insufficiency. Patient education

Patients with adrenal insufficiency require regular, specialised monitoring in order to optimise their replacement therapy, to detect signs of under- and over-dosage, and to examine for possible associated disorders (auto-immune disorders in the case of auto-immune primary adrenal insufficiency either isolated or as part of auto-immune polyendocrinopathy syndrome type 1; illnesses with underlying monogenic causes). The transition period between adolescence and adulthood represents an added risk of a breakdown in monitoring which requires particular attention from medical teams and coordination between adult and pediatric medical teams. It is essential to encourage patient autonomy in the management of their illness, notably their participation in treatment education programs, in particular programs that target avoidance of, or early treatment of acute adrenal insufficiency. The principal educational objectives for patients in such programs are: to be in possession of, and carry the necessary tools for their treatment in an emergency; to be able to identify situations of increased risk and the early signs of adrenal crisis; to know how to adjust their oral glucocorticoid treatment; to be capable of administering hydrocortisone by subcutaneous injection; to be able to predict and therefore adjust treatment to different situations (heat, physical exercise, travel) and to be able to correctly use the appropriate resources of the healthcare services. Other programs could also be developed to respond to needs and expectations of patients, notably concerning the adjustment of hydrocortisone dosage to avoid overdose in the context of chronic fatigue syndrome.

Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation.

Oesophageal candidiasis is a common, usually self-limiting opportunistic infection, but long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC). Permissive factors that lead to immune deficiencies can underlie persistent or recurring candidiasis, called chronic mucocutaneous candidiasis (CMC). Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy). Inborn errors of the immune system (primary immune deficiencies) can present with isolated CMC known as CMC disease (CMCD), which is most often found in patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)/APECED or in patients with an underlying gain-of-function STAT1 mutation (GOF-STAT1). To describe a new form of inherited/familial CMC with a high risk for developing squamous cell carcinoma of the oesophagus, due to a gain-of-function mutation in the STAT1 gene. This report describes a family of patients with CMC with confirmed GOF-STAT1 mutation. These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC. This case series describes six patients in three generations of the same family, two of whom developed and died of SCC. We recommend regular endoscopic surveillance to detect early oesophageal neoplasia in patients with CMCD as well as urgent endoscopy in symptomatic patients. CMC is not a well-recognised condition in gastroenterology practice and clinicians need to be aware of the genetics of the condition as well as the risk for oesophageal cancer so that they can counsel their patients and arrange surveillance appropriately.

Ocular manifestations of autoimmune polyendocrinopathy syndrome type 1.

The ocular manifestations in autoimmune polyendocrinopathy syndrome type 1 (APS1) are frequent and have a poor prognosis. The phenotype of these APS1-associated ocular features have been recently characterized in molecularly confirmed patients with APS1. Keratopathy and retinopathy can be severe manifestations of APS1. Heterogeneous corneal involvement can be observed, ranging from minimal superficial punctate staining to severe stromal scarring with deep corneal neovascularization. This phenotypic heterogeneity, observed even in patients with identical AIRE mutations, is suggestive of a poor genotype-phenotype correlation. Similarly, in patients with retinopathy, peripheral pigmentary changes are noted in all cases, yet with heterogeneous severity, ranging from isolated patchy atrophy of the retinal pigment epithelium to a retinitis pigmentosa-like fundus. Macular atrophy with vision loss is found in most cases. The severity of ophthalmic findings is uncorrelated to that of systemic manifestations. An autoimmune origin with specific autoantibodies directed against corneal and/or retinal autoantigens is the main mechanism believed to be responsible for the ocular manifestations of APS1. Progressive keratopathy and/or retinopathy can lead to severe visual loss and pain in patients with APS1. Although no treatment has shown efficacy regarding the APS1-associated ocular manifestations, ophthalmologic examinations are recommended in these patients.

Estrogen turns down "the AIRE".

Genetic alterations are known drivers of autoimmune disease; however, there is a much higher incidence of autoimmunity in women, implicating sex-specific factors in disease development. The autoimmune regulator (AIRE) gene contributes to the maintenance of central tolerance, and complete loss of AIRE function results in the development of autoimmune polyendocrinopathy syndrome type 1. In this issue of the JCI, Dragin and colleagues demonstrate that AIRE expression is downregulated in females as the result of estrogen-mediated alterations at the AIRE promoter. The association between estrogen and reduction of AIRE may at least partially account for the elevated incidence of autoimmune disease in women and has potential implications for sex hormone therapy.