Autoimmune Polyendocrinopathy Syndrome 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.

Clinical profile, etiology, and diagnostic challenges of primary adrenal insufficiency in Sudanese children: 14-years' experience from a resource limited setting.

Primary adrenal insufficiency (PAI) in children is an uncommon condition. Congenital adrenal hyperplasia (CAH) is the commonest cause followed by autoimmune disorders. Diagnosis and management are challenging especially in resource-limited settings. Studies from Africa are scanty and here we describe for the first time the clinical presentation, possible etiologies, and challenges in diagnosis and management of PAI in a large cohort of Sudanese children. This was a descriptive hospital-based study where all patients diagnosed with PAI between 2006 and 2020 were reviewed. The diagnosis was based on clinical presentation, low morning cortisol±high adrenocorticotropic hormone (ACTH), or inadequate response of cortisol to synacthen stimulation. Challenges faced in diagnosis and management were identified. From 422 PAI suspected patients, 309 (73.2%) had CAH, and 33 (7.8%) had PAI-like symptoms and were not furtherly discussed. Eighty patients (19%) had fulfilled the study criteria: 29 had Allgrove syndrome, nine auto-immune polyendocrinopathy syndrome, seven adrenoleukodystrophy, and one had an adrenal hemorrhage. Hyperpigmentation was the cardinal feature in 75 (93.8%) while the adrenal crisis was not uncommon. Lack of diagnostic facilities has obscured the etiology in 34 (42.5%) patients. PAI is not uncommon in Sudanese children where genetic causes outweigh the autoimmune ones. Many cases were missed due to nonspecific presentation, lack of awareness, and difficult access to tertiary health care facilities. In addition to the clinical findings, early morning cortisol±ACTH levels can be used in diagnosis where facilities are limited particularly synacthen stimulation test.

IPEX as a Consequence of Alternatively Spliced FOXP3.

The transcription factor FOXP3 controls the immunosuppressive program in CD4+ T cells that is crucial for systemic immune regulation. Mutations of the single X-chromosomal FOXP3 gene in male individuals cause the inherited autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome. Insufficient gene expression and impaired function of mutant FOXP3 protein prevent the generation of anti-inflammatory regulatory T (Treg) cells and fail to inhibit autoreactive T cell responses. Diversification of FOXP3 functional properties is achieved through alternative splicing that leads to isoforms lacking exon 2 (FOXP3Δ2), exon 7 (FOXP3Δ7), or both (FOXP3Δ2Δ7) specifically in human CD4+ T cells. Several IPEX mutations targeting these exons or promoting their alternative splicing revealed that those truncated isoforms cannot compensate for the loss of the full-length isoform (FOXP3fl). In this review, IPEX mutations that change the FOXP3 isoform profile and the resulting consequences for the CD4+ T-cell phenotype are discussed.

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.

27-Year-Old Woman With Fever, Headache, and Anemia

27-Year-Old Woman With Fever, Headache, and Anemia

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.

Autoimmune Polyendocrinopathy.

This mini-review offers an update on the rare autoimmune polyendocrinopathy (AP) syndrome with a synopsis of recent developments. Systematic search for studies related to pathogenesis, immunogenetics, screening, diagnosis, clinical spectrum, and epidemiology of AP. AP (orphan code ORPHA 282196) is defined as the autoimmune-induced failure of at least two glands. AP is divided into the rare juvenile type I and the adult types II to IV. The prevalence is 1:100,000 and 1:20,000 for types I and types II to IV, respectively. Whereas type I (ORPHA 3453) is a monogenetic syndrome with an autosomal recessive transmission related to mutations in the autoimmune regulator (AIRE) gene, types II to IV are genetically complex multifactorial syndromes that are strongly associated with certain alleles of HLA genes within the major histocompatibility complex located on chromosome 6, as well as the cytotoxic T lymphocyte antigen 4 and the protein tyrosine phosphatase nonreceptor type 22 genes. Addison disease is the major endocrine component of type II (ORPHA 3143), whereas the coexistence of type 1 diabetes and autoimmune thyroid disease is characteristic for type III (ORPHA 227982). Genetic screening for the AIRE gene is useful in patients with suspected type I, whereas serological screening (i.e., diabetes/adrenal antibodies) is required in patients with monoglandular autoimmunity and suspected AP. If positive, functional endocrine testing of the antibody-positive patients as well as serological screening of their first-degree relatives is recommended. Timely diagnosis, genetic counseling, and optimal long-term management of AP is best offered in specialized centers.

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.