Autoimmune polyendocrine syndrome type Ⅰ complicated by respiratory system diseases in 3 cases

The autoimmune targets in IPEX are dominated by gut epithelial proteins

Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.

Beta-cell function and islet cell antibodies were studied in six patients with autoimmune polyendocrine syndrome type I. All suffered from mucocutaneous candidiasis, five had adrenocortical insufficiency and three hypoparathyroidism. All sera contained high titres of antibodies staining islets of Langerhans. Reactivity against glutamate decarboxylase, predominantly the 65 kDa isoform, was detected by immunoprecipitations and Western blots in five of the six sera, and all six sera immunoprecipitated a 51 kDa antigen from [35S]-methionine labelled rat islet cell lysates. No reactivity against this latter antigen was found in sera of patients with Type 1 (insulin-dependent) diabetes mellitus (n = 9), Graves' disease (n = 5), autoimmune gastritis (n = 4), idiopathic Addison's disease (n = 7), or stiff-man syndrome (n = 2). The 51 kDa antigen was also detected by Western blots using homogenates of rat islets and autoimmune polyendocrine syndrome type I patient sera, whereas no such reactivity was found with homogenates of testes, adrenals, small intestine, spleen, exocrine pancreas or brain. Moreover, the 51 kDa antigen was present in the rat insulinoma cell line RINm 5F but not in the SV-40 transformed, monkey kidney cell line COS, when examined by immunoprecipitations of [35S]-methionine labelled cell lysates and by Western blots. None of the patients with autoimmune polyendocrine syndrome type I had symptoms of diabetes and their insulin responses to glucose challenge were normal. The data illustrate that patients with autoimmune polyendocrine syndrome type I present an autoimmune response against islets of Langerhans, which is apparently different from that associated with classic Type 1 diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-cell function and islet cell antibodies were studied in six patients with autoimmune polyendocrine syndrome type I. All suffered from mucocutaneous candidiasis, five had adrenocortical insufficiency and three hypoparathyroidism. All sera contained high titres of antibodies staining islets of Langerhans. Reactivity against glutamate decarboxylase, predominantly the 65 kDa isoform, was detected by immunoprecipitations and Western blots in five of the six sera, and all six sera immunoprecipitated a 51 kDa antigen from [35S]methionine labelled rat islet cell lysates. No reactivity against this latter antigen was found in sera of patients with Type 1 (insulin-dependent) diabetes mellitus (n=9), Graves' disease (n=5), autoimmune gastritis (n=4), idiopathic Addison's disease (n=7), or stiffman syndrome (n=2). The 51 kDa antigen was also detected by Western blots using homogenates of rat islets and autoimmune polyendocrine syndrome type I patient sera, whereas no such reactivity was found with homogenates of testes, adrenals, small intestine, spleen, exocrine pancreas or brain. Moreover, the 51 kDa antigen was present in the rat insulinoma cell line RINm 5F but not in the SV-40 transformed, monkey kidney cell line COS, when examined by immunoprecipitations of [35S]-methionine labelled cell lysates and by Western blots. None of the patients with autoimmune polyendocrine syndrome type I had symptoms of diabetes and their insulin responses to glucose challenge were normal. The data illustrate that patients with autoimmune polyendocrine syndrome type I present an autoimmune response against islets of Langerhans, which is apparently different from that associated with classic Type 1 diabetes. As most of the autoantigens in many autoimmune diseases are enzymes involved in important functions in the affected organs, it is possible that the anti-51 kDa antibodies are directed against a protein with important functional activity in the islet.

Event Abstract Back to Event A novel cell-based assay for measuring neutralizing autoantibodies against type I interferons in patients with autoimmune polyendocrine syndrome type 1. Lars Breivik1*, Bergithe E. Oftedal1, Anette S. Wolff1, Elizaveta Orlova2 and Eystein S. Husebye1, 3 1 University of Bergen, Department of Clinical Science, Norway 2 Endocrinology Research Center, Institute of Paediatric Endocrinology, Russia 3 Haukeland University hospital,, Department of Medicine, Norway Autoimmune polyendocrine syndrome type 1 (APS-1) is a unique monogenic disorder caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. The loss of a functional AIRE protein presumably causes defects in central thymic tolerance and the escape of pathogenic autoreactive T cells into peripheral tissues. The most prevalent clinical manifestations are chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenocortical failure although a wide range of other autoimmune manifestations may occur. An important characteristic feature of APS-1 is the presence of neutralizing serum autoantibodies against type I interferons (subtypes –α and -ω) at frequencies approaching 100 %. These autoantibodies may therefore serve as an important diagnostic tool, complementing genetic mutation analysis of AIRE when APS-1 is suspected. Several techniques for measuring these antibodies are currently available, including fluid-phase binding assays using recombinant antigens labeled with radioactivity (radioactive immunoassay; RIA) or luciferase, and assays measuring the actual interferon-neutralizing capabilities of the antibodies such as the antiviral interferon neutralizing assay (AVINA). We report here on a cell-based assay using a commercially available reporter cell-line that provides a simple, sensitive, rapid and reliable way of assaying neutralizing autoantibodies against the type I interferons subtypes –α and –ω as compared to a RIA assay. Acknowledgements We would like to thank all the doctors and patients that contributed to this work. The technical help from Elisabeth T. Halvorsen is greatly acknowledged. The study has been supported by grants from Helse-Vest and The Norwegian Research Council. Keywords: Autoantibodies, Interferon Type I, Assay development, APS-1, biomarker Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Breivik L, Oftedal BE, Wolff AS, Orlova E and Husebye ES (2013). A novel cell-based assay for measuring neutralizing autoantibodies against type I interferons in patients with autoimmune polyendocrine syndrome type 1.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00920 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Lars Breivik, University of Bergen, Department of Clinical Science, BERGEN, N-5021, Norway, larsbreivik@hotmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Lars Breivik Bergithe E Oftedal Anette S Wolff Elizaveta Orlova Eystein S Husebye Google Lars Breivik Bergithe E Oftedal Anette S Wolff Elizaveta Orlova Eystein S Husebye Google Scholar Lars Breivik Bergithe E Oftedal Anette S Wolff Elizaveta Orlova Eystein S Husebye PubMed Lars Breivik Bergithe E Oftedal Anette S Wolff Elizaveta Orlova Eystein S Husebye Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Autoimmune polyendocrine (or polyglandular) syndrome (APS) is a relatively rare clinical condition characterized by functional impairment of multiple endocrine glands due to loss of immune tolerance. APS is broadly categorized as rare monogenic forms, such as autoimmune polyendocrine syndrome type 1 (APS-1), and a more common polygenic variety, autoimmune polyendocrine syndrome type 2 (APS-2). Although many autoimmune conditions including autoimmune rheumatic diseases can develop in APS-2, systemic sclerosis or myositis as a complication is quite rare and no treatment strategy has yet been established. A 25-year-old man who had been diagnosed as having type 1 diabetes developed finger stiffness. Although the subjective symptoms were relatively mild, extensive examinations including various autoantibodies, hormones and biopsy of the skin and minor salivary glands revealed that he had APS-2 (type 1 diabetes and autoimmune thyroid disease) accompanied by systemic sclerosis, myositis and Sjögren's syndrome. Rituximab therapy was initiated for the progressive skin sclerosis, and this resulted in significant alleviation of both the sclerosis and the myositis. In APS, early diagnosis and immunomodulatory therapy may arrest the autoimmune process before irreversible organ damage has occurred. This case report suggests that rituximab may be a promising therapy for autoimmune rheumatic diseases associated with APS-2.

Autoantibodies against IFN-α and IFN-ω (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-α and IFN-ω. The ability of the patients' sera to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females and younger than 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete.

Autoantibodies directed against proteins of the adrenal cortex and the liver were studied in 88 subjects of Sardinian descent, namely six patients with autoimmune polyendocrine syndrome type 1 (APS1), 22 relatives of APS1 patients, 40 controls with other autoimmune diseases, and 20 healthy controls. Indirect immunofluorescence, using tissue sections of the adrenal cortex, revealed a cytoplasmatic staining pattern in 4 of 6 patients with APS1. Western blotting with adrenal mitochondria identified autoantigens of 54 kDa and 57 kDa, Western blotting with placental mitochondria revealed a 54-kDa autoantigen. The 54-kDa protein was recognized by 4 of 6 patients with APS1 both in placental and adrenal tissue, whereas the 57-kDa protein was detected only by one serum. Using recombinant preparations of cytochrome P450 proteins, the autoantigens were identified as P450 scc and P450 c17. One of six APS1 patients suffered from chronic hepatitis. In this patient, immunofluorescence revealed a centrolobular liver and a proximal renal tubule staining pattern. Western blots using microsomal preparations of human liver revealed a protein band of 52 kDa. The autoantigen was identified as cytochrome P450 1A2 by use of recombinant protein preparations. P450 1A2 represents the first hepatic autoantigen reported in APS1. P450 1A2 usually is not detected by sera of patients with isolated autoimmune liver disease and might be a hepatic marker autoantigen for patients with APS1.

Cytokine-specific autoantibodies shape the gut microbiome in autoimmune polyendocrine syndrome type 1

Our study explores the impact of human parathyroid hormone (PTH) 1-34 injections (PTH therapy) on growth, areal bone mineral density (BMD), and bone quality (measured by trabecular bone score, TBS) in hypoparathyroidism due to autoimmune polyendocrine syndrome type 1 (APS-1) or an activating variant of the calcium sensing receptor (CaR). To assess associations of (1) age and PTH therapy duration with age-standardized Z-scores for height (HAZ), BMD (BMD-Z), and TBS (TBS-Z) in CaR or APS-1, and (2) APS-1 disease severity with BMD-Z and TBS-Z. This secondary analysis pooled linear growth and lumbar spine (LS) dual-energy x-ray absorptiometry data from studies of hypoparathyroidism with mean baseline age of 13.7 ± 5.5 years. Comparing the 2 diagnostic etiologies (18 APS-1 and 9 CaR), we examined the impact of age and PTH duration on HAZ, LS-BMD-Z, and LS-TBS-Z using longitudinal mixed-effects modeling. During PTH therapy, mean HAZ remained below 0 in the APS-1 group at all ages, whereas HAZ increased in the CaR group (age by group interaction P < .0001). Mean LS-BMD-Z were normal (BMD-Z: 0 ± 1) for both groups. Mean LS-TBS-Z were near or above 0 and differed by group; CaR showed an upward trajectory according to time on PTH whereas the APS-1 group maintained a LS-TBS-Z of approximately 0 (time by group interaction P = .02). The APS-1 group with greater disease severity (≥7 manifestations) had lower LS-BMD-Z and LS-TBS-Z than the less severe APS-1 or CaR groups. Our study highlights distinct growth and BMD patterns in APS-1 and CaR and underscores the need for careful monitoring and tailored treatment strategies to optimize growth and bone health.

IntroductionAutoimmune polyendocrine syndrome type 2 is a rare disorder. Its prevalence in western populations has been reported as 1.5 to 4.5/100,000. On the other hand, its prevalence in Egypt is unknown. It is characterized by the association of autoimmune Addison’s disease with thyroid autoimmune diseases and/or type I diabetes mellitus. Hepatitis C virus infection is an important public health issue worldwide. Egypt has the highest prevalence of hepatitis C virus infection of any country in the world. It is estimated to be 8% in urban and 25% in rural areas. We present the case of an Egyptian child with autoimmune polyendocrine syndrome type 2 associated with chronic hepatitis C infection.Case presentationA 14-year-old Egyptian boy with type 1 diabetes mellitus was referred to our institution for an evaluation of recurrent attacks of hypoglycemia of two months duration. The initial clinical examination revealed hypotension as well as vitiligo of the skin. He had high potassium, low sodium, low cortisol, high adrenocorticotropic hormone, slightly high thyroid stimulating levels with strong positivity of anti-thyroglobulin and anti-thyroid peroxidase antibodies. The hepatitis C antibody and hepatitis C virus–polymerase chain reaction were positive. Based on these findings, a diagnosis of autoimmune polyendocrine syndrome type 2 with chronic hepatitis C was made. He was started on hydrocortisone (10mg twice daily), fludrocortisone (0.1mg twice daily) and multiple daily doses of insulin. He showed great improvement of his symptoms on the prescribed treatment.ConclusionsThe importance of the early diagnosis of autoimmune polyendocrine syndrome type 2 and the possibility of its association with chronic hepatitis C infection should be considered in order to implement the proper management of such cases.

The identification of autoantigens remains a critical challenge for understanding and treating autoimmune diseases. Autoimmune polyendocrine syndrome type 1 (APS1), a rare monogenic form of autoimmunity, presents as widespread autoimmunity with T and B cell responses to multiple organs. Importantly, autoantibody discovery in APS1 can illuminate fundamental disease pathogenesis, and many of the antigens found in APS1 extend to more common autoimmune diseases. Here, we performed proteome-wide programmable phage-display (PhIP-Seq) on sera from a cohort of people with APS1 and discovered multiple common antibody targets. These novel APS1 autoantigens exhibit tissue-restricted expression, including expression in enteroendocrine cells, pineal gland, and dental enamel. Using detailed clinical phenotyping, we find novel associations between autoantibodies and organ-restricted autoimmunity, including a link between anti-KHDC3L autoantibodies and premature ovarian insufficiency, and between anti-RFX6 autoantibodies and diarrheal-type intestinal dysfunction. Our study highlights the utility of PhIP-Seq for extensively interrogating antigenic repertoires in human autoimmunity and the importance of antigen discovery for improved understanding of disease mechanisms.

The identification of autoantigens remains a critical challenge for understanding and treating autoimmune diseases. Autoimmune polyendocrine syndrome type 1 (APS1), a rare monogenic form of autoimmunity, presents as widespread autoimmunity with T and B cell responses to multiple organs. Importantly, autoantibody discovery in APS1 can illuminate fundamental disease pathogenesis, and many of the antigens found in APS1 extend to more common autoimmune diseases. Here, we performed proteome-wide programmable phage-display (PhIP-Seq) on sera from a cohort of people with APS1 and discovered multiple common antibody targets. These novel APS1 autoantigens exhibit tissue-restricted expression, including expression in enteroendocrine cells, pineal gland, and dental enamel. Using detailed clinical phenotyping, we find novel associations between autoantibodies and organ-restricted autoimmunity, including a link between anti-KHDC3L autoantibodies and premature ovarian insufficiency, and between anti-RFX6 autoantibodies and diarrheal-type intestinal dysfunction. Our study highlights the utility of PhIP-Seq for extensively interrogating antigenic repertoires in human autoimmunity and the importance of antigen discovery for improved understanding of disease mechanisms.

BackgroundAutoimmune polyendocrine syndrome (APS) is a clinical disorder characterized by the loss of immune tolerance, leading to dysfunction in multiple endocrine glands. According to the latest disease classification, APS is categorized into three main subtypes: APS-1, APS-2, and IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. APS-2 is defined by the presence of at least two autoimmune endocrine disorders, such as type 1 diabetes mellitus, autoimmune thyroiditis, or Addison’s disease. APS-2 typically manifests later than APS-1, with onset most commonly occurring in early adulthood. However, pediatric cases involving a combination of autoimmune thyroid disease, type 1 diabetes mellitus, and myasthenia gravis, are extremely rare.Case presentationThis article reported the case of a 3-year-old girl diagnosed with autoimmune polyendocrine syndrome type 2 (APS-2). The patient initially presented with hyperthyroidism and exophthalmos and was subsequently diagnosed with type 1 diabetes mellitus and myasthenia gravis. To our knowledge, this case represents the youngest reported patient of APS-2 at the time of diagnosis, as well as the shortest documented interval between the onset of autoimmune disorders affecting distinct endocrine glands.ConclusionsThrough a retrospective analysis, we comprehensively reviewed the phenotypic characteristics of APS-2 and explored its potential immune mechanisms. This article aims to provide clinicians with a valuable reference case to enhance early recognition and facilitate the implementation of targeted prevention and treatment strategies.

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disorder caused by pathogenic variants in the AIRE gene, characterized by impaired central immune tolerance and multi-organ autoimmune damage. While relatively common in genetically isolated populations, genetically confirmed APS-1 cases remain exceptionally rare in Chinese individuals. To date, population-specific genotypic and phenotypic features of APS-1 in China have not been systematically summarized. We report a 31-year-old female patient who presented with hypocalcemic convulsions as the initial symptom, accompanied by a 20-year history of vitiligo and mild anemia, newly developed chronic diarrhea and positive islet autoimmunity. Laboratory examinations confirmed hypoparathyroidism and stage 1 type 1 diabetes mellitus (T1DM) with significantly elevated islet autoantibodies but normal islet function. Genetic analysis identified novel compound heterozygous pathogenic variants in the AIRE gene: a missense variant c.977C>T (p.Pro326Leu) inherited from her mother and a 1.6 kb deletion spanning exons 2-4 with an untraceable origin due to the lack of paternal specimen, both classified as pathogenic according to ACMG guidelines. We performed a systematic narrative review integrating 24 previously reported genetically confirmed Chinese APS-1 cases, forming a combined cohort of 25 cases for comprehensive analysis. This study identified the deletion of AIRE gene exons 2-4 as a recurrent pathogenic variant observed in Chinese APS-1 patients, and revealed distinct phenotypic patterns of Chinese patients including a male-to-female ratio of 2:1, a low incidence of the classic triad (44%) and a 16% prevalence of pancreatic autoimmunity. As the first genetically confirmed Chinese case of APS-1 complicated with stage 1 T1DM, this report fills the gap in early pancreatic autoimmunity phenotypic data for Chinese APS-1 patients and enriches the disease's clinical and genetic spectrum. Clinicians should suspect APS-1 and prioritize early AIRE gene testing in young patients with non-surgical hypoparathyroidism and concurrent autoimmune manifestations to prevent misdiagnosis or delayed diagnosis.