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Humbert L, Proust-Lemoine E, Dubucquoi S, Kemp EH, Saugier-Veber P, Fabien N, Raymond-Top I, Cardot-Bauters C, Carel JC, Cartigny M, Chabre O, Chanson P, Delemer B, Do Cao C, Guignat L, Kahn JE, Kerlan V, Lefebvre H, Linglart A, Mallone R, Reynaud R, Sendid B, Souchon PF, Touraine P, Wémeau JL, Vantyghem MC. Lessons From Prospective Longitudinal Follow-up of a French APECED Cohort. J Clin Endocrinol Metab 2025; 110:e757-e773. [PMID: 38605470 PMCID: PMC11834711 DOI: 10.1210/clinem/dgae211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 03/05/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC) and nonendocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations, and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS A national, multicenter prospective observational study to collect genetic, clinical, biological, and immunological data (NCT03751683). RESULTS Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had natural killer cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (P < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine manifestations was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination and targeted therapeutic approaches.
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Affiliation(s)
- Linda Humbert
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Emmanuelle Proust-Lemoine
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Sylvain Dubucquoi
- Institut d’Immunologie-HLA, Centre de Biologie-Pathologie, 59037 Lille Cedex, France
- University of Lille, 59000 Lille, France
| | - Elisabeth Helen Kemp
- Department of Oncology and Metabolism, Faculty of Medicine, Dentistry and Health, University of Sheffield, Medical School, Sheffield S10 2RX, UK
| | - Pascale Saugier-Veber
- Department of Genetics and Reference Center for Developmental Disorders, Univ Rouen Normandie, Inserm U1245, Normandie Univ and CHU Rouen, F-76000 Rouen, France
| | - Nicole Fabien
- Laboratory of biology, CHU Lyon, 69 000 Lyon Cedex, France
| | - Isabelle Raymond-Top
- Institut d’Immunologie-HLA, Centre de Biologie-Pathologie, 59037 Lille Cedex, France
| | - Catherine Cardot-Bauters
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Jean-Claude Carel
- Service d’Endocrinologie Diabétologie Pédiatrique and INSERM NeuroDiderot, Centre de Référence Maladies Endocriniennes Rares de la Croissance, AP-HP Nord Université Paris Cité, Hôpital Universitaire Robert-Debré, 75935 Paris Cedex 19, France
| | - Maryse Cartigny
- Department of Pediatry, Hôpital Jeanne de Flandres, Lille University Hospital, F-59000 Lille, France
| | - Olivier Chabre
- Unité mixte de recherche INSERM-CEA-UGA UMR1036, Service d’Endocrinologie CHU Grenoble Alpes, Université Grenoble Alpes, 38000 Grenoble Alpes, France
| | - Philippe Chanson
- Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l’Hypophyse, Université Paris-Saclay, 94275 Le Kremlin-Bicêtre, France
| | - Brigitte Delemer
- Department of Endocrinology and Diabetology, CHU Reims, 51 092 Reims, France
| | - Christine Do Cao
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
| | - Laurence Guignat
- Centre de Référence des Maladies Rares de la Surrénale, Endocrinologie, Hôpital Cochin, 75014 Paris, France
| | - Jean Emmanuel Kahn
- Institut d’Immunologie-HLA, Centre de Biologie-Pathologie, 59037 Lille Cedex, France
- Department of Internal Medicine, National Reference Center for Hypereosinophilic Syndromes (CEREO), Hôpital Foch, 92151 Suresnes, France
- APHP, CHU Ambroise Paré, University of Paris Saclay, 92104 Boulogne-Billancourt, France
| | - Veronique Kerlan
- Department of Endocrinology, Diabetology and Metabolism CHU Brest, Hôpital de la Cavale Blanche, 29609 Brest Cedex, France
| | - Herve Lefebvre
- Department of Endocrinology, University Hospital of Rouen, 76031 Rouen, France
| | - Agnès Linglart
- AP-HP, Service d'Endocrinologie et Diabète de l'Enfant, Hôpital Bicêtre Paris-Saclay, AP-HP, Centre de Référence des Maladies Rares du Métabolisme du Calcium et du Phosphate, Filière OSCAR, ERN BOND, ERN for Rare Endocrine Disorders, Plateforme d'Expertise des Maladies Rares de Paris Saclay, INSERM U1185, Université Paris Saclay, 94270 Le Kremlin-Bicêtre, France
| | - Roberto Mallone
- Clinical Department of Diabetology and Clinical Immunology, INSERM U1016 Cochin Institute, DeARLab Team Mallone-You, Groupe Hospitalier Cochin-Port-Royal, 75014 Paris, France
| | - Rachel Reynaud
- Service de Pediatrie Multidisciplinaire, CHU Timone Enfants, Centre de Reference Maladies Hypophysaire Rares, APHM Aix Marseile Université 13385, Marseille Cedex 05, France
| | - Boualem Sendid
- Institut de Microbiologie, Centre de Biologie Pathologie Génétique, Inserm U1285—CNRS UMR 8576, Centre Hospitalier Universitaire de Lille, 59037 Lille, France
| | | | - Philippe Touraine
- Department of Endocrinology and Reproductive Medicine, AP-HP, Sorbonne University Medicine, 75013 Paris, France
| | - Jean-Louis Wémeau
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
- University of Lille, 59000 Lille, France
| | - Marie-Christine Vantyghem
- Department of Endocrinology, Diabetology and Metabolism, Huriez Hospital, Lille University Hospital, F-59000 Lille, France
- University of Lille, 59000 Lille, France
- Inserm U1190, European Genomic Institute for Diabetes, Lille University, F-59000 Lille, France
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Wolff ASB, Oftedal BE. Aire Mutations and Autoimmune Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1471:223-246. [PMID: 40067589 DOI: 10.1007/978-3-031-77921-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
Autoimmune diseases were first recognized by Mackay and Macfarlane Burnet in 1962 (Burnet and Mackay 1962). It is defined as the failure of an organism to tolerate its own cells and tissue, resulting in an aberrant immune response by lymphocytes (T-cell-driven disease) and/or antibodies (B-cell-driven disease). Autoimmune diseases can be divided into systemic autoimmune diseases and specific organ- or body-system diseases, including the endocrine, gastro-intestinal, and neurological systems, and it's not uncommon for individuals to experience multiple autoimmune conditions simultaneously. Autoimmune diseases affect ~10% of the population (Conrad et al. 2023), causing chronic suffering, vital organ failure, and premature death at the level of cancer and cardiovascular diseases. The rising incidence of these disorders poses a significant challenge to healthcare systems, underscoring the critical need to elucidate disease mechanisms and translate these into effective diagnostic tests and therapeutics. Current therapeutic strategies are predominantly confined to symptomatic relief through replacement therapy and broad-spectrum anti-inflammatory drugs, often resulting in increased disease burden, diminished life quality, and elevated mortality rates. Most autoimmune diseases are likely a result of a combination of different genetic and environmental factors. However, there are a few exemptions, like the autoimmune polyendocrine syndrome type 1 (APS-1) caused by mutations in the Autoimmune Regulator (AIRE) gene.
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Affiliation(s)
- Anette S B Wolff
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Brad GF, Nicoară DM, Scutca AC, Bugi MA, Asproniu R, Olariu LG, Jugănaru I, Cristun LI, Mărginean O. Exploring Chronic Hypocalcemia: Insights into Autoimmune Polyglandular Syndrome Type 1-A Case Study and Literature Review. J Clin Med 2024; 13:2368. [PMID: 38673639 PMCID: PMC11051075 DOI: 10.3390/jcm13082368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/07/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Hypocalcemia is a common occurrence in pediatric patients, attributed to various causes and presenting with diverse clinical manifestations. A prompt evaluation is necessary to determine its underlying cause, whether it presents acutely or chronically, and to tailor treatment based on its severity. Among the potential causes of chronic hypocalcemia, primary hypoparathyroidism stands out. The case of a seven-year-old male patient with hypocalcemia reported in this article serves as an illustration, wherein targeted next-generation sequencing revealed a homozygous p.R257X mutation in the AIRE gene, indicative of autoimmune polyendocrine syndrome type 1 (APS-1). It poses challenges due to its multisystemic nature and involvement of specific autoantibodies, often leading to underdiagnosis, owing to its rarity, varied manifestations, and incomplete penetrance. A comprehensive review of the APS-1 literature was conducted to provide insights into the clinical manifestations, genetic spectrum, potential immunological mechanisms, and current medical strategies. Additionally, the recognition of AIRE gene mutations is crucial for facilitating genetic diagnosis, prognosis, and potential treatment strategies for APS-1. The management of such cases involves individualized approaches to treatment, regular monitoring, medication adjustments, and the early identification of associated conditions.
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Affiliation(s)
- Giorgiana-Flavia Brad
- Department XI Pediatrics, Discipline I Pediatrics, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania; (G.-F.B.); (A.-C.S.); (R.A.); (L.-G.O.); (I.J.); (O.M.)
- 1st Department of Pediatrics, Children’s Emergency Hospital ‘Louis Turcanu’, 300011 Timisoara, Romania;
| | - Delia-Maria Nicoară
- Department XI Pediatrics, Discipline I Pediatrics, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania; (G.-F.B.); (A.-C.S.); (R.A.); (L.-G.O.); (I.J.); (O.M.)
| | - Alexandra-Cristina Scutca
- Department XI Pediatrics, Discipline I Pediatrics, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania; (G.-F.B.); (A.-C.S.); (R.A.); (L.-G.O.); (I.J.); (O.M.)
- 1st Department of Pediatrics, Children’s Emergency Hospital ‘Louis Turcanu’, 300011 Timisoara, Romania;
| | - Meda-Ada Bugi
- 1st Department of Pediatrics, Children’s Emergency Hospital ‘Louis Turcanu’, 300011 Timisoara, Romania;
- Research Center for Disturbances of Growth and Development in Children BELIVE, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania
| | - Raluca Asproniu
- Department XI Pediatrics, Discipline I Pediatrics, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania; (G.-F.B.); (A.-C.S.); (R.A.); (L.-G.O.); (I.J.); (O.M.)
- 1st Department of Pediatrics, Children’s Emergency Hospital ‘Louis Turcanu’, 300011 Timisoara, Romania;
| | - Laura-Gratiela Olariu
- Department XI Pediatrics, Discipline I Pediatrics, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania; (G.-F.B.); (A.-C.S.); (R.A.); (L.-G.O.); (I.J.); (O.M.)
- 1st Department of Pediatrics, Children’s Emergency Hospital ‘Louis Turcanu’, 300011 Timisoara, Romania;
| | - Iulius Jugănaru
- Department XI Pediatrics, Discipline I Pediatrics, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania; (G.-F.B.); (A.-C.S.); (R.A.); (L.-G.O.); (I.J.); (O.M.)
- 1st Department of Pediatrics, Children’s Emergency Hospital ‘Louis Turcanu’, 300011 Timisoara, Romania;
- Research Center for Disturbances of Growth and Development in Children BELIVE, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania
| | - Lucian-Ioan Cristun
- Ph.D. School Department, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania;
| | - Otilia Mărginean
- Department XI Pediatrics, Discipline I Pediatrics, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania; (G.-F.B.); (A.-C.S.); (R.A.); (L.-G.O.); (I.J.); (O.M.)
- 1st Department of Pediatrics, Children’s Emergency Hospital ‘Louis Turcanu’, 300011 Timisoara, Romania;
- Research Center for Disturbances of Growth and Development in Children BELIVE, ‘Victor Babes’ University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania
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Sandru F, Petca RC, Dumitrascu MC, Petca A, Ionescu (Miron) AI, Baicoianu-Nitescu LC. Cutaneous Manifestations in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED): A Comprehensive Review. Biomedicines 2024; 12:132. [PMID: 38255237 PMCID: PMC10813467 DOI: 10.3390/biomedicines12010132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/04/2024] [Accepted: 01/07/2024] [Indexed: 01/24/2024] Open
Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), or polyglandular autoimmune syndrome type 1 (PAS-1/APS-1), is a rare autosomal recessive disorder linked to mutations in the autoimmune regulator (AIRE) gene. This review provides a detailed analysis of cutaneous manifestations in APECED, focusing on chronic mucocutaneous candidiasis (CMC), alopecia areata (AA), and vitiligo. The classic triad of hypoparathyroidism, adrenal insufficiency, and CMC serves as a diagnostic cornerstone. However, the varied clinical spectrum of APECED, particularly its cutaneous presentations, poses a diagnostic challenge. CMC, often an early sign, varies in prevalence across populations, including Finnish (100%), Irish (100%), Saudi Arabian (80%), Italian (60-74.7%), North American (51-86%), and Croatian (57.1%) populations. Similarly, AA prevalence varies in different populations. Vitiligo also exhibits variable prevalence across regions. The review synthesizes the current knowledge arising from a narrative analysis of 14 significant human studies published in English up to October 2023. Moreover, this paper underscores the importance of early detection and monitoring, emphasizing cutaneous manifestations as key diagnostic indicators. Ongoing research and clinical vigilance are crucial for unraveling the complexities of this rare autoimmune syndrome and enhancing patient care.
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Affiliation(s)
- Florica Sandru
- Department of Dermatovenerology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (F.S.); (L.-C.B.-N.)
- Dermatology Department, “Elias” University Emergency Hospital, 011461 Bucharest, Romania
| | - Razvan-Cosmin Petca
- Department of Urology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Urology, ‘Prof. Dr. Th. Burghele’ Clinical Hospital, 050659 Bucharest, Romania
| | - Mihai Cristian Dumitrascu
- Department of Obstetrics and Gynecology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Obstetrics and Gynecology, University Emergency Hospital of Bucharest, 050098 Bucharest, Romania
| | - Aida Petca
- Department of Obstetrics and Gynecology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Obstetrics and Gynecology, “Elias” University Emergency Hospital, 011461 Bucharest, Romania
| | - Andreea-Iuliana Ionescu (Miron)
- Department of Oncological Radiotherapy and Medical Imaging, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Medical Oncology, Colțea Clinical Hospital, 030167 Bucharest, Romania
| | - Livia-Cristiana Baicoianu-Nitescu
- Department of Dermatovenerology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (F.S.); (L.-C.B.-N.)
- Dermatology Department, “Elias” University Emergency Hospital, 011461 Bucharest, Romania
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Oftedal BE, Assing K, Baris S, Safgren SL, Johansen IS, Jakobsen MA, Babovic-Vuksanovic D, Agre K, Klee EW, Majcic E, Ferré EM, Schmitt MM, DiMaggio T, Rosen LB, Rahman MO, Chrysis D, Giannakopoulos A, Garcia MT, González-Granado LI, Stanley K, Galant-Swafford J, Suwannarat P, Meyts I, Lionakis MS, Husebye ES. Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes. iScience 2023; 26:106818. [PMID: 37235056 PMCID: PMC10206195 DOI: 10.1016/j.isci.2023.106818] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/20/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.
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Affiliation(s)
- Bergithe E. Oftedal
- Department of Clinical Science, University of Bergen and Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Kristian Assing
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
| | - Safa Baris
- Marmara University, Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
| | - Stephanie L. Safgren
- Center for Individualized Medicine, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Isik S. Johansen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
| | | | | | | | - Eric W. Klee
- Mayo Clinic, Department of Quantitative Health Sciences, Rochester, MN, USA
| | - Emina Majcic
- Department of Clinical Science, University of Bergen and Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Elise M.N. Ferré
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Monica M. Schmitt
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Tom DiMaggio
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Lindsey B. Rosen
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Muhammad Obaidur Rahman
- Department of Clinical Science, University of Bergen and Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Dionisios Chrysis
- Department of Pediatrics, Division of Pediatric Endocrinology, Medical School, University of Patras, Rion, Greece
| | - Aristeidis Giannakopoulos
- Department of Pediatrics, Division of Pediatric Endocrinology, Medical School, University of Patras, Rion, Greece
| | - Maria Tallon Garcia
- Pediatric Hematology and Oncology Department, Hospital Álvaro Cunqueiro, Vigo, Spain
| | - Luis Ignacio González-Granado
- Unidad de Inmunodeficiencias, Pediatría, Instituto de Investigación Hospital 12 de Octubre, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Katherine Stanley
- Mid-Atlantic Permanente Medical Group, Kaiser Permanente MidAtlantic, Rockville, MD, USA
| | | | - Pim Suwannarat
- Mid-Atlantic Permanente Medical Group, Kaiser Permanente MidAtlantic, Rockville, MD, USA
| | - Isabelle Meyts
- Department of Pediatrics, University Hospital Leuven, Laboratory for Inborn Errors of Immunity, Department of Microbiology Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Michail S. Lionakis
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Eystein S. Husebye
- Department of Clinical Science, University of Bergen and Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Sun R, Wang Y, Abolhassani H. Cellular mechanisms and clinical applications for phenocopies of inborn errors of immunity: infectious susceptibility due to cytokine autoantibodies. Expert Rev Clin Immunol 2023:1-14. [PMID: 37114623 DOI: 10.1080/1744666x.2023.2208863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
INTRODUCTION With a growing knowledge of Inborn error immunity (IEI), immunological profiling and genetic predisposition to IEI phenocopies have been developed in recent years. AREAS COVERED Here we summarized the correlation between various pathogen invasions, autoantibody profiles, and corresponding clinical features in the context of patients with IEI phenocopies. It has been extensively evident that patients with anti-cytokine autoantibodies underly impaired anti-pathogen immune responses and lead to broad unregulated inflammation and tissue damage. Several hypotheses of anti-cytokine autoantibodies production were summarized here, including a defective negative selection of autoreactive T cells, abnormal germinal center formation, molecular mimicry, HLA class II allele region, lack of auto-reactive lymphocyte apoptosis, and other possible hypotheses. EXPERT OPINION Phenocopies of IEI associated with anti-cytokine autoantibodies are increasingly recognized as one of the causes of acquired immunodeficiency and susceptibility to certain pathogen infections, especially facing the current challenge of the COVID-19 pandemic. By investigating clinical, genetic, and pathogenesis autoantibodies profiles associated with various pathogens' susceptibilities, we could better understand the IEI phenocopies with anti-cytokine autoantibodies, especially for those that underlie life-threatening SARS-CoV-2.
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Affiliation(s)
- Rui Sun
- Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
| | - Yating Wang
- Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
| | - Hassan Abolhassani
- Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
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Hasenmajer V, Ferrigno R, Minnetti M, Pellegrini B, Isidori AM, Lenzi A, Salerno M, Cappa M, Chan L, De Martino MC, Savage MO. Rare forms of genetic paediatric adrenal insufficiency: Excluding congenital adrenal hyperplasia. Rev Endocr Metab Disord 2023; 24:345-363. [PMID: 36763264 PMCID: PMC10023752 DOI: 10.1007/s11154-023-09784-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/03/2023] [Indexed: 02/11/2023]
Abstract
Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.
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Affiliation(s)
- Valeria Hasenmajer
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Rosario Ferrigno
- UOSD Auxology and Endocrinology, Department of Pediatric, AORN Santobono-Pausilipon, Naples, Italy
| | - Marianna Minnetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Bianca Pellegrini
- Dipartimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Marco Cappa
- Endocrinology Unit, Pediatric University Department, Bambino Gesù Children's Hospital, Rome, Italy
| | - Li Chan
- Endocrinology Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | | | - Martin O Savage
- Endocrinology Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
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Paparella R, Menghi M, Micangeli G, Leonardi L, Profeta G, Tarani F, Petrella C, Ferraguti G, Fiore M, Tarani L. Autoimmune Polyendocrine Syndromes in the Pediatric Age. CHILDREN 2023; 10:children10030588. [PMID: 36980146 PMCID: PMC10047132 DOI: 10.3390/children10030588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/13/2023] [Accepted: 03/17/2023] [Indexed: 03/22/2023]
Abstract
Autoimmune polyendocrine syndromes (APSs) encompass a heterogeneous group of rare diseases characterized by autoimmune activity against two or more endocrine or non-endocrine organs. Three types of APSs are reported, including both monogenic and multifactorial, heterogeneous disorders. The aim of this manuscript is to present the main clinical and epidemiological characteristics of APS-1, APS-2, and IPEX syndrome in the pediatric age, describing the mechanisms of autoimmunity and the currently available treatments for these rare conditions.
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Affiliation(s)
- Roberto Paparella
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Michela Menghi
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Ginevra Micangeli
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Lucia Leonardi
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Giovanni Profeta
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Francesca Tarani
- Department of Experimental Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Carla Petrella
- Institute of Biochemistry and Cell Biology, IBBC-CNR, 00185 Rome, Italy
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology, IBBC-CNR, 00185 Rome, Italy
- Correspondence: (M.F.); (L.T.)
| | - Luigi Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
- Correspondence: (M.F.); (L.T.)
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9
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Almaghrabi S, Lovewell T, Azzouz M, Tazi Ahnini R. Characterisation of APS-1 Experimental Models Is Crucial for Development of Novel Therapies. BIOMED RESEARCH INTERNATIONAL 2023; 2023:7960443. [PMID: 36685668 PMCID: PMC9848810 DOI: 10.1155/2023/7960443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 11/02/2022] [Accepted: 12/13/2022] [Indexed: 01/13/2023]
Abstract
Autoimmune polyglandular syndrome type 1 (APS-1) is an inherited autosomal disorder. The most common clinical features of the disease include adrenocortical failure, hypoparathyroidism (HP), and chronic mucocutaneous candidiasis (CMC). APS-1 is caused by mutations in the autoimmune regulator (AIRE) gene. AIRE is a transcriptional factor involved in the regulation of thousands of genes in the thymus. It facilitates central tolerance by promoting the ectopic expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), leading to the deletion of self-reactive thymocytes. Several Aire-deficient mice were developed separately, on different backgrounds; seven published Aire knockout mice show a variety of phenotypes depending on the strain used to generate the experimental model. The first Aire-deficient mice were generated on a "black 6" background almost 20 years ago. The model showed mild phenotype with relatively modest penetrance compared to models generated on BALBc or NOD backgrounds. The generation of all these experimental models is crucial for development and testing new therapeutics as well as reading the response to treatments.
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Affiliation(s)
- Sarah Almaghrabi
- Department of Infection, Immunity and Cardiovascular Disease, Sheffield, UK
| | - Thomas Lovewell
- Department of Infection, Immunity and Cardiovascular Disease, Sheffield, UK
| | - Mimoun Azzouz
- Sheffield Institute for Translational Neuroscience (SITRaN), Department of Neuroscience, The Medical School, University of Sheffield, Sheffield S10 2RX, UK
| | - Rachid Tazi Ahnini
- Department of Infection, Immunity and Cardiovascular Disease, Sheffield, UK
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10
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Qian G, Yan X, Xuan J, Zheng D, He Z, Shen J. A novel AIRE mutation leads to autoimmune polyendocrine syndrome type-1. Front Cell Dev Biol 2022; 10:948350. [PMID: 36072346 PMCID: PMC9441485 DOI: 10.3389/fcell.2022.948350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/14/2022] [Indexed: 11/13/2022] Open
Abstract
Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare inherited monogenic autoimmune disease characterized by the presence of at least two of three following major clinical features: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. Mutations in autoimmune regulator (AIRE) gene have been found to contribute to APS-1. In the present study, we reported a 36-years-old male APS-1 patient who presented with hypoparathyroidism and Addison’s disease. The proband underwent complete clinical examinations and mutation screening was performed by Sanger sequencing on AIRE gene. A novel homozygous mutation in exon 9 of the AIRE gene (c.1024C>T) was identified. Based on sequencing findings, HEK293T cell-based assays were conducted to analyze the subcellular localization and mutant transcript processing. Our results revealed that p.Q342X mutant localized in nuclear speckles and exerted a dominant-negative effect on wildtype AIRE function. We reported the c.1024C>T mutation of AIRE gene for the first time, which enriched the AIRE mutation database and contributed to further understanding of APS-1.
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Affiliation(s)
- Guofeng Qian
- Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Guofeng Qian, ; Jianguo Shen,
| | - Xiaoyi Yan
- Department of Cell Biology, College of Medicine, Zhejiang University, Hangzhou, China
| | - Junli Xuan
- Imaging Facility of Core Facilities, College of Medicine, Zhejiang University, Hangzhou, China
| | - Danfeng Zheng
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhiwen He
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianguo Shen
- Department of Endocrinology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Guofeng Qian, ; Jianguo Shen,
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11
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Bjørklund G, Pivin M, Hangan T, Yurkovskaya O, Pivina L. Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach. Clin Exp Rheumatol 2022; 21:103135. [PMID: 35690244 DOI: 10.1016/j.autrev.2022.103135] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/07/2022] [Indexed: 11/02/2022]
Abstract
Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive hereditary pathology that develops with endocrine and non-endocrine manifestations in childhood. The classic triad of APS-1 includes chronic candidiasis of the skin and mucous membranes, adrenal insufficiency, and hypoparathyroidism. APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis. The prevalence rate is highest in genetically isolated populations (up to 1:6500-1:9000). APS-1 occurs because of mutations in the autoimmune regulator (AIRE) gene, leading to a disrupted mechanism of normal antigen expression, the formation of abnormal clones of immune cells, and autoimmune damage to various organs. Analysis of the AIRE gene is the main diagnostic method for early detection of APS-1 and the choice of methods for its treatment. Timely genetic counseling makes it possible to identify the disease early, prescribe appropriate treatment and prevent serious complications. This paper analyzes scientific information characterizing clinical manifestations of autoimmune polyendocrine syndrome type 1 in association with its pathogenetic features, epidemiology, and current management.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway.
| | | | - Tony Hangan
- Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.
| | | | - Lyudmila Pivina
- Semey Medical University, Semey, Kazakhstan; CONEM Kazakhstan Environmental Health and Safety Research Group, Semey Medical University, Semey, Kazakhstan
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12
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Amaratunga SA, Tayeb TH, Dusatkova P, Pruhova S, Lebl J. Invaluable Role of Consanguinity in Providing Insight into Paediatric Endocrine Conditions: Lessons Learnt from Congenital Hyperinsulinism, Monogenic Diabetes, and Short Stature. Horm Res Paediatr 2022; 95:1-11. [PMID: 34847552 DOI: 10.1159/000521210] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 11/18/2021] [Indexed: 11/19/2022] Open
Abstract
Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over 8.5% of all children worldwide have consanguineous parents. Consanguinity is linked to demographic, cultural, and religious practises and is more common in some areas around the world than others. In children with endocrine conditions from consanguineous families, there is a greater probability that a single-gene condition with autosomal recessive inheritance is causative. From 1966 and the first description of Laron syndrome, through the discovery of the first KATP channel genes ABCC8 and KCNJ11 causing congenital hyperinsulinism (CHI) in the 1990s, to recent discoveries of mutations in YIPF5 as the first cause of monogenic diabetes due to the disruption of the endoplasmic reticulum (ER)-to-Golgi trafficking in the β-cell and increased ER stress; positive genetic findings in children from consanguinity have been important in elucidating novel genes and mechanisms of disease, thereby expanding knowledge into disease pathophysiology. The aim of this narrative review was to shed light on the lessons learned from consanguineous pedigrees with the help of 3 fundamental endocrine conditions that represent an evolving spectrum of pathophysiological complexity - from CHI, a typically single-cell condition, to monogenic diabetes which presents with uniform biochemical parameters (hyperglycaemia and glycosuria), despite varying aetiologies, up to the genetic regulation of human growth - the most complex developmental phenomenon.
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Affiliation(s)
- Shenali Anne Amaratunga
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czechia
| | - Tara Hussein Tayeb
- Department of Paediatrics, Sulaymani University, College of Medicine, Sulaymani, Iraq
| | - Petra Dusatkova
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czechia
| | - Stepanka Pruhova
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czechia
| | - Jan Lebl
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czechia
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13
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Skrabic V, Skrabic I, Skrabic R, Roje B, Simunovic M. Clinical Characteristics in the Longitudinal Follow-Up of APECED Syndrome in Southern Croatia—Case Series. Genes (Basel) 2022; 13:genes13040558. [PMID: 35456364 PMCID: PMC9027969 DOI: 10.3390/genes13040558] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/11/2022] [Accepted: 03/19/2022] [Indexed: 02/03/2023] Open
Abstract
Background: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare monogenetic autosomal recessive disorder caused by a mutation in the autoimmune regulator (AIRE) gene characterized by complex phenotypic characteristics discovered over years of follow-up. Methods: 7 patients were recruited in this case series in a period of the last 37 years from Southern Croatia. All patients were screened for AIRE R257X mutations. Results: This study group had a mean current age of 25.3 years (age range from 5.4 to 40.2 years), while the mean age at the onset of the disease was 6.5 years (age range from 0.7 to 9.2 years) and with a mean follow-up period of 17.8 years. The overall prevalence of APECED syndrome is estimated to be 1 in 75,000. The most common initial manifestation of the disease was onychodystrophy, while the first major component of APECED syndrome was chronic mucocutaneous candidiasis. Conclusions: APECED is a ‘‘multi-faced’’ disease based on the very unpredictable and inconsistent onset of major components. Furthermore, based on our results, we suggest that onychodystrophy could be included as a warning sign of APECED syndrome.
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Affiliation(s)
- Veselin Skrabic
- Department of Pediatrics, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (I.S.); (M.S.)
- Department of Pediatrics, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
- Correspondence:
| | - Ivna Skrabic
- Department of Pediatrics, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (I.S.); (M.S.)
| | - Roko Skrabic
- Department of Nephrology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia;
| | - Blanka Roje
- Laboratory for Cancer Research, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia;
| | - Marko Simunovic
- Department of Pediatrics, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (I.S.); (M.S.)
- Department of Pediatrics, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
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14
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Besnard M, Sérazin C, Ossart J, Moreau A, Vimond N, Flippe L, Sein H, Smith GA, Pittaluga S, Ferré EM, Usal C, Anegon I, Ranki A, Lionakis MS, Peterson P, Guillonneau C. Anti-CD45RC antibody immunotherapy prevents and treats experimental Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy syndrome. J Clin Invest 2022; 132:156507. [PMID: 35167497 PMCID: PMC8970675 DOI: 10.1172/jci156507] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 02/08/2022] [Indexed: 11/17/2022] Open
Abstract
Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T cells (Tconv, CD45RChigh), their precursors and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs, CD45RClow/-). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation but its potential has not been examined in autoimmune diseases. APECED is a rare genetic syndrome caused by loss-of-function mutations of the key central tolerance mediator, autoimmune regulator (AIRE) leading to abnormal auto-reactive T cell responses and autoantibodies production. Herein, we showed that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective both as prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChigh T cells, inhibited CD45RChigh B cells, and restored the Treg/Tconv ratio and the altered Tregs transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells and lesioned organs from APECED patients were infiltrated by CD45RChigh cells. Our observations highlight the potential role for CD45RChigh cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.
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Affiliation(s)
- Marine Besnard
- Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, University of Nantes, Nantes, France
| | - Céline Sérazin
- Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, University of Nantes, Nantes, France
| | - Jason Ossart
- Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, University of Nantes, Nantes, France
| | - Anne Moreau
- Department of Pathology, CHU Nantes, Nantes, France
| | - Nadège Vimond
- Department of Immunology, AbolerIS Pharma, Nantes, France
| | - Léa Flippe
- Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, University of Nantes, Nantes, France
| | - Hanna Sein
- Department of Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Grace A Smith
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States of America
| | | | - Elise Mn Ferré
- Laboratory of Clinical Immunology and Microbiology, NIAID/NIH, Bethesda, United States of America
| | - Claire Usal
- Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, University of Nantes, Nantes, France
| | - Ignacio Anegon
- Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, University of Nantes, Nantes, France
| | - Annamari Ranki
- Department of Dermatology and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Michail S Lionakis
- Laboratory of Clinical Immunology and Microbiology, NIAID/NIH, Bethesda, United States of America
| | - Pärt Peterson
- Department of Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Carole Guillonneau
- Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, University of Nantes, Nantes, France
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15
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Setoodeh A, Panjeh-Shahi S, Bahmani F, Vand-Rajabpour F, Jalilian N, Sayarifard F, Abbasi F, Sayarifard A, Rostami P, Parvaneh N, Akhavan-Niaki H, Ahmadifard M, Tabrizi M. Molecular and clinical characterization of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) in Iranian non-Jewish patients: report of two novel AIRE gene pathogenic variants. Orphanet J Rare Dis 2022; 17:10. [PMID: 34991662 PMCID: PMC8734050 DOI: 10.1186/s13023-021-02170-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/19/2021] [Indexed: 12/22/2022] Open
Abstract
Objective Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare autosomal recessive systemic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Incidence of this genetic disorder is estimated at 1/90,000–200,000 worldwide and 1/6500–9000 in genetically isolated populations such as Iran. Here, we investigated AIRE gene mutations in eight independent Iranian non-Jewish families. Methods We sequenced the coding regions of the AIRE gene and documented mutations which were further confirmed in respective parents. Results In total, 11 cases from 8 independent families were recruited. Mucosal candidiasis, Addison’s disease and hypoparathyroidism were the most common clinical manifestations in these patients. One novel homozygous splice acceptor mutation (c.308-1G>C), and one novel heterozygous stop-gain mutation (c.1496delC) combined with a known heterozygous c.232T>C missense mutation were found. Moreover, we observed previously described splice donor (c.1095+2T>A), frameshift (c.967-979del), stop-gain (c.415C>T), and missense (c.62C>T) mutations among the patients. All results were co-segregated in parents. Conclusion Here, we reported two novel mutations in the AIRE gene leading to APECED. Our data could provide insight into the phenotypic and genotypic spectrum of APECED in the non-Jewish Iranian population. These findings, in addition to future functional assays, can elucidate disease-causing mechanisms related to the AIRE gene and assist in genetic counseling and diagnosis.
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Affiliation(s)
- Aria Setoodeh
- Division of Endocrinology and Metabolism, Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Samareh Panjeh-Shahi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Fariba Bahmani
- Division of Endocrinology and Metabolism, Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Vand-Rajabpour
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nazanin Jalilian
- Department of Clinical Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Sayarifard
- Division of Endocrinology and Metabolism, Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Abbasi
- Division of Endocrinology and Metabolism, Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Azadeh Sayarifard
- Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Parastoo Rostami
- Division of Endocrinology and Metabolism, Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Parvaneh
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Haleh Akhavan-Niaki
- Department of Medical Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohamadreza Ahmadifard
- Department of Medical Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mina Tabrizi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Cruz Marino T, Villeneuve H, Leblanc J, Duranceau C, Caron P, Morin C, Milot M, Chrétien R, Gagnon MM, Mathieu J, Ellezam B, Buhas D. French-Canadian families from Saguenay-Lac-Saint-Jean: a new founder population for APECED. Endocrine 2022; 75:48-58. [PMID: 34846681 DOI: 10.1007/s12020-021-02826-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 07/11/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is more prevalent in some founder populations, but relatively unexplored in Canada. This study aimed at investigating the French-Canadian patients through phenotypic and genotypic characterization. METHOD Phenotype and demographic characterization were done for 12 affected individuals belonging to eight unrelated families. Samples from 11 cases were analyzed in a molecular clinical laboratory, and muscle biopsies were reviewed for two individuals with a limb-girdle muscle dystrophy. RESULTS The clinical phenotype was similar to that observed in European Caucasian populations but differed in the non-endocrine spectrum from the American-reported series of cases. Two cases exhibited a limb-girdle muscle dystrophy, and we found preliminary evidence of a mitochondrial dysfunction, since all three biopsies examined showed COX-deficient fibers in excess of what would be expected for age. Electron microscopy showed mitochondrial accumulation without abnormal cristea or inclusions. The c.1616C > T variant in the AIRE gene was responsible for 100% of APECED cases in the French-Canadian population of Saguenay-Lac-Saint-Jean in Quebec, Canada. CONCLUSIONS We report the first series of French-Canadian cases affected with APECED. The Saguenay-Lac-Saint-Jean region was uncovered as a new founder population for this condition. Muscle biopsy findings expanded the range of previously described APECED-related myopathology. Long term follow-up of our genetically homogeneous French-Canadian cases may help determine if the c.1616C > T variant increases the risk of muscle involvement. A neonatal screening program is under consideration to prevent undesired life-threatening endocrine manifestations.
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Affiliation(s)
- Tania Cruz Marino
- Department of Laboratory Medicine, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada.
| | - Hélène Villeneuve
- Department of Endocrinology, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada
| | - Josianne Leblanc
- Department of Laboratory Medicine, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada
| | - Caroline Duranceau
- Department of Endocrinology, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada
| | - Philippe Caron
- Department of Endocrinology, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada
| | - Charles Morin
- Department of Pediatrics, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada
| | - Marcel Milot
- Department of Pediatrics, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada
| | - Raphaëlle Chrétien
- Department of Pediatrics, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada
| | - Maude-Marie Gagnon
- Clinique des Maladies Neuromusculaires, CIUSSS Saguenay-Lac-St-Jean, Saguenay, QC, Canada
| | - Jean Mathieu
- Department of Neurology, Université de Sherbrooke, QC, Sherbrooke, Canada
| | - Benjamin Ellezam
- Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Daniela Buhas
- Division of Medical Genetics, Department of Specialized Medicine; Department of Human Genetics, McGill University, Montreal, QC, Canada
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17
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Garelli S, Dalla Costa M, Sabbadin C, Barollo S, Rubin B, Scarpa R, Masiero S, Fierabracci A, Bizzarri C, Crinò A, Cappa M, Valenzise M, Meloni A, De Bellis AM, Giordano C, Presotto F, Perniola R, Capalbo D, Salerno MC, Stigliano A, Radetti G, Camozzi V, Greggio NA, Bogazzi F, Chiodini I, Pagotto U, Black SK, Chen S, Rees Smith B, Furmaniak J, Weber G, Pigliaru F, De Sanctis L, Scaroni C, Betterle C. Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients. J Endocrinol Invest 2021; 44:2493-2510. [PMID: 34003463 PMCID: PMC8502131 DOI: 10.1007/s40618-021-01585-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 04/29/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.
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Affiliation(s)
- S Garelli
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
- Unit of Internal Medicine, Ospedale dell'Angelo, Mestre-Venice, Italy
| | - M Dalla Costa
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
- Unit of Internal Medicine, Ospedale di Feltre, Belluno, Italy
| | - C Sabbadin
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
| | - S Barollo
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
| | - B Rubin
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
| | - R Scarpa
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
| | - S Masiero
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
| | - A Fierabracci
- Infectivology and Clinical Trials Research Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - C Bizzarri
- Endocrine Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - A Crinò
- Endocrine Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - M Cappa
- Endocrine Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - M Valenzise
- Unit of Pediatrics, Department of Adulthood and Childhood Human Pathology, University of Messina, Messina, Italy
| | - A Meloni
- Ospedale Microcitemico and Dipartimento di Scienze Biomediche e Biotecnologiche, University of Cagliari, Cagliari, Italy
| | - A M De Bellis
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - C Giordano
- Endocrine Unit, Department of Biomedical Internal and Specialist Medicine (DIBIMIS), Palermo University, Palermo, Italy
| | - F Presotto
- Unit of Internal Medicine, Ospedale dell'Angelo, Mestre-Venice, Italy
| | - R Perniola
- Department of Pediatrics, Regional Hospital Vito Fazzi, Lecce, Italy
| | - D Capalbo
- Department of Mother and Child, University Federico II, Naples, Italy
| | - M C Salerno
- Pediatric Section, Department of Translational Medical Sciences, University Federico II, Naples, Italy
| | - A Stigliano
- Endocrinology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - G Radetti
- Marienklinik, General Hospital, Bolzano, Italy
| | - V Camozzi
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
| | - N A Greggio
- EU-Endo-ERN Advisory Board Member, National Coordinator Endo-ERN Pediatric (SIEDP), Padua, Italy
| | - F Bogazzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - I Chiodini
- Unit of Bone Metabolism Diseases and Diabetes, Istituto Auxologico Italiano, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - U Pagotto
- Unit of Endocrinology and Prevention and Care of Diabetes, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - S K Black
- FIRS Laboratories RSR Ltd, Cardiff, UK
| | - S Chen
- FIRS Laboratories RSR Ltd, Cardiff, UK
| | | | | | - G Weber
- Unit of Pediatrics, Vita-Salute San Raffaele University, IRCSS San Raffaele Scientific Institute, Milan, Italy
| | - F Pigliaru
- Endocrine Unit, Azienda Ospedaliera-Universitaria of Cagliari, Cagliari, Italy
| | - L De Sanctis
- Pediatric Endocrinology, Department of Public Health and Pediatric Sciences, Regina Margherita Children's Hospital, University of Turin, Turin, Italy
| | - C Scaroni
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy
| | - C Betterle
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128, Padua, Italy.
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Ferré EMN, Schmitt MM, Lionakis MS. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. Front Pediatr 2021; 9:723532. [PMID: 34790633 PMCID: PMC8591095 DOI: 10.3389/fped.2021.723532] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/07/2021] [Indexed: 12/12/2022] Open
Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.
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Affiliation(s)
| | | | - Michail S. Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
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19
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Oikonomou V, Break TJ, Gaffen SL, Moutsopoulos NM, Lionakis MS. Infections in the monogenic autoimmune syndrome APECED. Curr Opin Immunol 2021; 72:286-297. [PMID: 34418591 PMCID: PMC8578378 DOI: 10.1016/j.coi.2021.07.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022]
Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune Regulator (AIRE) gene, which impair the thymic negative selection of self-reactive T-cells and underlie the development of autoimmunity that targets multiple endocrine and non-endocrine tissues. Beyond autoimmunity, APECED features heightened susceptibility to certain specific infections, which is mediated by anti-cytokine autoantibodies and/or T-cell driven autoimmune tissue injury. These include the 'signature' APECED infection chronic mucocutaneous candidiasis (CMC), but also life-threatening coronavirus disease 2019 (COVID-19) pneumonia, bronchiectasis-associated bacterial pneumonia, and sepsis by encapsulated bacteria. Here we discuss the expanding understanding of the immunological mechanisms that contribute to infection susceptibility in this prototypic syndrome of impaired central tolerance, which provide the foundation for devising improved diagnostic and therapeutic strategies for affected patients.
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Affiliation(s)
- Vasileios Oikonomou
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology (LCIM), National Institute of Allergy & Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Timothy J Break
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology (LCIM), National Institute of Allergy & Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Sarah L Gaffen
- University of Pittsburgh, Division of Rheumatology and Clinical Immunology, Pittsburgh PA, USA
| | - Niki M Moutsopoulos
- Oral Immunity and Inflammation Section, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD, USA
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology (LCIM), National Institute of Allergy & Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.
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20
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Wolff ASB, Braun S, Husebye ES, Oftedal BE. B Cells and Autoantibodies in AIRE Deficiency. Biomedicines 2021; 9:1274. [PMID: 34572460 PMCID: PMC8466229 DOI: 10.3390/biomedicines9091274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/11/2021] [Accepted: 09/17/2021] [Indexed: 12/15/2022] Open
Abstract
Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare but severe monogenetic autoimmune endocrine disease caused by failure of the Autoimmune Regulator (AIRE). AIRE regulates the negative selection of T cells in the thymus, and the main pathogenic mechanisms are believed to be T cell-mediated, but little is known about the role of B cells. Here, we give an overview of the role of B cells in thymic and peripheral tolerance in APS-1 patients and different AIRE-deficient mouse models. We also look closely into which autoantibodies have been described for this disorder, and their implications. Based on what is known about B cell therapy in other autoimmune disorders, we outline the potential of B cell therapies in APS-1 and highlight the unresolved research questions to be answered.
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Affiliation(s)
- Anette S. B. Wolff
- Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway; (A.S.B.W.); (S.B.); (E.S.H.)
- Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
- KG Jebsen Center for Autoimmune Disorders, University of Bergen, 5021 Bergen, Norway
| | - Sarah Braun
- Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway; (A.S.B.W.); (S.B.); (E.S.H.)
- Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University, 69120 Heidelberg, Germany
| | - Eystein S. Husebye
- Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway; (A.S.B.W.); (S.B.); (E.S.H.)
- Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
- KG Jebsen Center for Autoimmune Disorders, University of Bergen, 5021 Bergen, Norway
| | - Bergithe E. Oftedal
- Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway; (A.S.B.W.); (S.B.); (E.S.H.)
- Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
- KG Jebsen Center for Autoimmune Disorders, University of Bergen, 5021 Bergen, Norway
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Chen J, Lu T, Liu C, Zhao Y, Huang A, Hu X, Li M, Xiang R, Feng M, Lu H. Autoimmune polyglandular syndrome type 1 with diabetes insipidus: a case report. BMC Endocr Disord 2021; 21:154. [PMID: 34344344 PMCID: PMC8336383 DOI: 10.1186/s12902-021-00822-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/20/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic inherited disease caused by mutations of the autoimmune regulator gene (AIRE). The three major components of this syndrome are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. CASE PRESENTATION We report a 20-year-old male who was clinically diagnosed with APS-1 at the age of 15. He was admitted to our department this time for suffering from polyuria and polydipsia for 6 months and was finally diagnosed with diabetes insipidus. Whole-exome sequencing (WES) revealed a novel compound heterozygous mutation of the AIRE gene -the c.239 T > G (p.Val80Gly) variant on one allele and the copy number variant (CNV) of 21q22.3(chr21:45,670,150-45,706,528)*1 on the other. CONCLUSIONS This case suggests that diabetes insipidus is a rare component of APS-1 and expands the variety of mutations on AIRE gene.
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Affiliation(s)
- JiaQi Chen
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Ting Lu
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - ChenXiao Liu
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Yun Zhao
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - AiJie Huang
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - XingNa Hu
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Min Li
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Rong Xiang
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - Min Feng
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China
| | - HongHong Lu
- Department of Endocrinology and Metabolism, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China.
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22
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Wang YB, Wang O, Nie M, Jiang Y, Li M, Xia WB, Xing XP. Characterization of the clinical and genetic spectrum of autoimmune polyendocrine syndrome type 1 in Chinese case series. Orphanet J Rare Dis 2021; 16:296. [PMID: 34217342 PMCID: PMC8254246 DOI: 10.1186/s13023-021-01933-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/27/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Autoimmune polyendocrine syndrome type 1 (APS1) is a hereditary disease caused by mutations in the AIRE gene with both endocrine and non-endocrine organ involvement. The existing data from China are limited, and this study aims to describe the phenotypes and genetic characterization in Chinese APS1 patients. In this single-center, retrospective, observational study, comprehensive endocrine and extra-endocrine manifestations were collected, and genetic analysis in AIRE was conducted in patients with APS1 between the years of 1984 and 2018 at Peking Union Medical College Hospital. RESULTS In total, 13 patients from 12 unrelated families were enrolled, seven of whom were female, with hypoparathyroidism, chronic mucocutaneous candidiasis, and Addison's disease being the most frequently observed manifestations. Up to 84.7% presented with two or three of the above-mentioned manifestations, and nearly 4.9 ± 1.8 components presented in patients aged 21.2 ± 7.9 years old. Several less common phenotypes, such as myeloproliferative disease, pure red cell aplasia, renal tubular acidosis, asplenia, autoimmune hepatitis, and ankylosing spondylitis, were also observed in patients. Altogether, seven different AIRE mutations were found in six patients, four of which (K161fs, G208V, A246fs, and L308F) had not been previously reported in patients with APS1. CONCLUSION We have provided a comprehensive profile of Chinese patients with APS1, with less commonly observed features being observed in addition to more regularly seen manifestations. Additionally, different AIRE mutations that were observed have expanded the genetic spectrum, which will help with future understanding of the molecular pathogenesis of APS1.
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Affiliation(s)
- Ya-Bing Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Dongcheng District, Shuaifuyuan No.1, Beijing, 100730 China
- Department of Endocrinology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100730 China
| | - Ou Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Dongcheng District, Shuaifuyuan No.1, Beijing, 100730 China
| | - Min Nie
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Dongcheng District, Shuaifuyuan No.1, Beijing, 100730 China
| | - Yan Jiang
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Dongcheng District, Shuaifuyuan No.1, Beijing, 100730 China
| | - Mei Li
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Dongcheng District, Shuaifuyuan No.1, Beijing, 100730 China
| | - Wei-Bo Xia
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Dongcheng District, Shuaifuyuan No.1, Beijing, 100730 China
| | - Xiao-Ping Xing
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Dongcheng District, Shuaifuyuan No.1, Beijing, 100730 China
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Sharifinejad N, Zaki-Dizaji M, Tebyanian S, Zainaldain H, Jamee M, Rizvi FS, Hosseinzadeh S, Fayyaz F, Hamedifar H, Sabzevari A, Matloubi M, Heropolitańska-Pliszka E, Aghamahdi F, Abolhassani H, Azizi G. Clinical, immunological, and genetic features in 938 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a systematic review. Expert Rev Clin Immunol 2021; 17:807-817. [PMID: 33957837 DOI: 10.1080/1744666x.2021.1925543] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Background: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error characterized by a triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (ADI).Methods: Literature search was conducted in PubMed, Web of Science, and Scopus databases using related keywords, and included studies were systematically evaluated.Results: We reviewed 938 APECED patients and the classic triad of APECED was detected in 57.3% (460 of 803) of patients. CMC (82.5%) was reported as the earliest, HP (84.2%) as the most prevalent, and ADI (72.2%) as the latest presentation within the classic triad. A broad spectrum of non-triad involvements has also been reported; mainly included ectodermal dystrophy (64.5%), infections (58.7%), gastrointestinal disorders (52.0%), gonadal failure (42.0%), neurologic involvements (36.4%), and ocular manifestations (34.3%). A significant positive correlation was detected between certain tissue-specific autoantibodies and particular manifestations including ADI and HP. Neutralizing autoantibodies were detected in at least 60.0% of patients. Nonsense and/or frameshift insertion-deletion mutations were detected in 73.8% of patients with CMC, 70.9% of patients with HP, and 74.6% of patients with primary ADI.Conclusion: Besides penetrance diversity, our review revealed a diverse affected ethnicity (mainly from Italy followed by Finland and Ireland). APECED can initially present in adolescence as 5.2% of the patients were older than 18 years at the disease onset. According to the variety of clinical conditions, which in the majority of patients appear gradually over time, clinical management deserves a separate analysis.
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Affiliation(s)
- Niusha Sharifinejad
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran.,Alborz Office of USERN, Universal Scientific Education and Research Network (USERN), Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Zaki-Dizaji
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
| | - Shafi Tebyanian
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran.,Alborz Office of USERN, Universal Scientific Education and Research Network (USERN), Alborz University of Medical Sciences, Karaj, Iran
| | - Hamed Zainaldain
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Mahnaz Jamee
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran.,Alborz Office of USERN, Universal Scientific Education and Research Network (USERN), Alborz University of Medical Sciences, Karaj, Iran
| | - Fatema Sadaat Rizvi
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Soheila Hosseinzadeh
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran.,Alborz Office of USERN, Universal Scientific Education and Research Network (USERN), Alborz University of Medical Sciences, Karaj, Iran
| | - Farimah Fayyaz
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran.,Alborz Office of USERN, Universal Scientific Education and Research Network (USERN), Alborz University of Medical Sciences, Karaj, Iran
| | - Haleh Hamedifar
- CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran.,CinnaGen Research and Production Co., Alborz, Iran
| | - Araz Sabzevari
- CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Orchid Pharmed Company, Tehran, Iran
| | - Mojdeh Matloubi
- Medical Immunology Department, School of Medicine, Iran University of Medical Science, Tehran, Iran
| | | | - Fatemeh Aghamahdi
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pediatric Endocrinology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.,Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Hassan Abolhassani
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
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Brenchley L, Ferré EMN, Schmitt MM, Gardner PJ, Lionakis MS, Moutsopoulos NM. Case Report: Dental Findings Can Aid in Early Diagnosis of APECED Syndrome. FRONTIERS IN DENTAL MEDICINE 2021; 2:670624. [PMID: 38148990 PMCID: PMC10751037 DOI: 10.3389/fdmed.2021.670624] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type 1 (APS-1), is a rare genetic disorder caused most often by biallelic mutations in the AIRE gene. Classic clinical findings of the disease are chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues, such as hypoparathyroidism and adrenal insufficiency. Recently, however, it has been appreciated that enamel hypoplasia, together with intestinal malabsorption and a characteristic APECED rash, is a prominent early disease manifestation of APECED which can aid in the diagnosis of disease before other potentially life-threatening disease manifestations occur. To demonstrate this point, we present data from a cohort of APECED patients, approximately 70% of who present with enamel dysplasia at an early age. Importantly, early life presentation with enamel dysplasia was predictive of likelihood of development of a subsequent APECED diagnosis. Furthermore, we present a case of a patient with APECED and severe enamel defects and discuss the utility of medical-dental professional co-operation in the diagnosis and management of this complex disorder.
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Affiliation(s)
- Laurie Brenchley
- Oral Immunity and Inflammation Section, NIDCR, NIH, Bethesda, MD, USA
| | - Elise M. N. Ferré
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, NIAID, NIH, Bethesda, MD, USA
| | - Monica M. Schmitt
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, NIAID, NIH, Bethesda, MD, USA
| | | | - Michail S. Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, NIAID, NIH, Bethesda, MD, USA
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Perniola R, Fierabracci A, Falorni A. Autoimmune Addison's Disease as Part of the Autoimmune Polyglandular Syndrome Type 1: Historical Overview and Current Evidence. Front Immunol 2021; 12:606860. [PMID: 33717087 PMCID: PMC7953157 DOI: 10.3389/fimmu.2021.606860] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene, located in the chromosomal region 21q22.3. The related protein, AIRE, enhances thymic self-representation and immune self-tolerance by localization to chromatin and anchorage to multimolecular complexes involved in the initiation and post-initiation events of tissue-specific antigen-encoding gene transcription. Once synthesized, the self-antigens are presented to, and cause deletion of, the self-reactive thymocyte clones. The clinical diagnosis of APS1 is based on the classic triad idiopathic hypoparathyroidism (HPT)-chronic mucocutaneous candidiasis-autoimmune Addison's disease (AAD), though new criteria based on early non-endocrine manifestations have been proposed. HPT is in most cases the first endocrine component of the syndrome; however, APS1-associated AAD has received the most accurate biochemical, clinical, and immunological characterization. Here is a comprehensive review of the studies on APS1-associated AAD from initial case reports to the most recent scientific findings.
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Affiliation(s)
- Roberto Perniola
- Department of Pediatrics-Neonatal Intensive Care, V. Fazzi Hospital, ASL LE, Lecce, Italy
| | - Alessandra Fierabracci
- Infectivology and Clinical Trials Research Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Alberto Falorni
- Section of Internal Medicine and Endocrinological and Metabolic Sciences, Department of Medicine, University of Perugia, Perugia, Italy
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Besnard M, Padonou F, Provin N, Giraud M, Guillonneau C. AIRE deficiency, from preclinical models to human APECED disease. Dis Model Mech 2021; 14:dmm046359. [PMID: 33729987 PMCID: PMC7875492 DOI: 10.1242/dmm.046359] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare life-threatening autoimmune disease that attacks multiple organs and has its onset in childhood. It is an inherited condition caused by a variety of mutations in the autoimmune regulator (AIRE) gene that encodes a protein whose function has been uncovered by the generation and study of Aire-KO mice. These provided invaluable insights into the link between AIRE expression in medullary thymic epithelial cells (mTECs), and the broad spectrum of self-antigens that these cells express and present to the developing thymocytes. However, these murine models poorly recapitulate all phenotypic aspects of human APECED. Unlike Aire-KO mice, the recently generated Aire-KO rat model presents visual features, organ lymphocytic infiltrations and production of autoantibodies that resemble those observed in APECED patients, making the rat model a main research asset. In addition, ex vivo models of AIRE-dependent self-antigen expression in primary mTECs have been successfully set up. Thymus organoids based on pluripotent stem cell-derived TECs from APECED patients are also emerging, and constitute a promising tool to engineer AIRE-corrected mTECs and restore the generation of regulatory T cells. Eventually, these new models will undoubtedly lead to main advances in the identification and assessment of specific and efficient new therapeutic strategies aiming to restore immunological tolerance in APECED patients.
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Affiliation(s)
- Marine Besnard
- Université de Nantes, Inserm, CNRS, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Francine Padonou
- Université de Nantes, Inserm, CNRS, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Nathan Provin
- Université de Nantes, Inserm, CNRS, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Matthieu Giraud
- Université de Nantes, Inserm, CNRS, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Carole Guillonneau
- Université de Nantes, Inserm, CNRS, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
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Ferré EMN, Lionakis MS. An AIREless Breath: Pneumonitis Caused by Impaired Central Immune Tolerance. Front Immunol 2021; 11:609253. [PMID: 33584685 PMCID: PMC7873437 DOI: 10.3389/fimmu.2020.609253] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 12/01/2020] [Indexed: 12/17/2022] Open
Abstract
Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by biallelic mutations in the AIRE gene, has historically been defined by the development of chronic mucocutaneous candidiasis together with autoimmune endocrinopathies, primarily hypoparathyroidism and adrenal insufficiency. Recent work has drawn attention to the development of life-threatening non-endocrine manifestations such as autoimmune pneumonitis, which has previously been poorly recognized and under-reported. In this review, we present the clinical, radiographic, autoantibody, and pulmonary function abnormalities associated with APECED pneumonitis, we highlight the cellular and molecular basis of the autoimmune attack in the AIRE-deficient lung, and we provide a diagnostic and a therapeutic roadmap for patients with APECED pneumonitis. Beyond APECED, we discuss the relevance and potential broader applicability of these findings to other interstitial lung diseases seen in secondary AIRE deficiency states such as thymoma and RAG deficiency or in common polygenic autoimmune disorders such as idiopathic Sjögren's syndrome.
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Affiliation(s)
| | - Michail S. Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
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Cinque L, Angeletti C, Orrico A, Castellana S, Ferrito L, Ciuoli C, Mazza T, Castori M, Guarnieri V. Novel Pathogenic Variants of the AIRE Gene in Two Autoimmune Polyendocrine Syndrome Type I Cases with Atypical Presentation: Role of the NGS in Diagnostic Pathway and Review of the Literature. Biomedicines 2020; 8:biomedicines8120631. [PMID: 33352647 PMCID: PMC7767245 DOI: 10.3390/biomedicines8120631] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/16/2020] [Accepted: 12/18/2020] [Indexed: 01/08/2023] Open
Abstract
Background. Autoimmune polyglandular syndrome type 1 (APS-1) with or without reversible metaphyseal dysplasia is a rare genetic disorder due to inactivating variants of the autoimmune regulator, AIRE, gene. Clinical variability of APS-1 relates to pleiotropy, and the general dysfunction of self-tolerance to organ-specific antigens and autoimmune reactions towards peripheral tissues caused by the underlying molecular defect. Thus, early recognition of the syndrome is often delayed, mostly in cases with atypical presentation, and the molecular confirm through the genetic analysis of the AIRE gene might be of great benefit. Methods. Our methods were to investigate, with a multigene panel next generation sequencing approach, two clinical cases, both presenting with idiopathic hypoparathyroidism, also comprising the AIRE gene; as well as to comment our findings as part of a more extensive review of literature data. Results. In the first clinical case, two compound heterozygote pathogenic variants of the AIRE gene were identified, thus indicating an autosomal recessive inheritance of the disease. In the second case, only one AIRE gene variant was found and an atypical dominant negative form of APS-1 suggested, later confirmed by further medical ascertainments. Conclusions. APS-1 might present with variable and sometimes monosymptomatic presentations and, if not recognized, might associate with severe complications. In this context, next generation diagnostics focused on a set of genes causative of partially overlapping disorders may allow early diagnosis.
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Affiliation(s)
- Luigia Cinque
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (L.C.); (M.C.)
| | - Cristina Angeletti
- UOC Pediatrics and Neonatology, POU AV2, 60122 Senigallia, Italy; (C.A.); (L.F.)
| | - Alfredo Orrico
- Molecular Diagnosis and Characterization of Pathogenic Mechanisms of Rare Genetic Diseases, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;
- Clinical Genetics, ASL Toscana SudEst. Ospedale della Misericordia, 58100 Grosseto, Italy
| | - Stefano Castellana
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (S.C.); (T.M.)
| | - Lucia Ferrito
- UOC Pediatrics and Neonatology, POU AV2, 60122 Senigallia, Italy; (C.A.); (L.F.)
| | - Cristina Ciuoli
- Department of Medical, Surgical and Neurological Sciences, UOC Endocrinology, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;
| | - Tommaso Mazza
- Clinical Genetics, ASL Toscana SudEst. Ospedale della Misericordia, 58100 Grosseto, Italy
| | - Marco Castori
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (L.C.); (M.C.)
| | - Vito Guarnieri
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (L.C.); (M.C.)
- Correspondence: ; Tel.: +39-0882-416347
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Minka BM, Sibetcheu T A, Sap SNU, Bissa MC. Chronic cutaneous candidiasis in children: should we stop there? Report of two cases associated with auto-immune polyendocrinopathy syndrome type I. BMC Pediatr 2020; 20:128. [PMID: 32188450 PMCID: PMC7081563 DOI: 10.1186/s12887-020-02030-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 03/12/2020] [Indexed: 11/25/2022] Open
Abstract
Background Auto-immune polyendocrinopathy syndrome type I is a rare genetic disease, usually revealed by chronic superficial candidiasis and autoimmune endocrine dysfunction in childhood. Cases presentation We 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. Conclusion The occurrence of chronic cutaneous candidiasis in a child should always imply endocrine screening, to exclude auto-immune polyendocrine syndrome type I.
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Zheng WB, Li LJ, Zhao DC, Wang O, Jiang Y, Xia WB, Li M. A novel variant in AIRE causing a rare, non‑classical autoimmune polyendocrine syndrome type 1. Mol Med Rep 2020; 22:1285-1294. [PMID: 32627016 PMCID: PMC7339480 DOI: 10.3892/mmr.2020.11227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 05/14/2020] [Indexed: 11/06/2022] Open
Abstract
Autoimmune polyendocrine syndrome type 1 (APS‑1) is a rare inherited autoimmune disease, characterized by a classic triad, including chronic mucocutaneous candidiasis, primary adrenocortical insufficiency and hypoparathyroidism. The present study investigated phenotypes and pathogenic variants in a Chinese woman with non‑classical APS‑1. Disease‑associated variants in a patient with APS‑1 were identified via targeted next generation sequencing and the variant was confirmed via Sanger sequencing. Serum levels of calcium, phosphorus, parathyroid hormone (PTH), follicle‑stimulating hormone (FSH), luteinizing hormone (LH), estradiol and urinary levels of calcium were measured. Blood count assays and bone marrow morphology were investigated. The patient was a 32‑year‑old woman who had suffered from typical carpopedal spasms since she was 7 years old. She developed syncope, primary amenorrhea, intermittent diarrhea and general fatigue in subsequent years. Hypocalcemia, hyperphosphatemia, low levels of PTH and estradiol, elevated levels of FSH and LH, and absence of erythroblasts were observed, which indicated hypoparathyroidism, primary ovarian insufficiency and pure red cell aplasia. A novel heterozygous missense variant (NM_000383.2: c.623G>T, NP_000374.1: p.Gly208Val) in exon 5 of autoimmune regulator and a reported variant (NM_000383.2: c.371C>T, NP_000374.1: p.Pro124Leu) in exon 3 were detected, of which the c.623G>T variant may be a pathogenic variation that induces APS‑1. Under a regular follow‑up and therapeutic adjustment of calcium, calcitriol, hormone replacement therapy and methylprednisolone, the endocrine function and clinical symptoms of the patient were notably improved. The results of the present study expand the known genetic and phenotypical spectra of APS‑1.
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Affiliation(s)
- Wen-Bin Zheng
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Lu-Jiao Li
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Di-Chen Zhao
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Ou Wang
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Yan Jiang
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Wei-Bo Xia
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Mei Li
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
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Borchers J, Pukkala E, Mäkitie O, Laakso S. Patients With APECED Have Increased Early Mortality Due to Endocrine Causes, Malignancies and infections. J Clin Endocrinol Metab 2020; 105:5809346. [PMID: 32185376 PMCID: PMC7150614 DOI: 10.1210/clinem/dgaa140] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 03/16/2020] [Indexed: 01/12/2023]
Abstract
CONTEXT Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autoimmune endocrinopathy with severe and unpredictable course. The impact of APECED on mortality has not been determined. OBJECTIVE To assess overall and cause-specific mortality of patients with APECED. DESIGN AND SETTING A follow-up study of Finnish patients with APECED from 1971 to 2018. Causes and dates of death were collected from Finnish registries. PATIENTS Ninety-one patients with APECED. MAIN OUTCOME MEASURE Overall and cause-specific standardized mortality ratios (SMRs) determined by comparing the observed numbers of death and those expected on the basis of respective population death rates in Finland. RESULTS The overall disease mortality was significantly increased (29 deaths, SMR 11; 95% confidence interval [CI] 7.2-16; P < 0.001). The relative risk (SMR) was highest in the youngest age groups but the absolute excess risk was similar (about 10 per 10 000 person-years) in all age categories. The highest SMRs were seen for endocrine and metabolic diseases (SMR 570; 95% CI, 270-1000; P < 0.001) and for oral and esophageal malignancies (SMR 170; 95% CI, 68-360; P < 0.001). Mortality was also increased for infections, diseases of digestive system, alcohol-related deaths, and for accidents. Due to the small number of cases we were unable to evaluate whether mortality was affected by disease severity. CONCLUSIONS Patients with APECED have significantly increased mortality in all age groups. Highest SMRs are found for causes that are directly related to APECED but also for infections. Increased alcohol- and accident-related deaths may be influenced by psychosocial factors.
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Affiliation(s)
- Joonatan Borchers
- Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Eero Pukkala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
- Finnish Cancer Registry – Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
| | - Outi Mäkitie
- Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Saila Laakso
- Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Correspondence and Reprint Requests: Saila Laakso, MD, PhD, PO. Box 347, 00029 HUS, Finland. E-mail:
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Yan Z, Gang X, Xie X, Gao Y, Li Z, Wang G. A case report and literature review: Identification of a novel AIRE gene mutation associated with Autoimmune Polyendocrine Syndrome Type 1 in East Asians. Medicine (Baltimore) 2020; 99:e20000. [PMID: 32358377 PMCID: PMC7440052 DOI: 10.1097/md.0000000000020000] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 12/15/2019] [Accepted: 03/23/2020] [Indexed: 01/06/2023] Open
Abstract
RATIONALE Autoimmune polyendocrine syndrome type 1 (APS-1), also referred as the autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED), is a rare autosomal inherited disease predominantly among Caucasians from Northern Europe. This syndrome is very rare in East Asian population. PATIENTS CONCERNS Here, we describe a case of a 15-year-old Chinese boy admitted due to a 1-month history of intermittent fatigue, nausea, vomiting, and diarrhea. His symptom became worse accompanied with chest tightness 4 days before admission. On physical examination, his temperature was 38.5°C, blood pressure was 75/38 mm Hg, and pulse was 98/min. He was a thin boy with mild hyperpigmentation and xanthochromia. DIAGNOSIS After abdominal computed technology and laboratory tests, his diagnosis was APS-1 accompanied with adrenal crisis. Further investigation on whole-exome sequencing revealed a novel homozygous mutation c.47C>G (p.T16R) in exon 1 in the autoimmune regulator (AIRE) gene. INTERVENTIONS This patient underwent replacement therapy of glucocorticoids, corticosteroid, and levothyroxine, as well as calcium and calcitriol supplementation. OUTCOMES He continues to do well 4 years after his hospitalization. During his last follow-up, he had serum thyroid-stimulating hormone level of 3.07 μIU/mL, free triiodothyronine level of 1.92 pg/mL, and free thyroxine level of 13.95 pg/mL. His serum cortisol and ACTH (8 a.m.) levels were 28.53 μg/dL and 69.48 pg/mL, respectively. LESSONS APS-1 is very rare in East Asians and the variable clinical presentations of the disease make the initial diagnosis especially difficult. Autoimmune thyroiditis, type 1 diabetes mellitus, and hepatitis were the three most frequent minor components of APS-1 in East Asian patients with age of onset in late teens and 20s. Sequence analysis of AIRE gene is necessary to verify its diagnostic efficacy in association with clinical findings.
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Jamee M, Mahdaviani SA, Mansouri D, Azizi G, Joneidi N, Ghaffaripour H, Eskandarzade S, Ghaini M, Marjani M, Moniri A, Migaud M, Casanova J, Puel A, Velayati A. Delay in the Diagnosis of APECED: A Case Report and Review of Literature from Iran. Immunol Invest 2020; 49:299-306. [PMID: 31588815 DOI: 10.1080/08820139.2019.1671451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the AIRE (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.
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Affiliation(s)
- Mahnaz Jamee
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Seyed Alireza Mahdaviani
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Mansouri
- Clinical Tuberculosis and Epidemiology Research Centre, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Nematollah Joneidi
- Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Hosseinali Ghaffaripour
- Clinical Tuberculosis and Epidemiology Research Centre, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Eskandarzade
- Clinical Tuberculosis and Epidemiology Research Centre, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Ghaini
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Marjani
- Clinical Tuberculosis and Epidemiology Research Centre, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Moniri
- Clinical Tuberculosis and Epidemiology Research Centre, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mélanie Migaud
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France
| | - Jl Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Imagine Institute, Paris Descartes University, Paris, France
- Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France
- Howard Hughes Medical Institute, New York, New York, USA
| | - Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Imagine Institute, Paris Descartes University, Paris, France
| | - Aliakbar Velayati
- Clinical Tuberculosis and Epidemiology Research Centre, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Suh J, Choi HS, Kwon A, Chae HW, Lee JS, Kim HS. A novel compound heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrine syndrome type 1. Ann Pediatr Endocrinol Metab 2019; 24:248-252. [PMID: 31905445 PMCID: PMC6944864 DOI: 10.6065/apem.2019.24.4.248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 05/14/2019] [Indexed: 12/19/2022] Open
Abstract
Autoimmune polyendocrine syndrome type 1 (APS-1), or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare, autosomal recessive autoimmune disease caused by a mutation of the autoimmune regulator (AIRE) gene. The main symptom triad in APS-1 comprises chronic mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. Various autoimmune diseases and ectodermal abnormalities are also commonly associated with the syndrome. The treatment of APS-1 includes hormone replacement and symptom control. It is important to monitor such patients for clinical manifestations of their disease through regular follow-up. We report the case of a 10-year-old Korean girl with APS-1 due to a novel compound heterozygous mutation of the AIRE gene. This patient's main clinical manifestations were adrenal insufficiency and chronic mucocutaneous candidiasis. The patient had a previously known pathogenic variant of c.1513delG (p.Ala505ProfsTer16), and a newly discovered variant of c.1360dupC (p.His454ProfsTer50).
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Affiliation(s)
- Junghwan Suh
- Department of Pediatrics, Severance Children’s Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Han Saem Choi
- Department of Pediatrics, Severance Children’s Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Ahreum Kwon
- Department of Pediatrics, Severance Children’s Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Wook Chae
- Department of Pediatrics, Severance Children’s Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jin-Sung Lee
- Division of Clinical Genetics, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
| | - Ho-Seong Kim
- Department of Pediatrics, Severance Children’s Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea,Address for correspondence: Ho-Seong Kim, MD, PhD Department of Pediatrics, Severance Children’s Hospital, Endocrine Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2228-2069 Fax: +82-2-393-9118 E-mail:
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Fardi Golyan F, Ghaemi N, Abbaszadegan MR, Dehghan Manshadi SH, Vakili R, Druley TE, Rahimi HR, Ghahraman M. Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1. Immunobiology 2019; 224:728-733. [PMID: 31526676 DOI: 10.1016/j.imbio.2019.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/16/2019] [Accepted: 09/03/2019] [Indexed: 12/27/2022]
Abstract
PURPOSE Autoimmune polyendocrine type 1 (APS-1) is a complex inherited autosomal recessive disorder. Classically, it appears within the first decade of life followed by adrenocortical insufficiency, mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. The clinical phenotype of APS-1 varies depending upon mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. METHODS In this study, we performed Sanger sequencing ofAIRE in Iranian patients to identify different variants and probable new mutations corresponding to a clinical diagnosis of APS-1. RESULTS After analyzing 14AIRE exons, we detected a novel insertion mutation in exon 2 in a patient who presented with severe APS-1, Lys50AsnfsX168. Furthermore, the known mutations in AIRE, including Arg139X, Arg257X, and Leu323SerfsX51, were detected in enrolled patients. DISCUSSION According to our results, sequencing analysis ofAIRE provides a useful screening method to diagnose patients with incomplete or unusual clinical presentations of APS-1.
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Affiliation(s)
- Fatemeh Fardi Golyan
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nosrat Ghaemi
- Department of Pediatric Endocrinology and Metabolism, Imam Reza Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Rahim Vakili
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pediatric Endocrinology and Metabolism, Imam Reza Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Todd E Druley
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Hamid Reza Rahimi
- Department of Modern Sciences & technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Martha Ghahraman
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Ferré EMN, Break TJ, Burbelo PD, Allgäuer M, Kleiner DE, Jin D, Xu Z, Folio LR, Mollura DJ, Swamydas M, Gu W, Hunsberger S, Lee CCR, Bondici A, Hoffman KW, Lim JK, Dobbs K, Niemela JE, Fleisher TA, Hsu AP, Snow LN, Darnell DN, Ojaimi S, Cooper MA, Bozzola M, Kleiner GI, Martinez JC, Deterding RR, Kuhns DB, Heller T, Winer KK, Rajan A, Holland SM, Notarangelo LD, Fennelly KP, Olivier KN, Lionakis MS. Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance. Sci Transl Med 2019; 11:eaav5597. [PMID: 31167928 PMCID: PMC6647037 DOI: 10.1126/scitranslmed.aav5597] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 04/05/2019] [Indexed: 12/19/2022]
Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.
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Affiliation(s)
- Elise M N Ferré
- Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Timothy J Break
- Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Peter D Burbelo
- Dental Clinical Research Core, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, MD 20892, USA
| | - Michael Allgäuer
- Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - David E Kleiner
- Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
| | - Dakai Jin
- Radiology and Imaging Sciences, NIH Clinical Center (CC), NIH, Bethesda, MD 20892, USA
| | - Ziyue Xu
- Radiology and Imaging Sciences, NIH Clinical Center (CC), NIH, Bethesda, MD 20892, USA
| | - Les R Folio
- Radiology and Imaging Sciences, NIH Clinical Center (CC), NIH, Bethesda, MD 20892, USA
| | - Daniel J Mollura
- Radiology and Imaging Sciences, NIH Clinical Center (CC), NIH, Bethesda, MD 20892, USA
| | - Muthulekha Swamydas
- Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Wenjuan Gu
- Biostatistics Research Branch, Division of Clinical Research (DCR), NIAID, NIH, Bethesda, MD 20892, USA
| | - Sally Hunsberger
- Biostatistics Research Branch, Division of Clinical Research (DCR), NIAID, NIH, Bethesda, MD 20892, USA
| | - Chyi-Chia R Lee
- Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
| | - Anamaria Bondici
- Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Kevin W Hoffman
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jean K Lim
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kerry Dobbs
- Immune Deficiency Genetics Section, LCIM, NIAID, NIH, Bethesda, MD 20892, USA
| | - Julie E Niemela
- Immunology Service, Department of Laboratory Medicine (DLM), NIH CC, NIH, Bethesda, MD 20892, USA
| | - Thomas A Fleisher
- Immunology Service, Department of Laboratory Medicine (DLM), NIH CC, NIH, Bethesda, MD 20892, USA
| | - Amy P Hsu
- Immunopathogenesis Section, LCIM, NIAID, NIH, Bethesda, MD 20892, USA
| | - Laquita N Snow
- Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Dirk N Darnell
- Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Samar Ojaimi
- Department of Infectious Diseases, Monash Health, Melbourne, VIC 3800, Australia
- Centre for Inflammatory Diseases, Monash University, Melbourne, VIC 3800, Australia
| | - Megan A Cooper
- Department of Pediatrics, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Martin Bozzola
- Department of Pediatrics, British Hospital, Perdriel 74, CABA-Buenos Aires, Argentina
| | - Gary I Kleiner
- University of Miami Department of Pediatrics, Miami, FL 33136, USA
| | - Juan C Martinez
- Cystic Fibrosis, Pulmonary, and Sleep Division, Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA
| | - Robin R Deterding
- Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO 80045, USA
| | - Douglas B Kuhns
- Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21701, USA
| | - Theo Heller
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA
| | - Karen K Winer
- Pediatric Growth and Nutrition Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD 20892, USA
| | - Arun Rajan
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
| | - Steven M Holland
- Immunopathogenesis Section, LCIM, NIAID, NIH, Bethesda, MD 20892, USA
| | - Luigi D Notarangelo
- Immune Deficiency Genetics Section, LCIM, NIAID, NIH, Bethesda, MD 20892, USA
| | - Kevin P Fennelly
- Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD 20892, USA
| | - Kenneth N Olivier
- Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD 20892, USA
| | - Michail S Lionakis
- Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
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Amaya-Uribe L, Rojas M, Azizi G, Anaya JM, Gershwin ME. Primary immunodeficiency and autoimmunity: A comprehensive review. J Autoimmun 2019; 99:52-72. [PMID: 30795880 DOI: 10.1016/j.jaut.2019.01.011] [Citation(s) in RCA: 119] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/24/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023]
Abstract
The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented.
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Affiliation(s)
- Laura Amaya-Uribe
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Manuel Rojas
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia; Doctoral Program in Biomedical Sciences, Universidad Del Rosario, Bogota, Colombia
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, School of Medicine, Davis, CA, USA.
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Meloni A, Corda G, Saba L, Ferri GL, Mariotti S, Cocco C. Reduction of Total Brain and Cerebellum Volumes Associated With Neuronal Autoantibodies in Patients With APECED. J Clin Endocrinol Metab 2019; 104:150-162. [PMID: 30339230 DOI: 10.1210/jc.2018-01313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/15/2018] [Indexed: 01/16/2023]
Abstract
CONTEXT In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoantibodies (AutoAbs) labeling brain neurons were reported; conversely, brain MRI alterations associated with these AutoAbs were never reported. OBJECTIVES To describe brain alterations in APECED and to correlate them with AutoAbs against glutamic acid decarboxylase (GAD), tyrosine hydroxylase (TH), and 5-tryptophan hydroxylase (5-HT) neurons. DESIGN AND PARTICIPANTS Fourteen Sardinian patients with APECED and age-matched control subjects were recruited for MRI analysis and blood sampling to detect AutoAbs to GAD, TH, and 5-HT neurons by using rat brain sections. The majority of patients (n = 12) were investigated for AutoAbs a decade earlier, and 7 of 12 were positive for AutoAbs to GAD and TH neurons. MAIN OUTCOMES Patients with APECED had smaller cerebellum and gray matter volumes, with a ventricular enlargement and a total cerebrospinal fluid (CSF) increase, compared with controls (P < 0.01). In 11 of 14 patients, brain abnormalities were associated with AutoAbs to GAD or TH neurons (titer 1:100 to 15,000) that had persisted for 10 years in 7 of 11 patients. AutoAbs to 5-HT neurons were revealed in all patients with AutoAbs to TH neurons. A decrease in whole brain and cerebellum volumes (P = 0.028) was associated with AutoAbs to GAD neurons, and a CSF increase was associated with AutoAbs to GAD and TH/5-HT neurons (P < 0.05). HLA alleles did not appear to be involved in neuronal autoimmunity. CONCLUSIONS Brain alterations and neuronal AutoAbs were observed in 78.6% of Sardinian patients with APECED, suggesting a brain autoimmune reaction. Prolonged clinical follow-up must be conducted for the possible appearance of clinical neurologic consequences.
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Affiliation(s)
- Antonella Meloni
- Clinica Pediatrica II, Ospedale Pediatrico Microcitemico Antonio Cao, Clinical and Molecular Medicine, University of Cagliari, Cagliari (CA), Italy
- Sardinian APECED Association, Baunei (OG), Italy
| | - Giulia Corda
- NEF Laboratory, Department of Biomedical Sciences, University of Cagliari, Monserrato (CA), Italy
| | - Luca Saba
- Department of Radiology, AOU, University of Cagliari, Monserrato (CA), Italy
| | - Gian-Luca Ferri
- NEF Laboratory, Department of Biomedical Sciences, University of Cagliari, Monserrato (CA), Italy
| | - Stefano Mariotti
- Endocrinology Department of Medical Sciences and Public Health, University of Cagliari, Monserrato (CA), Italy
| | - Cristina Cocco
- NEF Laboratory, Department of Biomedical Sciences, University of Cagliari, Monserrato (CA), Italy
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Constantine GM, Lionakis MS. Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Immunol Rev 2019; 287:103-120. [PMID: 30565240 PMCID: PMC6309421 DOI: 10.1111/imr.12714] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 08/19/2018] [Indexed: 12/12/2022]
Abstract
The discovery of the autoimmune regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.
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Affiliation(s)
- Gregory M Constantine
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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40
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Abstract
Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and is due to insufficient levels of circulating parathyroid hormone. Hypoparathyroidism may be an isolated condition or a component of a complex syndrome. Although genetic disorders are not the most common cause of hypoparathyroidism, molecular analyses have identified a growing number of genes that when defective result in impaired formation of the parathyroid glands, disordered synthesis or secretion of parathyroid hormone, or postnatal destruction of the parathyroid glands.
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Affiliation(s)
- Rebecca J Gordon
- Division of Endocrinology and Diabetes, The Center for Bone Health, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, 11 Northwest Tower, Suite 30, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA.
| | - Michael A Levine
- Division of Endocrinology and Diabetes, The Center for Bone Health, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, 3615 Civic Center Boulevard, Abramson Research Building, Room 510A, Philadelphia, PA 19104, USA
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Weiler FG, Peterson P, Costa-Carvalho BT, de Barros Dorna M, Correia-Deur JE, Sader SL, Espíndola-Antunes D, Guerra-Junior G, Dias-da-Silva MR, Lazaretti-Castro M. The heterogeneity of autoimmune polyendocrine syndrome type 1: Clinical features, new mutations and cytokine autoantibodies in a Brazilian cohort from tertiary care centers. Clin Immunol 2018; 197:231-238. [PMID: 30287219 DOI: 10.1016/j.clim.2018.09.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 09/16/2018] [Accepted: 09/26/2018] [Indexed: 12/31/2022]
Abstract
Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by multiorgan autoimmunity. We aim at characterizing a multi-center Brazilian cohort of APS1 patients by clinical evaluation, searching mutation in the AIRE gene, measuring serum autoantibodies, and investigating correlations between findings. We recruited patients based on the clinical criteria and tested them for AIRE mutations, antibodies against interferon type I and interleukins 17A, 17F and 22. We identified 12 unrelated families (13 patients) with typical signs of APS1 in the proband, and the screening of relatives recognized an asymptomatic child. Candidiasis was present in all cases, and 19 other manifestations were observed. All patients carried one of 10 different mutations in AIRE, being 3 new ones, and were positive for anti-interferon type I serum antibody. Anti-interleukin-17A levels inversely correlated with the number of manifestations in each patient. This negative correlation may suggest a protective effect of anti-interleukin-17A with a potential therapeutic application.
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Affiliation(s)
- Fernanda Guimarães Weiler
- Division of Endocrinology, Department of Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Sao Paulo, Brazil
| | - Pärt Peterson
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | | | - Mayra de Barros Dorna
- Allergy and immunology unit, Department of Pediatrics, Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil
| | | | - Soraya Lopes Sader
- Department of Pediatrics, Ribeirao Preto Medical School, Universidade de Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
| | | | - Gil Guerra-Junior
- Department of Pediatrics, Universidade Estadual de Campinas, Campinas, Sao Paulo, Brazil
| | - Magnus Régios Dias-da-Silva
- Division of Endocrinology, Department of Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.
| | - Marise Lazaretti-Castro
- Division of Endocrinology, Department of Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Sao Paulo, Brazil
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Humbert L, Cornu M, Proust-Lemoine E, Bayry J, Wemeau JL, Vantyghem MC, Sendid B. Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1. Front Immunol 2018; 9:2570. [PMID: 30510552 PMCID: PMC6254185 DOI: 10.3389/fimmu.2018.02570] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 10/18/2018] [Indexed: 11/13/2022] Open
Abstract
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.
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Affiliation(s)
- Linda Humbert
- Department of Endocrinology and Metabolism, CHU Lille, Lille, France
| | - Marjorie Cornu
- Department Parasitology-Mycology, CHU, Lille, France
- Inserm, U995-LIRIC, Fungal Associated Invasive & Inflammatory Diseases, Lille, France
| | | | - Jagadeesh Bayry
- Inserm, Center de Recherche des Cordeliers, Sorbonne Université, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Jean-Louis Wemeau
- Department of Endocrinology and Metabolism, CHU Lille, Lille, France
| | - Marie-Christine Vantyghem
- Department of Endocrinology and Metabolism, CHU Lille, Lille, France
- UMR 1190, Translational Research in Diabetes Inserm, Lille, France
- European Genomic Institute for Diabetes, Univ Lille, Lille, France
| | - Boualem Sendid
- Department Parasitology-Mycology, CHU, Lille, France
- Inserm, U995-LIRIC, Fungal Associated Invasive & Inflammatory Diseases, Lille, France
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Fierabracci A, Pellegrino M, Frasca F, Kilic SS, Betterle C. APECED in Turkey: A case report and insights on genetic and phenotypic variability. Clin Immunol 2018; 194:60-66. [PMID: 30018023 DOI: 10.1016/j.clim.2018.06.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 06/27/2018] [Accepted: 06/29/2018] [Indexed: 01/06/2023]
Abstract
APECED is a rare monogenic recessive disorder caused by mutations in the AIRE gene. In this manuscript, we report a male Turkish patient with APECED syndrome who presented with chronic mucocutaneous candidiasis associated with other autoimmune manifestations developed over the years. The presence of the homozygous R257X mutation of the AIRE gene confirmed the diagnosis of APECED syndrome. We further performed literature review in 23 published Turkish APECED patients and noted that Finnish major mutation R257X is common in Turks. In particular, we assessed retrospectively how often the Ferre/Lionakis criteria would have resulted in earlier diagnosis in Finns, Sardinians and Turks in respect to the classic criteria. Since an earlier diagnosis could have been possible in 18.8% of Turkish, in 23.8% of Sardinian and 38.55% of Finnish patients we reviewed from literature, Ferre/Lionakis criteria could indeed allow in future earlier initiation of immunomodulatory treatments, if found effective in future studies.
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Affiliation(s)
- Alessandra Fierabracci
- Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Viale S. Paolo 15, 00146 Rome, Italy.
| | - Marsha Pellegrino
- Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Viale S. Paolo 15, 00146 Rome, Italy.
| | - Federica Frasca
- Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Viale S. Paolo 15, 00146 Rome, Italy.
| | - Sara Sebnem Kilic
- Pediatric Immunology -Rheumatology, Uludag University, Medical Faculty Department of Pediatrics, Gorukle-Bursa 16059, Turkey.
| | - Corrado Betterle
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Via Ospedale Civile 105, 35128 Padua, Italy.
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Pellegrino M, Bellacchio E, Dhamo R, Frasca F, Betterle C, Fierabracci A. A Novel Homozygous Mutation of the AIRE Gene in an APECED Patient From Pakistan: Case Report and Review of the Literature. Front Immunol 2018; 9:1835. [PMID: 30150985 PMCID: PMC6099424 DOI: 10.3389/fimmu.2018.01835] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 07/25/2018] [Indexed: 11/13/2022] Open
Abstract
Autoimmune-poly-endocrinopathy-candidiasis-ectodermal-dystrophy syndrome (APECED) is a rare monogenic recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Criteria for the diagnosis of APECED are the presence of two of the following disorders: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CHP), and Addison's disease. APECED develops at high incidence in Finns, Sardinians, and Iranian Jews and presents with a wide range of clinical phenotypes and genotypes. In this manuscript, we report the clinical, endocrinological, and molecular features of a 16-year-old female patient from Pakistan living in Italy and presenting the major APECED clinical manifestations CMC, CHP, and primary adrenal insufficiency. Premature ovarian failure, chronic bronchopneumopathy, vitiligo, Hashimoto's thyroiditis emerged as associated diseases. In our patient, AIRE gene screening revealed the novel c.396G>C (p.Arg132Ser; p.R132S) mutation in homozygosity thus confirming APECED diagnosis. This is the first reported mutation within the nuclear localization signal (NLS) that is associated with APECED. The NLS mutation affects the nuclear import of classical transcription factors through nuclear pore by recognition of nuclear import receptors, the importin α molecules. By displaying crystal structures of the peptide containing the KRK basic residue cluster bound to α importins, we show that p.R132S replacement in 131-KRK-133 does not reproduce these interactions. Thus, we propose that the novel mutation exerts its pathogenetic effect by impairing the nuclear import of the Aire protein. The present case report is added to a limited series of Pakistani APECED patients who we reviewed from the scientific literature, mostly diagnosed on clinical findings.
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Affiliation(s)
- Marsha Pellegrino
- Infectivology and Clinical Trials Research Division, Bambino Gesù Children’s Hospital, Rome, Italy
| | - Emanuele Bellacchio
- Molecular Genetics and Functional Genomics, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, Rome, Italy
| | | | - Federica Frasca
- Infectivology and Clinical Trials Research Division, Bambino Gesù Children’s Hospital, Rome, Italy
| | - Corrado Betterle
- Endocrine Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Alessandra Fierabracci
- Infectivology and Clinical Trials Research Division, Bambino Gesù Children’s Hospital, Rome, Italy
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Zhu F, Hu Y. Integrity of IKK/NF-κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis. Bioessays 2018. [PMID: 29522649 DOI: 10.1002/bies.201700131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell-mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α (IKKα) is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases.
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Affiliation(s)
- Feng Zhu
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, 21701, Maryland, USA
| | - Yinling Hu
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, 21701, Maryland, USA
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Abstract
About two decades ago, cloning of the autoimmune regulator (AIRE) gene materialized one of the most important actors on the scene of self-tolerance. Thymic transcription of genes encoding tissue-specific antigens (ts-ags) is activated by AIRE protein and embodies the essence of thymic self-representation. Pathogenic AIRE variants cause the autoimmune polyglandular syndrome type 1, which is a rare and complex disease that is gaining attention in research on autoimmunity. The animal models of disease, although not identically reproducing the human picture, supply fundamental information on mechanisms and extent of AIRE action: thanks to its multidomain structure, AIRE localizes to chromatin enclosing the target genes, binds to histones, and offers an anchorage to multimolecular complexes involved in initiation and post-initiation events of gene transcription. In addition, AIRE enhances mRNA diversity by favoring alternative mRNA splicing. Once synthesized, ts-ags are presented to, and cause deletion of the self-reactive thymocyte clones. However, AIRE function is not restricted to the activation of gene transcription. AIRE would control presentation and transfer of self-antigens for thymic cellular interplay: such mechanism is aimed at increasing the likelihood of engagement of the thymocytes that carry the corresponding T-cell receptors. Another fundamental role of AIRE in promoting self-tolerance is related to the development of thymocyte anergy, as thymic self-representation shapes at the same time the repertoire of regulatory T cells. Finally, AIRE seems to replicate its action in the secondary lymphoid organs, albeit the cell lineage detaining such property has not been fully characterized. Delineation of AIRE functions adds interesting data to the knowledge of the mechanisms of self-tolerance and introduces exciting perspectives of therapeutic interventions against the related diseases.
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Affiliation(s)
- Roberto Perniola
- Department of Pediatrics, Neonatal Intensive Care, Vito Fazzi Regional Hospital, Lecce, Italy
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Abstract
BACKGROUND In recent years, scientific knowledge pertaining to the rare ORPHAN polyglandular autoimmune syndrome (registered code ORPHA 282196) has accumulated. OBJECTIVE To offer current demographic, clinical, serological and immunogenic data on PAS. METHODS Review of the pertinent and current literature. RESULTS Polyglandular autoimmune syndromes (PAS) are multifactorial diseases with at least two coexisting autoimmune-mediated endocrinopathies. PAS show a great heterogeneity of syndromes and manifest sequentially with a large time interval between the occurrence of the first and second glandular autoimmune disease. PAS cluster with several non-endocrine autoimmune diseases. In most endocrinopathies of PAS, the autoimmune process causes an irreversible loss of function, while chronic autoimmune aggressions can simultaneously modify physiological processes in the affected tissue and lead to altered organ function. The rare juvenile PAS type I is inherited in a monogenetic manner, whereas several susceptibility gene polymorphisms have been reported for the more prevalent adult types. Relevant for a timely diagnosis at an early stage is the screening for polyglandular autoimmunity in patients with monoglandular autoimmune disease and/or first degree relatives of patients with PAS. The most prevalent adult PAS type is the combination of type 1 diabetes with autoimmune thyroid disease. CONCLUSIONS Early detection of specific autoantibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown PAS disease.
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Affiliation(s)
- G J Kahaly
- Department of Medicine I, Johannes Gutenberg University Medical Center, 55101, Mainz, Germany.
| | - L Frommer
- Department of Medicine I, Johannes Gutenberg University Medical Center, 55101, Mainz, Germany
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Zirilli G, Santucci S, Cuzzupè C, Corica D, Pitrolo E, Salzano G. Peculiarities of autoimmune polyglandular syndromes in children and adolescents. ACTA BIO-MEDICA : ATENEI PARMENSIS 2017; 88:271-275. [PMID: 29083330 DOI: 10.23750/abm.v88i3.5898] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 11/05/2016] [Indexed: 01/15/2023]
Abstract
BACKGROUND no reviews have specifically addressed , to now, whether autoimmune polyglandular syndromes (APSs) may have a peculiar epidemiology and phenotypical expression in pediatric ageObjectives: to review the most recent literature data about the specific epidemiological and clinical peculiarities of APSs in childhood and adolescenceDesign: the main features of the different APSs in pediatric age were compared among them. CONCLUSIONS 1) Among the different APSs, the one that is most typical of pediatric age is APS-1; 2) APS-1 is not characterized only by the classical triad (chronic moniliasis-hyposurrenalism-hypoparathyroidism) and its clinical spectrum is enlarging over time; 3)APS-2 may have a different epidemiological and clinical expression according to two different nosological classifications.
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Affiliation(s)
- Giuseppina Zirilli
- Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy.
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Proust-Lemoine E, Guyot S. [Oral diseases in auto-immune polyendocrine syndrome type 1]. Presse Med 2017; 46:853-863. [PMID: 28683959 DOI: 10.1016/j.lpm.2017.05.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 04/28/2017] [Accepted: 05/29/2017] [Indexed: 11/26/2022] Open
Abstract
Auto-immune polyendocrine syndrome type 1 (APS1) also called Auto-immune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) is a rare monogenic childhood-onset auto-immune disease. This autosomal recessive disorder is caused by mutations in the auto-immune regulator (AIRE) gene, and leads to autoimmunity targeting peripheral tissues. There is a wide variability in clinical phenotypes in patients with APSI, with auto-immune endocrine and non-endocrine disorders, and chronic mucocutaneous candidiasis. These patients suffer from oral diseases such as dental enamel hypoplasia and candidiasis. Both are frequently described, and in recent series, enamel hypoplasia and candidiasis are even the most frequent components of APS1 together with hypoparathyroidism. Both often occur during childhood (before 5 years old for canrdidiasis, and before 15 years old for enamel hypoplasia). Oral candidiasis is recurrent all life long, could become resistant to azole antifungal after years of treatment, and be carcinogenic, leading to severe oral squamous cell carcinoma. Oral components of APS1 should be diagnosed and rigorously treated. Dental enamel hypoplasia and/or recurrent oral candidiasis in association with auto-immune diseases in a young child should prompt APS1 diagnosis.
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Affiliation(s)
| | - Sylvie Guyot
- Polyclinique Aguilera, 21, rue de l'Estagnas, 64200 Biarritz, France
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Orlova EM, Sozaeva LS, Kareva MA, Oftedal BE, Wolff ASB, Breivik L, Zakharova EY, Ivanova ON, Kämpe O, Dedov II, Knappskog PM, Peterkova VA, Husebye ES. Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1. J Clin Endocrinol Metab 2017; 102:3546-3556. [PMID: 28911151 DOI: 10.1210/jc.2017-00139] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 07/13/2017] [Indexed: 02/07/2023]
Abstract
Context Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare. Objective To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort. Subjects and Methods Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing. Results We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21). Conclusions The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1.
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Affiliation(s)
- Elizaveta M Orlova
- Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow 117036, Russia
- I. M. Sechenov First Moscow State Medical University, Moscow 117036, Russia
| | - Leila S Sozaeva
- Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow 117036, Russia
| | - Maria A Kareva
- Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow 117036, Russia
| | - Bergithe E Oftedal
- Department of Clinical Science, University of Bergen, Bergen 5020, Norway
| | - Anette S B Wolff
- Department of Clinical Science, University of Bergen, Bergen 5020, Norway
| | - Lars Breivik
- Department of Clinical Science, University of Bergen, Bergen 5020, Norway
| | - Ekaterina Y Zakharova
- Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow 117036, Russia
- Research Centre for Medical Genetics, Laboratory of Metabolic Disorders, Moscow 115478, Russia
| | - Olga N Ivanova
- Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow 117036, Russia
| | - Olle Kämpe
- Department of Medicine, Solna, Karolinska Institutet, Stockholm 17177, Sweden
| | - Ivan I Dedov
- Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow 117036, Russia
| | - Per M Knappskog
- Center for Medical Genetics and Molecular Medicine, Haukeland University and Hospital, Bergen 5021, Norway
| | - Valentina A Peterkova
- Endocrinology Research Centre, Institute of Paediatric Endocrinology, Moscow 117036, Russia
- I. M. Sechenov First Moscow State Medical University, Moscow 117036, Russia
| | - Eystein S Husebye
- Department of Clinical Science, University of Bergen, Bergen 5020, Norway
- Department of Medicine, Solna, Karolinska Institutet, Stockholm 17177, Sweden
- Department of Medicine, Haukeland University and Hospital, Bergen 5021, Norway
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