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.
Highlights
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autoimmune disease (OMIM#, 240300) caused by loss-of-function autoimmune regulator (AIRE) mutations that impair central immune tolerance and result in the peripheral escape of selfreactive T lymphocytes, which infiltrate various endocrine and non-endocrine organs and cause autoimmune tissue destruction
These data suggest that the presence of neutralizing autoantibodies to typeI IFNs and the inflammation-prone lung tissue of APECED patients may heighten their risk for life-threatening COVID-19 complications [11, 84, 101]
chronic mucocutaneous candidiasis (CMC) is the “signature” infection of APECED, these patients are not at risk for invasive candidiasis or other invasive fungal infections, which rely on myeloid phagocytes for effective host defense [125]. These findings show that, in certain defined settings, mucosal fungal susceptibility may be driven by aberrant T lymphocyte-mediated immunopathology, by impaired type-17 immunity, and support a novel conceptual framework for classifying distinct molecular subtypes of CMC based on the balance between impaired type-17 immunity and/or immunopathology-promoting excessive type-1 inflammation [124]
Summary
APECED is a rare monogenic autoimmune disease (OMIM#, 240300) caused by loss-of-function AIRE mutations that impair central immune tolerance and result in the peripheral escape of selfreactive T lymphocytes, which infiltrate various endocrine (e.g., parathyroids, adrenals, gonads, thyroid, pancreas) and non-endocrine (e.g., enamel, stomach, small intestine, lungs, liver, salivary glands, kidneys, spleen, skin) organs and cause autoimmune tissue destruction. Recent patient cohort studies have uncovered an expanded clinical spectrum of APECED [7, 8], which has led to novel observations that may help (a) accelerate diagnosis via earlier recognition of certain disease manifestations and (b) devise effective screening, preventive, and treatment strategies for affected patients. We present our current knowledge of the genetic and immunological underpinnings of AIRE deficiency and discuss the clinical presentation, diagnostic criteria, and management of APECED patients
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