Autoimmune Addison's Disease as Part of the Autoimmune Polyglandular Syndrome Type 1: Historical Overview and Current Evidence.

Roberto Perniola,Alessandra Fierabracci,Alberto Falorni

doi:10.3389/fimmu.2021.606860

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.

Highlights

The term autoimmune polyglandular syndrome (APS) designates a heterogeneous group of diseases sharing a common fundamental characteristic—damage to more than one organ, essentially but not exclusively endocrine—caused by pathological processes identifiable as autoimmune [1, 2]
The view is somewhat richer if we look at the gonadal selfantigens; testis-specific protein 10 (TSGA10) was identified by immunoscreening of testis and pituitary cDNA expression library with sera from patients with autoimmune polyglandular syndrome type 1 (APS1), but no clinical phenotype correlated with antibody positivity [320, 321]
The delineation of CYP 21-hydroxylase (CYP21) epitopes benefited from interferon-γ (IFNγ, a type-2 IFN) assay in cultures of peripheral blood mononuclear cells challenged with several CYP21 fragments: some patients with APS1 carrying the MHCI HLA-B35 allele were included in these studies

Summary

Introduction

The term autoimmune polyglandular syndrome (APS) designates a heterogeneous group of diseases sharing a common fundamental characteristic—damage to more than one organ, essentially but not exclusively endocrine—caused by pathological processes identifiable as autoimmune [1, 2]. APS type 1 (APS1), often referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) to summarize clinical features, is a monogenic disease with an autosomal recessive inheritance [6, 7]. At least two of the major components—chronic mucocutaneous candidiasis (CMC), idiopathic hypoparathyroidism (HPT), and autoimmune Addison’s disease (AAD)—are required for clinical diagnosis [8,9,10]. The diagnostic pathway of APS1 cases with uncommon presentation and course may take advantage of early non-triad components, such as urticaria-like eruptions, gastrointestinal dysfunction, and enamel hypoplasia, along with type-1 interferon (IFN) antibody assay, pending molecular confirmation [11,12,13,14,15,16]

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Conclusion