Exploring and redefining Autoimmune polyendocrine syndrome type 1

Abstract

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare, monogenic, childhood-onset disorder caused by mutations in the autoimmune regulator (AIRE) gene. Multi-organ autoimmune disease and chronic mucocutaneous candidiasis (CMC) dominate the clinical phenotype, making it an important model disease for autoimmunity. The objective of this thesis was to perform a detailed clinical, genetic and immunological characterisation of Norwegian APS-1 patients and explore the mechanisms behind CMC susceptibility. Fifty-two patients were included, revealing highly variable phenotypes. Most patients presented with one of the major disease components during childhood, hypoparathyroidism, primary adrenal insufficiency or CMC; enamel hypoplasia, hypoparathyroidism and CMC were the most frequent features. The prevalence of CMC indicates a specific immunodeficiency, which was underpinned by our finding of dysregulated immune responses to a Candida challenge. Specifically, monocytes produced significantly less interleukin-23p19 (IL), an important mediator in the Candida defence. Properly treatment of Candida infections is important as long-term inflammation in the oral cavity contributes to the development of oral malignancies, described here as a novel entity of APS-1. All Norwegian patients presented tissue-specific autoantibodies, and most had reactivity against IL-17, IL-22, and interferon-ω. The most common AIRE mutation was c.967_979del13. The splice mutation c.879+1G>A was associated with a mild adult-onset phenotype. Possible explanations are partial activity by AIRE lacking exon 7 and/or a certain amount of wild-type transcripts being produced despite mutation in a conserved splice donor site. Finally, the influence of environmental factors was explored by characterizing the oral microbiome. Indeed, APS-1 patients have significantly altered oral microbiota, with a general reduction in the total number of bacterial genera and species and altered relative abundance of major phyli compared to healthy subjects. This research has implications for the diagnosis and clinical care of patients with APS-1 and organ-specific autoimmune diseases and offers further insight into some of the mechanisms underlying autoimmune disorders and CMC.