Autoimmune polyendocrine syndrome type I. Novel diagnostic assays and immune regulation

Abstract

Autoimmune polyendocrine syndrome type I (APS-I) is a rare, monogenetic recessively inherited disease caused by mutations in the autoimmune regulator (AIRE) gene. The patients display different endocrine and ectodermal manifestations, where the majority develop at least two of the three main components of autoimmune adrenocortical failure (Addison’s disease), hypoparathyroidism and chronic mucocutaneous candidiasis (CMC). In addition, patients frequently develop autoantibodies against molecular targets in their affected organs and against cytokines of the immune system. In two studies, robust immunoassays detecting APS-I patients with high sensitivity and specificity were developed. Autoantibodies against in vitro transcribed and translated interferon omega (IFN- ) and interleukin (IL) 17F and IL-22 were measured, the latter shown to correlate to CMC. Antibodies against IFN- were confirmed as a universal marker for APS-I, suggesting this assay as an ideal screening tool preceding mutational analyses in suspected APS-I cases. We have shown that single nucleotide polymorphisms and variation in copy number of AIRE have no association with Addison’s disease. However, large deletions in one allele of AIRE together with a concomitant disease-causing mutation were discovered in two APS-I patients, underpinning the importance of copy number analysis. A wide range of immune cell subsets were studied, identifying disturbances in the regulatory T cell compartment together with less CCR6+CXCR3+ T cells and a reduction in CD16+ monocytes in patients with APS-I, possibly resulting in susceptibility for developing autoimmune manifestations. The characterisation of genetic variations in AIRE and of abnormalities in the immune cell subsets contribute to our understanding of the function of AIRE, while establishing immunoassays ease the identification of APS-I patients.