Novel Findings into AIRE Genetics and Functioning: Clinical Implications

Abstract

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), formerly known as autoimmune polyendocrine syndrome type 1, is a paradigm of a monogenic autoimmune disease caused by mutations of a gene, named autoimmune regulator (AIRE). AIRE acts as a transcription regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens. Although the syndrome is a monogenic disease, it is characterized by a wide variability of the clinical expression with no significant correlation between genotype and phenotype. Indeed, many aspects regarding the exact role of AIRE and APECED pathogenesis still remain unraveled. In the last decades, several studies in APECED and in its mouse experimental counterpart have revealed new insights on how immune system learns self-tolerance. Moreover, novel interesting findings have extended our understanding of AIRE's function and regulation thus improving our knowledge on the pathogenesis of APECED. In this review, we will summarize recent novelties on molecular mechanisms underlying the development of APECED and their clinical implications.

Keywords: AIRE; APECED; autoimmune disease; diagnosis; mutations.

Figure 1

AIRE controls gene expression with ordered stochasticity. AIRE seems to regulate pGE in mTECs in an apparently stochastic manner. Thus, single mTECs would express TRAs of mixed tissue origin rather than emulating cell line age-affiliated patterns displaying the highest degree and diversity of pGE. Indeed, different sets of TSAs are expressed in mTECs but whether a particular AIRE-regulated TSA is expressed in a given mTEC seems to be highly probabilistic. The “ordered” TSA expression refers to the increased likelihood that a particular set of TSA genes will be coexpressed in an individual mTEC. Coexpressed gene loci tend to colocalize to the same nuclear subdomain and TSA subsets align along progressive differentiation stages within the mature mTEC subset.