Where AIRE we now? Where AIRE we going?

Abstract

Purpose of review: The purpose of the review is to describe the most recent advancement in understanding of the pivotal role of autoimmune regulator ( AIRE ) gene expression in central and peripheral tolerance, and the implications of its impairment in the genetic and pathogenesis of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) manifestations with insight into possible treatment options.

Recent findings: AIRE gene expression has an important role of central and peripheral tolerance. Different AIRE gene mutations cause APECED, whereas polymorphisms and some variants may be implicated in development of other more frequently autoimmune diseases. Impaired negative T cell selection, reduction of T regulatory function, altered germinal center response, activated B cells and production of autoantibodies explain the development of autoimmunity in APECED. Recent data suggest that an excessive interferon-γ response may be the primer driver of the associated organ damage. Therefore, Janus kinase (JAK)-inhibitors may be promising therapies for treatment of broad spectrum of manifestations.

Summary: AIRE has a pivotal role in immune tolerance. Disruption of this delicate equilibrium results in complex immune perturbation, ranging from severe autoimmunity, like APECED, to more common organ-specific disorders. Therefore, a deeper understanding of the correlation between AIRE function and clinical phenotype is warranted given the potential translational implication in clinical practice.

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FIGURE 1

Human AIRE gene structure, regulation and mutations. (a) The structure and principal functions of protein domains of AIRE are depicted. (b) Aire functions depend on the tight regulation of CARD-dependent polymerization. In particular, CTT binds to CBP/p300 rich-loci and favours CARD-dependent polymerization of Aire, inducing transcription of tissue specific genes (TSA). On the other hand, PHD1 unspecific binding to chromatin (through H3K4me0) prevents Aire homopolymerization [^▪▪]. (c) Implications of different type of mutations on expression and function of the protein AIRE with consequent clinical implications. In absence of mutations, the immunological tolerance prevents autoimmunity. SNPs reduce function of AIRE which predispose to development of organ specific autoimmunity. In case of dominant negative mutations, augmented expression but reduced functionality is expected with development of a mild phenotype. In the case of exon 7 splice mutations, regular and truncated protein coexist with reduced function with a mild and late-onset phenotype. In case of autosomal recessive defects, the protein is frequently absent (or the function severely impaired) and patients develop a multiple organ autoimmunity. Abbreviations: CARD, caspase activation recruitment domain; SAND, named after Sp100, AIRE-1, NucP41/75, DEAF-1; PHD1, plant homeodomains 1; PHD2, plant homeodomains 2; CTT, C-terminal tail; CBP/p300, CREB-binding protein.