APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors

Raffaella Di Mase,Federica D’Elia,Donatella Capalbo,Claudio Pignata,Mariacarolina Salerno,Roberta D’Assante,Nicola Improda,Ida D’Acunzo,Lucia De Martino

doi:10.3389/fimmu.2013.00331

Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named Autoimmune regulator gene (AIRE) which results in a failure of T-cell tolerance. Central tolerance takes place within the thymus and represents the mechanism by which potentially auto-reactive T-cells are eliminated through the negative selection process. The expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs) in the thymus is a key process in the central tolerance and is driven by the protein encoded by AIRE gene, the transcription factor autoimmune regulator (AIRE). A failure in this process caused by AIRE mutations is thought to be responsible of the systemic autoimmune reactions of APECED. APECED is characterized by several autoimmune endocrine and non-endocrine manifestations and the phenotype is often complex. Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression even between siblings with the same genotype, thus implying that additional mechanisms, other than the failure of Aire function, are involved in the pathogenesis of the disease. Unraveling open issues of the molecular basis of APECED, will help improve diagnosis, management, and therapeutical strategies of this complex disease.

Highlights

Autoimmune Polyglandular Syndrome Type 1 (APS-1), called Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autosomal recessive disease caused by mutations of the autoimmune regulator gene (AIRE)
We will focus on the complex pathogenesis of APECED and on the potential interfering factors involved in the clinical expression of the disease
T-cell tolerance is crucial for the creation of a proper T-cell repertoire, able to respond to a huge number of foreign antigens, but preventing autoimmune reactions

Summary

INTRODUCTION

Autoimmune Polyglandular Syndrome Type 1 (APS-1), called Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autosomal recessive disease caused by mutations of the autoimmune regulator gene (AIRE). We will focus on the complex pathogenesis of APECED and on the potential interfering factors involved in the clinical expression of the disease. THE BASIS OF THE IMMUNOLOGICAL TOLERANCE Tolerance represents a state of immunologic non-responsiveness in the presence of a particular antigen In this context, T-cell tolerance is crucial for the creation of a proper T-cell repertoire, able to respond to a huge number of foreign antigens, but preventing autoimmune reactions. T-cell central tolerance, established within the thymus, mostly relies on two main mechanisms: negative selection, referred to as clonal deletion of maturing thymocytes and positive selection of maturing T-cells able to bind to a surface major histocompatibility complex (MHC) molecule with mild threshold of reactivity (Figure 1). DP thymocytes expressing TCRs that do not bind selfpeptide-MHC complexes are programed to undergo “death by www.frontiersin.org

Factors involved in the pathogenesis of APECED

Findings

Abs against parietal cells and IF