Models of Aire-Dependent Gene Regulation for Thymic Negative Selection

Stephanie Humblet-Baron,Dina Danso-Abeam,James Dooley,Adrian Liston

doi:10.3389/fimmu.2011.00014

Abstract

Mutations in the autoimmune regulator (AIRE) gene lead to autoimmune polyendocrinopathy syndrome type 1 (APS1), characterized by the development of multi-organ autoimmune damage. The mechanism by which defects in AIRE result in autoimmunity has been the subject of intense scrutiny. At the cellular level, the working model explains most of the clinical and immunological characteristics of APS1, with AIRE driving the expression of tissue-restricted antigens (TRAs) in the epithelial cells of the thymic medulla. This TRA expression results in effective negative selection of TRA-reactive thymocytes, preventing autoimmune disease. At the molecular level, the mechanism by which AIRE initiates TRA expression in the thymic medulla remains unclear. Multiple different models for the molecular mechanism have been proposed, ranging from classical transcriptional activity, to random induction of gene expression, to epigenetic tag recognition effect, to altered cell biology. In this review, we evaluate each of these models and discuss their relative strengths and weaknesses.

Highlights

The autoimmune regulator, AIRE (OMIM #607358), has been the focus of intense research since mutations in the gene were identified in 1997 as the cause of autoimmune polyendocrinopathy syndrome type 1 (APS1, OMIM #2400300, known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome; Finnish-German APECED Consortium, 1997; Nagamine et al, 1997)
The working model explains most of the clinical and immunological characteristics of APS1, with AIRE driving the expression of tissue-restricted antigens (TRAs) in the epithelial cells of the thymic medulla
The cell biology models provide an alternative approach to the mechanism of Aire target gene regulation and encompass two contrasting models – “developmental retardation” and “dysregulated death” models – in which both propose Aire to influence the differentiation of medullary thymic epithelial cells to enhance TRA expression

Summary

Introduction

The autoimmune regulator, AIRE (OMIM #607358), has been the focus of intense research since mutations in the gene were identified in 1997 as the cause of autoimmune polyendocrinopathy syndrome type 1 (APS1, OMIM #2400300, known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome; Finnish-German APECED Consortium, 1997; Nagamine et al, 1997). The working model explains most of the clinical and immunological characteristics of APS1, with AIRE driving the expression of tissue-restricted antigens (TRAs) in the epithelial cells of the thymic medulla.

Results

Conclusion