Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue

Abstract

Educational immune tolerance to self-antigens is induced primarily in the thymus where tissue-restricted antigens (TRAs) are presented to T lymphocytes by cells of the thymic stroma - a process known as central tolerance. The expression of these TRAs is controlled in part by a transcription factor encoded by the autoimmune regulatory (Aire) gene. Patients with a mutation of this gene develop a condition known as autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED), characterized by autoimmune destruction of endocrine organs, fungal infection and dental abnormalities. There is now evidence for TRA expression and for mechanisms of functional tolerance outside the thymus. This has led to a number of studies examining Aire expression and function at these extra-thymic sites. These investigations have been conducted across different animal models using different techniques and have often shown discrepant results. Here we review the studies of extra thymic Aire and discuss the evidence for its expression and function in both human and murine systems.

Fig. 1

The autoimmune regulatory (Aire) protein. (a) Schematic representation of the human AIRE protein indicating the functional protein domains (adapted from [28,36]). (b) Ribbon representation of the PHD1 domain of AIRE 1 (taken from [35]). (c) AIRE staining (green) [using Santa Cruz, AIRE (D17)] in the thymus has a characteristic punctate nuclear appearance; here, Ulex europaeus agglutinin (UEA) staining (blue) identifies the medulla and 4′-6-diamidino-2-phenylindole (DAPI) staining (white) the nucleus (Eldershaw et al., unpublished data). L: LXXLL nuclear receptor interaction motif; HSR: homogeneously staining region; SAND: Sp100, AIRE, NucP41/75 and DEAF-1; PHD: plant homeodomain zinc finger; PRR: proline-rich region; N: N-terminus; C: C-terminus. Fig.1(b) reproduced by kind permission of Journal of Biological Chemistry. © 2005 The American Society for Biochemistry and Molecular Biology. Bottomley MJ, Stier G, Pennacchini D et al. NMR Structure of the First PHD Finger of Autoimmune Regulator Protein (AIRE1). Insights into autoimmune polyendocrinopathy-candiasis-ectodermal dystrophy (APECED) disease. J Biol Chem 2005; 280:11505–11512.

Fig. 2

Autoimmune regulatory (Aire) protein and TRAs in the thymus and periphery. (a) Cartoon of Aire expression and function in the thymus and peripheral lymphoid tissue. TRAs are expressed by medullary thymic epithelial cells (mTECs) and myeloid cells. T cells which recognize these TRAs with too high affinity/avidity die by apoptosis. Self-reactive T cells which do not interact with their cognate antigen escape to the periphery and are eliminated following exposure to TRAs displayed in the periphery. Aire expressed in the periphery may control the expression of different TRAs to those under Aire control in the thymus. TRAs: tissue restricted antigens; DCs: dendritic cells; ✓: expressed; ✗: not expressed; : not done. (b) Comparison of thymic and peripheral Aire-restricted TRAs. *Human homologues of these mouse proteins have been described as autoantigens in human autoimmune diseases.