Journal Article

An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus

Gajdos, Philippe, Vandiedonck, Claire, Baralle, Francisco E., Taubert, Richard, Tranchant, Christine, Pagani, Franco, Kyewski, Bruno, Vincent, Angela, Ke, Xiayi, Lévi-Strauss, Matthieu, Willcox, Nick, Beeson, David, Giraud, Matthieu, Garchon, Henri-Jean, Eymard, Bruno

2007

Overview

Trigger for autoimmunity The human thymus is tasked to teach T-cells which antigens are foreign and which are 'self', a process that appears to go wrong in autoimmune disorders. A study of the variation in the promoter of one gene expressed in the thymus shows that a single nucleotide change can disrupt gene regulation, and increase susceptibility to autoimmune disease. The gene, CHRNA1 , encodes a subunit of the muscle acetylcholine receptor, a target for autoantibodies in the neuromuscular disease autoimmune myasthenia gravis. The human thymus is given the difficult task of teaching T-cells which antigens are 'foreign' and which are 'self', a process which seems to go wrong in autoimmune disorders. A study of variation in the promoter of one gene expressed in thymus shows that one nucleotide change can disrupt gene regulation, and might lead to increased risk for autoimmune disease. Promiscuous expression of tissue-restricted auto-antigens in the thymus imposes T-cell tolerance and provides protection from autoimmune diseases 1 , 2 , 3 . Promiscuous expression of a set of self-antigens occurs in medullary thymic epithelial cells 4 , 5 and is partly controlled by the autoimmune regulator (AIRE), a nuclear protein for which loss-of-function mutations cause the type 1 autoimmune polyendocrine syndrome 6 , 7 . However, additional factors must be involved in the regulation of this promiscuous expression. Here we describe a mechanism controlling thymic transcription of a prototypic tissue-restricted human auto-antigen gene, CHRNA1 . This gene encodes the α-subunit of the muscle acetylcholine receptor, which is the main target of pathogenic auto-antibodies in autoimmune myasthenia gravis 8 , 9 . On re-sequencing the CHRNA1 gene, we identified a functional bi-allelic variant in the promoter that is associated with early onset of disease in two independent human populations (France and United Kingdom). We show that this variant prevents binding of interferon regulatory factor 8 (IRF8) and abrogates CHRNA1 promoter activity in thymic epithelial cells in vitro . Notably, both the CHRNA1 promoter variant and AIRE modulate CHRNA1 messenger RNA levels in human medullary thymic epithelial cells ex vivo and also in a transactivation assay. These findings reveal a critical function of AIRE and the interferon signalling pathway in regulating quantitative expression of this auto-antigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Age of Onset / AIRE Protein / Alleles / Autoimmune diseases / Biological and medical sciences / Cell Line / Epithelial Cells - metabolism / France - epidemiology / Fundamental and applied biological sciences. Psychology / Fundamental immunology / Gene expression / Gene Expression Regulation / Genetic markers / Genetics of the immune response / Human populations / Humanities and Social Sciences / Humans / Immunobiology / Immunology / Interferon Regulatory Factors - metabolism / letter / multidisciplinary / Mutation / Myasthenia Gravis - epidemiology / Myasthenia Gravis - genetics / Polymorphism, Single Nucleotide - genetics / Promoter Regions, Genetic - genetics / Protein Binding / Receptors, Nicotinic - genetics / Risk factors / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Thymus Gland - cytology / Thymus Gland - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism / Transcription, Genetic - genetics / United Kingdom - epidemiology