1. Inserm, U580, 75015 Paris, France; Université Paris-Descartes, 75015 Paris, France
2. Neuroscience Group, Weatherhall Institute of Molecular Medicine, Oxford University, Headington, Oxford OX3 9DS, UK
3. Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Centre, INF 280, D-69120 Heidelberg, Germany
4. Centre for Integrated Genomic Medical Research (CIGMR) and Arthritis Research Campaign (ARC) Epidemiology Unit, University of Manchester, Manchester M13 9PT, UK
5. International Centre for Genetic Engineering and Biotechnology Padriciano 99, 34012 Trieste, Italy
6. Institut de Myologie, Hôpital de la Salpêtrière, 75013 Paris, France
7. Service de Neurologie, Hôpital Civil, CHRU, 67091 Strasbourg, France
8. Service de Réanimation, Hôpital Raymond Poincaré, 92380 Garches, France

Correspondence to: Henri-Jean Garchon1 Correspondence and requests for materials should be addressed to H.-J.G. (Email: garchon@necker.fr).

Promiscuous expression of tissue-restricted auto-antigens in the thymus imposes T-cell tolerance and provides protection from autoimmune diseases1, 2, 3. Promiscuous expression of a set of self-antigens occurs in medullary thymic epithelial cells4, 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 syndrome6, 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 -subunit of the muscle acetylcholine receptor, which is the main target of pathogenic auto-antibodies in autoimmune myasthenia gravis8, 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.

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