title: Association of an SNP with intrathymic transcription of TSHR and Graves' disease: a role for defective thymic tolerance.
abstract: Graves' disease (GD) is the paradigm of an anti-receptor autoimmune disease, with agonistic auto-antibodies against the thyrotropin receptor (TSHR-thyroid-stimulating hormone receptor) being the underlying pathogenic effector mechanism. The TSHR belongs to the category of tissue-restricted antigens, which are promiscuously expressed in the thymus and thereby induce central T cell tolerance. In order to understand the association between TSHR gene polymorphisms and GD, we tested the hypothesis that TSHR gene variants affect susceptibility to GD by influencing levels of TSHR transcription in the thymus. We show that thymic glands from non-autoimmune donors homozygous for the rs179247 SNP predisposing allele of TSHR had significantly fewer TSHR mRNA transcripts than carriers of the protective allele. In addition, in heterozygous individuals, the TSHR predisposing allele was expressed at a lower level than the protective one as demonstrated by allele-specific transcript quantification. This unbalanced allelic expression was detectable in both thymic epithelial cells and thymocytes. Since the level of self-antigen expression is known to influence the threshold of central tolerance, these results are compatible with the notion that defective central tolerance contributes to the pathogenesis of GD, a scenario already implicated in type 1 diabetes mellitus, myasthenia gravis and autoimmune myocarditis.
authors.affiliation: Laboratory of Immunobiology for Research and Applications to Diagnostic, Banc de Sang i Teixits, Institut d'Investigacióen Ciències de Salut Germans Trias i Pujol, Badalona 08916, Catalonia, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Colobran
authors.forename: Maria Del Pilar
authors.initials: Mdel P
authors.lastname: Armengol
authors.forename: Rosa
authors.initials: R
authors.lastname: Faner
authors.forename: Martina
authors.initials: M
authors.lastname: Gärtner
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Tykocinski
authors.forename: Anna
authors.initials: A
authors.lastname: Lucas
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz
authors.forename: Manel
authors.initials: M
authors.lastname: Juan
authors.forename: Bruno
authors.initials: B
authors.lastname: Kyewski
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pujol-Borrell
mesh_terms: D000369:Aged, 80 and over; D000483:Alleles; D005260:Female; D005434:Flow Cytometry; D006111:Graves Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013950:Thymus Gland / Q000378:metabolism*
chemical_list: D011989:Receptors, Thyrotropin