Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6119146 | Journal of Autoimmunity | 2015 | 8 Pages |
Abstract
Promiscuous gene expression (pGE) of tissue-restricted self-antigens (TRA) in medullary thymic epithelial cells (mTECs) is in part driven by the Autoimmune Regulator gene (AIRE) and essential for self-tolerance. The link between AIRE functional mutations and multi-organ autoimmunity in human and mouse supports the role of pGE. Deep sequencing of the transcriptome revealed that mouse mTECs potentially transcribe an unprecedented range of >90% of all genes. Yet, it remains unclear to which extent these low-level transcripts are actually translated into proteins, processed and presented by thymic APCs to induce tolerance. To address this, we analyzed the HLA-DR-associated thymus peptidome. Within a large panel of peptides from abundant proteins, two TRA peptides were identified: prostate-specific semenogelin-1 (an autoantigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome) and central nervous system-specific contactin-2 (an autoantigen in multiple sclerosis). Thymus expression of both genes was restricted to mTECs. SEMG1 expression was confined to mature HLA-DRhi mTECs of male and female donors and was AIRE-dependent, whereas CNTN2 was apparently AIRE-independent and was expressed by both populations of mTECs. Our findings establish a link between pGE, MHC-II peptide presentation and autoimmunity for bona fide human TRAs.
Keywords
mTECAPS-1APCTFAPGEautoantigensTCrAPECEDAutoimmune polyendocrine syndrome type 1FDRPSAPromiscuous gene expressiongDNAM-MLV RTgenomic DNALC/MScycle thresholdTrifluoroacetic acidHumanToleranceautoimmune regulatorThymusDendritic cellmedullary thymic epithelial cellantigen presenting cellautoimmune polyendocrinopathy candidiasis ectodermal dystrophymajor histocompatibility complexMHCtrafalse discovery rateAIREmoloney murine leukemia virus reverse transcriptaseprostate-specific antigenPeptidesLiquid chromatography/mass spectrometryT cell receptor
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Authors
Iñaki Alvarez, Javier A. Collado, Roger Colobran, Montserrat Carrascal, M. Teresa Ciudad, Françesc Canals, Eddie A. James, William W. Kwok, Martina Gärtner, Bruno Kyewski, Ricardo Pujol-Borrell, Dolores Jaraquemada,