PMID- 35332318 OWN - NLM STAT- MEDLINE DCOM- 20220414 LR - 20221113 IS - 1546-1718 (Electronic) IS - 1061-4036 (Print) IS - 1061-4036 (Linking) VI - 54 IP - 4 DP - 2022 Apr TI - HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors. PG - 393-402 LID - 10.1038/s41588-022-01032-z [doi] AB - Polymorphisms in the human leukocyte antigen (HLA) genes strongly influence autoimmune disease risk. HLA risk alleles may influence thymic selection to increase the frequency of T cell receptors (TCRs) reactive to autoantigens (central hypothesis). However, research in human autoimmunity has provided little evidence supporting the central hypothesis. Here we investigated the influence of HLA alleles on TCR composition at the highly diverse complementarity determining region 3 (CDR3), which confers antigen recognition. We observed unexpectedly strong HLA-CDR3 associations. The strongest association was found at HLA-DRB1 amino acid position 13, the position that mediates genetic risk for multiple autoimmune diseases. We identified multiple CDR3 amino acid features enriched by HLA risk alleles. Moreover, the CDR3 features promoted by the HLA risk alleles are more enriched in candidate pathogenic TCRs than control TCRs (for example, citrullinated epitope-specific TCRs in patients with rheumatoid arthritis). Together, these results provide genetic evidence supporting the central hypothesis. CI - (c) 2022. The Author(s), under exclusive licence to Springer Nature America, Inc. FAU - Ishigaki, Kazuyoshi AU - Ishigaki K AUID- ORCID: 0000-0003-2881-0657 AD - Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. AD - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. FAU - Lagattuta, Kaitlyn A AU - Lagattuta KA AD - Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. AD - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. AD - Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, USA. FAU - Luo, Yang AU - Luo Y AUID- ORCID: 0000-0001-7385-6166 AD - Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. AD - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - James, Eddie A AU - James EA AUID- ORCID: 0000-0002-7217-5729 AD - Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA. FAU - Buckner, Jane H AU - Buckner JH AD - Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA. FAU - Raychaudhuri, Soumya AU - Raychaudhuri S AUID- ORCID: 0000-0002-1901-8265 AD - Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org. AD - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org. AD - Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. soumya@broadinstitute.org. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org. AD - Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. soumya@broadinstitute.org. LA - eng GR - U01 HG012009/HG/NHGRI NIH HHS/United States GR - T32 GM007753/GM/NIGMS NIH HHS/United States GR - R01 HG006399/HG/NHGRI NIH HHS/United States GR - U19 AI111224/AI/NIAID NIH HHS/United States GR - R01 AR063759/AR/NIAMS NIH HHS/United States GR - U01 HG009379/HG/NHGRI NIH HHS/United States GR - UH2 AR067677/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220324 PL - United States TA - Nat Genet JT - Nature genetics JID - 9216904 RN - 0 (Amino Acids) RN - 0 (Complementarity Determining Regions) RN - 0 (HLA-DRB1 Chains) RN - 0 (Receptors, Antigen, T-Cell) SB - IM CIN - Nat Rev Rheumatol. 2022 Jun;18(6):305. PMID: 35440763 MH - Alleles MH - Amino Acids/genetics MH - *Autoimmune Diseases/genetics MH - Complementarity Determining Regions/genetics MH - HLA-DRB1 Chains/genetics/metabolism MH - Humans MH - *Receptors, Antigen, T-Cell/genetics/metabolism PMC - PMC9010379 MID - NIHMS1777915 COIS- COMPETING INTERESTS The authors declare no competing interests. EDAT- 2022/03/26 06:00 MHDA- 2022/04/15 06:00 PMCR- 2022/09/24 CRDT- 2022/03/25 05:37 PHST- 2021/08/03 00:00 [received] PHST- 2022/02/04 00:00 [accepted] PHST- 2022/03/26 06:00 [pubmed] PHST- 2022/04/15 06:00 [medline] PHST- 2022/03/25 05:37 [entrez] PHST- 2022/09/24 00:00 [pmc-release] AID - 10.1038/s41588-022-01032-z [pii] AID - 10.1038/s41588-022-01032-z [doi] PST - ppublish SO - Nat Genet. 2022 Apr;54(4):393-402. doi: 10.1038/s41588-022-01032-z. Epub 2022 Mar 24.