{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T14:42:24Z","timestamp":1788532944635,"version":"build-2803163510"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"University of California, San Francisco, Program for Breakthrough Biomedical Research"},{"DOI":"10.13039\/100007100","name":"Sandler Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007100","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U. S. 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Department of Human and Health Services\/National Institutes of Health\/National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL122533"],"award-info":[{"award-number":["R01HL122533"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the coatomer protein complex subunit \u03b1 (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis, which requires life-saving measures, such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a CopaE241K\/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells. In this study, we show that mutant Copa in epithelial cells of the thymus impairs the thymic selection of T cells and results in both an increase in autoreactive T cells and decrease in regulatory T cells in peripheral tissues. We demonstrate that T cells from CopaE241K\/+ mice are pathogenic and cause ILD through adoptive transfer experiments. In conclusion, to our knowledge, we establish a new mouse model of COPA syndrome to identify a previously unknown function for Copa in thymocyte selection and demonstrate that a defect in central tolerance is a putative mechanism by which COPA mutations lead to autoimmunity in patients.<\/jats:p>","DOI":"10.4049\/jimmunol.2000028","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T14:45:10Z","timestamp":1584715510000},"page":"2360-2373","source":"Crossref","is-referenced-by-count":44,"title":["A Defect in Thymic Tolerance Causes T Cell\u2013Mediated Autoimmunity in a Murine Model of COPA Syndrome"],"prefix":"10.1093","volume":"204","author":[{"given":"Zimu","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California , San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S","family":"Law","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California , San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances O","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California , San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2108-9900","authenticated-orcid":false,"given":"Kristin M","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California , San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0275-3503","authenticated-orcid":false,"given":"Kirk D","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California , San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0711-8234","authenticated-orcid":false,"given":"Jeoung-Sook","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of California , San Francisco, San Francisco, CA 94143"},{"name":"Sandler Asthma Basic Research Center, University of California , San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony K","family":"Shum","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California , San Francisco, San Francisco, CA 94143"},{"name":"Cardiovascular Research Institute, University of California , San Francisco, San Francisco, CA 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,1]]},"reference":[{"key":"2025030417511614800_r1","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/ng.3279","article-title":"COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis","volume":"47","author":"Watkin","year":"2015","journal-title":"Nat. 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