{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:53:25Z","timestamp":1792612405062,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,2,6]],"date-time":"2018-02-06T00:00:00Z","timestamp":1517875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000411","name":"Raynaud's and Scleroderma Association","doi-asserted-by":"publisher","award":["UC5"],"award-info":[{"award-number":["UC5"]}],"id":[{"id":"10.13039\/501100000411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000341","name":"Arthritis Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic sclerosis (<jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c) has the highest case\u2010specific mortality of any rheumatic disease, and no\u00a0effective therapy is available. A clear manifestation of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c is the presence of autoantibodies. However, the origin of autoantibody\u2010producing B lymphocytes, their mechanisms of activation and autoantibody production, and their role remain unclear. This study was undertaken to identify mechanisms that contribute to pathogenic B cell generation and involvement in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and to assess the altered distribution and function of B cells in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Multicolor flow cytometry was performed to determine B cell subset distribution, cytokine production, and tolerance induction in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients and healthy controls. Cytokine production following stimulation of the cells ex\u00a0vivo was determined by multiplex assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A range of defects in B lymphocyte tolerance and cytokine production in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c were noted. There was evidence of altered distribution of transitional B cell subsets, increased production of interleukin\u20106 (<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20106) and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20108, and defective tolerance induction in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c B cells. In addition, B cells from <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients had a reduced ability to produce <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u201010 when stimulated through innate immune pathways. In contrast to healthy individuals, tolerance checkpoints in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients failed to suppress the emergence of B cells that produce autoantibodies with specificity to the Scl\u201070 antigen, which is strongly associated with <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c. These defects were paralleled by altered intracellular signaling and apoptosis following B cell receptor engagement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings provide new insights into mechanisms underlying defective B lymphocyte responses in patients with <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and their contribution to disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40390","type":"journal-article","created":{"date-parts":[[2017,11,29]],"date-time":"2017-11-29T12:14:35Z","timestamp":1511957675000},"page":"450-461","source":"Crossref","is-referenced-by-count":60,"title":["Association of Defective Regulation of Autoreactive Interleukin\u20106\u2013Producing Transitional B Lymphocytes With\u00a0Disease in Patients With Systemic Sclerosis"],"prefix":"10.1002","volume":"70","author":[{"given":"Taher E.","family":"Taher","sequence":"first","affiliation":[{"name":"Queen Mary University of London London UK"},{"name":"University of Birmingham Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Voon H.","family":"Ong","sequence":"additional","affiliation":[{"name":"University College London Royal Free Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Bystrom","sequence":"additional","affiliation":[{"name":"Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Hillion","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Brest INSERM Labex IGO Centre Hospitalier Universitaire de Brest Brest France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Simon","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Brest INSERM Labex IGO Centre Hospitalier Universitaire de Brest Brest France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Denton","sequence":"additional","affiliation":[{"name":"University College London Royal Free Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques\u2010Olivier","family":"Pers","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Brest INSERM Labex IGO Centre Hospitalier Universitaire de Brest Brest France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Abraham","sequence":"additional","affiliation":[{"name":"University College London Royal Free Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizgar A.","family":"Mageed","sequence":"additional","affiliation":[{"name":"Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,2,6]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"202","article-title":"Scleroderma (systemic sclerosis): classification, subsets and pathogenesis","volume":"15","author":"LeRoy EC","year":"1988","journal-title":"J Rheumatol"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2005.09.004"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.11173"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1635114100"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22847"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.bor.0000179945.73518.28"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215078"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.060205"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.071049"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24249"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.095463"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63328-7"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep093"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-010-1485-3"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204522"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.181.6.2129"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.190.1.75"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.09.014"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111675"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636483"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38098"},{"issue":"100","key":"e_1_2_6_23_1","first-page":"106","article-title":"UK Scleroderma Study Group (UKSSG) guidelines on the diagnosis and management of scleroderma renal crisis","volume":"34","author":"Lynch BM","year":"2016","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-201024"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew224"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.11.009"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni833"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151182"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.3.1506"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-07-234799"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.6.3593"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0090-1229(90)90114-6"},{"key":"e_1_2_6_33_1","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/978-1-4939-2694-7_42","article-title":"B\u2010cell ELISPOT: for the identification of antigen\u2010specific antibody\u2010secreting cells","volume":"1312","author":"Shah HB","year":"2015","journal-title":"Methods Mol Biol"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(02)00406-5"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.5.2101"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.12.6834"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.10.017"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2011.02.003"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1078231"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04753"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802218105"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-009-0014-x"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900270"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1086907"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042321"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042251"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03724"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.12.004"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.40390","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.40390","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T17:46:26Z","timestamp":1759945586000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.40390"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,6]]},"references-count":47,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,3]]}},"alternative-id":["10.1002\/art.40390"],"URL":"https:\/\/doi.org\/10.1002\/art.40390","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,6]]}}}