{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:06:31Z","timestamp":1789578391867,"version":"build-2803163510"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:00:00Z","timestamp":1711065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Government | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["174901"],"award-info":[{"award-number":["174901"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Severe SARS-CoV-2 infection is associated with significant immune dysregulation involving different immune cell subsets. In this study, when analyzing critically ill COVID-19 patients versus those with mild disease, we observed a significant reduction in total and memory B cell subsets but an increase in naive B cells. Moreover, B cells from COVID-19 patients displayed impaired effector functions, evidenced by diminished proliferative capacity, reduced cytokine, and Ab production. This functional impairment was accompanied by an increased apoptotic potential upon stimulation in B cells from severely ill COVID-19 patients. Our further studies revealed the expansion of B cells expressing coinhibitory molecules (PD-1, PD-L1, TIM-1, VISTA, CTLA-4, and Gal-9) in intensive care unit (ICU)\u2013admitted patients but not in those with mild disease. The coinhibitory receptor expression was linked to altered IgA and IgG expression and increased the apoptotic capacity of B cells. Also, we found a reduced frequency of CD24hiCD38hi regulatory B cells with impaired IL-10 production. Our mechanistic studies revealed that the upregulation of PD-L1 was linked to elevated plasma IL-6 levels in COVID-19 patients. This implies a connection between the cytokine storm and altered B cell phenotype and function. Finally, our metabolomic analysis showed a significant reduction in tryptophan but elevation of kynurenine in ICU-admitted COVID-19 patients. We found that kynurenine promotes PD-L1 expression in B cells, correlating with increased IL-6R expression and STAT1\/STAT3 activation. Our observations provide novel insights into the complex interplay of B cell dysregulation, implicating coinhibitory receptors, IL-6, and kynurenine in impaired B cell effector functions, potentially contributing to the pathogenesis of COVID-19.<\/jats:p>","DOI":"10.4049\/jimmunol.2300783","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T13:57:37Z","timestamp":1711115857000},"page":"1540-1552","source":"Crossref","is-referenced-by-count":16,"title":["The Role of Coinhibitory Receptors in B Cell Dysregulation in SARS-CoV-2\u2013Infected Individuals with Severe Disease"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2235-8866","authenticated-orcid":false,"given":"Suguru","family":"Saito","sequence":"first","affiliation":[{"name":"School of Dentistry, Division of Foundational Sciences, University of Alberta , Edmonton, AB ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najmeh","family":"Bozorgmehr","sequence":"additional","affiliation":[{"name":"School of Dentistry, Division of Foundational Sciences, University of Alberta , Edmonton, AB ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Sligl","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, University of Alberta , Edmonton, AB ,","place":["Canada"]},{"name":"Department of Medicine, Division of Infectious Diseases, University of Alberta , Edmonton, AB ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Osman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, University of Alberta , Edmonton, AB ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-2009","authenticated-orcid":false,"given":"Shokrollah","family":"Elahi","sequence":"additional","affiliation":[{"name":"School of Dentistry, Division of Foundational Sciences, University of Alberta , Edmonton, AB ,","place":["Canada"]},{"name":"Department of Oncology, University of Alberta , Edmonton, AB ,","place":["Canada"]},{"name":"Li Ka Shing Institute of Virology, University of Alberta , Edmonton, AB ,","place":["Canada"]},{"name":"Women and Children Health Research Institute, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, AB ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,22]]},"reference":[{"key":"2025020405494092300_r1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41579-020-00459-7","article-title":"Characteristics of SARS-CoV-2 and COVID-19","volume":"19","author":"Hu","year":"2021","journal-title":"Nat. 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