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Although the allele is uniquely enriched in European descent, the mechanism for the widespread selective sweep is not clear. In this study, we find the rs3184504*T allele had a strong association with reduced mortality in a human sepsis cohort. The rs3184504*T allele associates with a loss-of-function amino acid change (p.R262W) in the adaptor protein SH2B3, a likely causal variant. To better understand the role of SH2B3 in sepsis, we used mouse modeling and challenged SH2B3-deficient mice with a polymicrobial cecal-ligation puncture (CLP) procedure. We found SH2B3 deficiency improved survival and morbidity with less organ damage and earlier bacterial clearance compared with control mice. The peritoneal infiltrating cells exhibited augmented phagocytosis in Sh2b3\u2212\/\u2212 mice with enriched recruitment of Ly6Chi inflammatory monocytes despite equivalent or reduced chemokine expression. Rapid cycling of monocytes and progenitors occurred uniquely in the Sh2b3\u2212\/\u2212 mice following CLP, suggesting augmented myelopoiesis. To model the hypomorphic autoimmune risk allele, we created a novel knockin mouse harboring a similar point mutation in the murine pleckstrin homology domain of SH2B3. At baseline, phenotypic changes suggested a hypomorphic allele. In the CLP model, homozygous knockin mice displayed improved mortality and morbidity compared with wild-type or heterozygous mice. Collectively, these data suggest that hypomorphic SH2B3 improves the sepsis response and that balancing selection likely contributed to the relative frequency of the autoimmune risk variant.<\/jats:p>","DOI":"10.4049\/jimmunol.2100454","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T16:55:14Z","timestamp":1636131314000},"page":"2710-2719","source":"Crossref","is-referenced-by-count":15,"title":["The Autoimmune Risk R262W Variant of the Adaptor SH2B3 Improves Survival in Sepsis"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7346-5835","authenticated-orcid":false,"given":"Eric J","family":"Allenspach","sequence":"first","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"},{"name":"Department of Pediatrics, University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J","family":"Shubin","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7403-6239","authenticated-orcid":false,"given":"Karen","family":"Cerosaletti","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute at Virginia Mason , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Mikacenic","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute at Virginia Mason , Seattle, WA"},{"name":"Department of Medicine, Division of Pulmonary and Critical Care, University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquelyn A","family":"Gorman","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A","family":"MacQuivey","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron B I","family":"Rosen","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8808-4012","authenticated-orcid":false,"given":"Andrew E","family":"Timms","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle N","family":"Wray-Dutra","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1989-9100","authenticated-orcid":false,"given":"Kerri","family":"Niino","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4511-1700","authenticated-orcid":false,"given":"Denny","family":"Liggitt","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark M","family":"Wurfel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary and Critical Care, University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9005-1885","authenticated-orcid":false,"given":"Jane H","family":"Buckner","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute at Virginia Mason , Seattle, WA"},{"name":"Department of Immunology, University of Washington , Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian M","family":"Piliponsky","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute , Seattle, WA"},{"name":"Department of Pediatrics, University of Washington School of Medicine , Seattle, WA"},{"name":"Department of Pathology, University of Washington School of Medicine , Seattle, WA"},{"name":"Department of Global Health, University of Washington School of Medicine , Seattle, 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