The Autoimmune Risk R262W Variant of the Adaptor SH2B3 Improves Survival in Sepsis.
The Autoimmune Risk R262W Variant of the Adaptor SH2B3 Improves Survival in Sepsis.
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DOI：
10.4049/jimmunol.2100454
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发表时间：
2021-12-01
期刊：
影响因子：
--
通讯作者：
Rawlings DJ
中科院分区：
文献类型：
--
作者：
Allenspach EJ;Shubin NJ;Cerosaletti K;Mikacenic C;Gorman JA;MacQuivey MA;Rosen ABI;Timms AE;Wray-Dutra MN;Niino K;Liggitt D;Wurfel MM;Buckner JH;Piliponsky AM;Rawlings DJ
The single-nucleotide polymorphism (SNP), rs3184504, is broadly associated with increased risk for multiple autoimmune and cardiovascular diseases. Although the allele is uniquely enriched in European descent, the mechanism for the widespread selective sweep is not clear. Here, 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 utilized 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 to control mice. The peritoneal infiltrating cells exhibited augmented phagocytosis in SH2B3KO mice with enriched recruitment of Ly6Chi inflammatory monocytes despite equivalent or reduced chemokine expression. Rapid cycling of monocytes and progenitors occurred uniquely in the Sh2b3KO 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 PH domain of SH2B3. At baseline, phenotypic changes suggested a hypomorphic allele. In the CLP model, homozygous knockin mice displayed improved mortality and morbidity compared to wildtype 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.
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影响因子：
17.1
作者：
Housley WJ;Fernandez SD;Vera K;Murikinati SR;Grutzendler J;Cuerdon N;Glick L;De Jager PL;Mitrovic M;Cotsapas C;Hafler DA
通讯作者：
Hafler DA
影响因子：
3.5
作者：
Mai SHC;Sharma N;Kwong AC;Dwivedi DJ;Khan M;Grin PM;Fox-Robichaud AE;Liaw PC
通讯作者：
Liaw PC
影响因子：
8.8
作者：
Levy, MM;Fink, MP;Ramsay, G
通讯作者：
Ramsay, G
影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole
影响因子：
2.6
作者：
Hay SB;Ferchen K;Chetal K;Grimes HL;Salomonis N
通讯作者：
Salomonis N