biostudies-literatureBrian BFNCI NIH HHSNIAMS NIH HHSeabj5227https://www.ebi.ac.uk/biostudies/studies/S-EPMC9032976biostudies-literatureUnknown8(16)Here, we report that the LynB splice variant of the Src-family kinase Lyn exerts a dominant immunosuppressive function in vivo, whereas the LynA isoform is uniquely required to restrain autoimmunity in female mice. We used CRISPR-Cas9 gene editing to constrain <i>lyn</i> splicing and expression, generating single-isoform LynA knockout (LynA^KO) or LynB^KO mice. Autoimmune disease in total Lyn^KO mice is characterized by production of antinuclear antibodies, glomerulonephritis, impaired B cell development, and overabundance of activated B cells and proinflammatory myeloid cells. Expression of LynA or LynB alone uncoupled the developmental phenotype from the autoimmune disease: B cell transitional populations were restored, but myeloid cells and differentiated BScience advancesA dominant function of LynB kinase in preventing autoimmunity.PMC9032976R01 AR073966T32 CA009138P30 CA077598Sauer MLGreene JTBinstadt BAFunk OLRamirez LAAuger JLNunez MGMoriarity BSFreedman TSBrian BFLindstedt AJLowell CASwanson WLSenevirathne SERuis BLfalseA dominant function of LynB kinase in preventing autoimmunity.Here, we report that the LynB splice variant of the Src-family kinase Lyn exerts a dominant immunosuppressive function in vivo, whereas the LynA isoform is uniquely required to restrain autoimmunity in female mice. We used CRISPR-Cas9 gene editing to constrain <i>lyn</i> splicing and expression, generating single-isoform LynA knockout (LynA^KO) or LynB^KO mice. Autoimmune disease in total Lyn^KO mice is characterized by production of antinuclear antibodies, glomerulonephritis, impaired B cell development, and overabundance of activated B cells and proinflammatory myeloid cells. Expression of LynA or LynB alone uncoupled the developmental phenotype from the autoimmune disease: B cell transitional populations were restored, but myeloid cells and differentiated B2022-01-01T00:00:00Z2022 Apr2025-04-19T08:21:17.789Z2024-11-21T06:15:47.479ZS-EPMC90329763545229110.1126/sciadv.abj5227