Brian Ben F, Sauer Monica L, Greene Joseph T, Senevirathne S Erandika, Lindstedt Anders J, Funk Olivia L, Ruis Brian L, Ramirez Luis A, Auger Jennifer L, Swanson Whitney L, Nunez Myra G, Moriarity Branden S, Lowell Clifford A, Binstadt Bryce A, Freedman Tanya S
Graduate Program in Molecular Pharmacology and Therapeutics, University of Minnesota, Minneapolis, MN 55455, USA.
Graduate Program in Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
Sci Adv. 2022 Apr 22;8(16):eabj5227. doi: 10.1126/sciadv.abj5227.
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 splicing and expression, generating single-isoform LynA knockout (LynA) or LynB mice. Autoimmune disease in total Lyn 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 B cells were dysregulated. These changes were isoform-specific, sexually dimorphic, and distinct from the complete Lyn. Despite the apparent differences in disease etiology and penetrance, loss of either LynA or LynB had the potential to induce severe autoimmune disease with parallels to human systemic lupus erythematosus (SLE).
在此，我们报告Src家族激酶Lyn的LynB剪接变体在体内发挥主要的免疫抑制功能，而LynA亚型是雌性小鼠抑制自身免疫所独特必需的。我们使用CRISPR-Cas9基因编辑来限制剪接和表达，生成单亚型LynA敲除（LynA）或LynB小鼠。完全缺失Lyn的小鼠中的自身免疫性疾病的特征是产生抗核抗体、肾小球肾炎、B细胞发育受损以及活化B细胞和促炎性髓样细胞过多。单独表达LynA或LynB可将发育表型与自身免疫性疾病解偶联：B细胞过渡群体得以恢复，但髓样细胞和分化的B细胞失调。这些变化是亚型特异性的、具有性别二态性，且与完全缺失Lyn不同。尽管在疾病病因和发病率方面存在明显差异，但LynA或LynB的缺失都有可能诱发与人类系统性红斑狼疮（SLE）相似的严重自身免疫性疾病。
