A dominant function of LynB kinase in preventing autoimmunity

Ben F Brian 4th; Monica L Sauer; Joseph T Greene; S Erandika Senevirathne; Anders J Lindstedt; Olivia L Funk; Brian L Ruis; Luis A Ramirez; Jennifer L Auger; Whitney L Swanson; Myra G Nunez; Branden S Moriarity; Clifford A Lowell; Bryce A Binstadt; Tanya S Freedman

doi:10.1126/sciadv.abj5227

A dominant function of LynB kinase in preventing autoimmunity

Sci Adv. 2022 Apr 22;8(16):eabj5227. doi: 10.1126/sciadv.abj5227. Epub 2022 Apr 22.

Authors

Ben F Brian 4th¹, Monica L Sauer², Joseph T Greene³, S Erandika Senevirathne¹, Anders J Lindstedt^{4

5}, Olivia L Funk³, Brian L Ruis⁶, Luis A Ramirez³, Jennifer L Auger⁷, Whitney L Swanson³, Myra G Nunez³, Branden S Moriarity^{6

8

9

10}, Clifford A Lowell¹¹, Bryce A Binstadt^{7

12}, Tanya S Freedman^{3

9

12

13}

Affiliations

¹ Graduate Program in Molecular Pharmacology and Therapeutics, University of Minnesota, Minneapolis, MN 55455, USA.
² Graduate Program in Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
³ Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
⁴ Graduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Medical Scientist Training Program, University of Minnesota, Minneapolis, MN 55455, USA.
⁶ Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
⁷ Department of Pediatrics, Division of Rheumatology, Allergy and Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
⁸ Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
⁹ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁰ Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
¹¹ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
¹² Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
¹³ Center for Autoimmune Diseases Research, University of Minnesota, Minneapolis, MN 55455, USA.

Abstract

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 lyn 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 B cells were dysregulated. These changes were isoform-specific, sexually dimorphic, and distinct from the complete Lyn^KO. 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).

Abstract

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