B cell Fcγ receptor IIb modulates atherosclerosis in male and female mice by controlling adaptive germinal center and innate B1-cell responses

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Bagchi-Chakraborty, J 
Francis, A 
Bray, T 
Masters, L 
Tsiantoulas, D 

Objective. Investigate the impact of modulating B cell FcγRIIb (Fcγ receptor IIb) expression on atherosclerosis. Approach and Results. Western diet–induced atherosclerosis was assessed in Ldlr−/− or Apoe−/− mice with B cell–specific overexpression of FcγRIIb or with an FcγRIIb promoter mutation that alters FcγRIIb expression in germinal center (GC) B cells. In males, overexpression of FcγRIIb on B cells severely reduced activated, class switched B cell responses, as indicated by reductions in GC B cells, plasma cells, and serum IgG but not IgM antibodies. Male mice overexpressing FcγRIIb developed less atherosclerosis, suggesting a pathogenic role for GC B cell IgG responses. In support of this hypothesis, male mice with a promoter polymorphism-driven reduction in FcγRIIb on GC B cells but not plasma cells have a converse phenotype of enhanced GC responses and IgG2c antibodies and enhanced atherosclerosis. IgG2c significantly enhanced TNF (tumor necrosis factor) secretion by CD11b+ CD11c+ cells expressing the high-affinity receptor FcγRIV. In females, overexpression of FcγRIIb on B cells not only reduced GC B cell responses but also substantially reduced B-1 cells and IgM antibodies, which translated into acceleration of atherosclerosis. Promoter-driven reduction in FcγRIIb did not alter GC B cell responses in females and, therefore, had no impact on atherosclerosis. Conclusions. B cell FcγRIIb differentially alters proatherogenic adaptive GC B cell and atheroprotective innate B-1 responses in male and female mice fed a western diet. Our results highlight the importance of a better understanding and ability to selectively target B cell responses in future immunotherapeutic approaches against human cardiovascular disease.

atherosclerosis, cardiovascular diseases, germinal center, inflammation, plasma cells, Animals, Apolipoproteins E, Atherosclerosis, B-Lymphocytes, Female, Germinal Center, Immunity, Innate, Immunoglobulin M, Male, Mice, Mice, Inbred C57BL, Receptors, IgG, Tumor Necrosis Factor-alpha
Journal Title
Arteriosclerosis, Thrombosis, and Vascular Biology
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Ovid Technologies (Wolters Kluwer Health)
British Heart Foundation (None)
British Heart Foundation (CH/10/001/27642)
British Heart Foundation (FS/15/57/31557)
Medical Research Council (MR/N024907/1)
British Heart Foundation (PG/17/73/33251)
This work was supported by British Heart Foundation grants to A.P. Sage (FS/15/57/31557) and Z. Mallat.