B Cell Fcγ Receptor IIb Modulates Atherosclerosis in Male and Female Mice by Controlling Adaptive Germinal Center and Innate B-1-Cell Responses.
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. Visual Overview- An online visual overview is available for this article.
['Bagchi-Chakraborty|Jayashree|J|', 'Francis|Anna|A|', 'Bray|Toni|T|', 'Masters|Leanne|L|', 'Tsiantoulas|Dimitrios|D|', 'Nus|Meritxell|M|', 'Harrison|James|J|', 'Broekhuizen|Michelle|M|', 'Leggat|Jennifer|J|', 'Clatworthy|Menna R|MR|', 'Espéli|Marion|M|', 'Smith|Kenneth G C|KGC|', 'Binder|Christoph J|CJ|', 'Mallat|Ziad|Z|', 'Sage|Andrew P|AP|']
D000818:Animals D001057:Apolipoproteins E D050197:Atherosclerosis D001402:B-Lymphocytes D005260:Female D018858:Germinal Center D007113:Immunity, Innate D007075:Immunoglobulin M D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D017452:Receptors, IgG D014409:Tumor Necrosis Factor-alpha
atherosclerosis germinal center plasma cells cardiovascular diseases inflammation