Open AccessB Cell Fcγ Receptor IIb Modulates Atherosclerosis in Male and Female Mice by Controlling Adaptive Germinal Center and Innate B-1-Cell Responses
Author(s) -
Jayashree Bagchi-Chakraborty,
Anna Francis,
Timothy J P Bray,
Leanne Masters,
Dimitrios Tsiantoulas,
Meritxell Nus,
James Harrison,
Michelle Broekhuizen,
Jennifer Leggat,
Menna R. Clatworthy,
Marion Espéli,
Kenneth G. C. Smith,
Christoph J. Binder,
Ziad Mallat,
Andrew P. Sage
Publication year - 2019
Publication title -
arteriosclerosis, thrombosis, and vascular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.007
H-Index - 270
eISSN - 1524-4636
pISSN - 1079-5642
DOI - 10.1161/atvbaha.118.312272
Subject(s) - germinal center , b cell , cd11c , biology , antibody , receptor , ldl receptor , immunology , memory b cell , tumor necrosis factor alpha , cell , b 1 cell , endocrinology , microbiology and biotechnology , medicine , t cell , phenotype , antigen presenting cell , lipoprotein , immune system , cholesterol , biochemistry , genetics , gene
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.