Anti-FCGR2B monoclonal antibody, clone 04 [APC]

Objective-Fc gamma receptors (Fc gamma Rs) are classified as activating (Fc gamma RI, III, and IV) and inhibitory (Fc gamma RII) receptors. We have reported that deletion of activating Fc gamma Rs in apolipoprotein E (apoE) single knockout mice attenuated atherosclerosis. In this report, we investigated the hypothesis that deficiency of inhibitory Fc gamma RIIb exacerbates atherosclerosis. Approach and Results-ApoE-Fc gamma RIIb double knockout mice, congenic to the C57BL/6 (apoE-Fc gamma RIIb(B6)(-/-)), were generated and atherosclerotic lesions were assessed. In contrary to our hypothesis, when compared with apoE single knockout mice, arterial lesions were significantly decreased in apoE-Fc gamma RIIb(B6)(-/-) male and female mice fed chow or high-fat diets. Chimeric mice generated by transplanting apoE-Fc gamma RIIb(B6)(-/-) marrow into apoE single knockout mice also developed reduced lesions. CD4(+) T cells from apoE-Fc gamma RIIb(B6)(-/-) mice produced higher levels of interleukin-10 and transforming growth factor-beta than their apoE single knockout counterparts. As our findings conflict with a previous report using apoE-Fc gamma RIIb(129/B6)(-/-) mice on a mixed genetic background, we investigated whether strain differences contributed to the anti-inflammatory response. Macrophages from Fc gamma RIIb(129/B6)(-/-) mice on a mixed genetic background produced more interleukin-1 beta and MCP-1 (monocyte chemoattractant protein-1) in response to immune complexes, whereas congenic Fc gamma RIIb(B6)(-/-) mice generated more interleukin-10 and significantly less interleukin-1 beta. Interestingly, the expression of lupus-associated slam genes, located in proximity to fcgr2b in mouse chromosome 1, is upregulated only in mixed Fc gamma RIIb(129/B6)(-/-) mice. Conclusions-Our findings demonstrate a detrimental role for Fc gamma RIIb signaling in atherosclerosis and the contribution of anti-inflammatory cytokine responses in the attenuated lesions observed in apoE-Fc gamma RIIb(B6) (-/-) mice. As 129/sv genome-derived lupus-associated genes have been implicated in lupus phenotype in Fc gamma RIIb(129/B6)(-/-) mice, our findings suggest possible epistatic mechanism contributing to the decreased lesions.

Background and aims: Circulating levels of oxidized lipoprotein oxLDL) correlate with myocardial infarction risk and atherosclerosis severity. Our previous study demonstrates that oxLDL immune complexes oxLDL-ICs) can signal through Fc gamma Rs on bone marrow-derived dendritic cells BMDCs) and enhance their activation and inflammatory cytokine secretion. While global Fc gamma R-/- studies have shown that activating Fc gamma Rs are proatherogenic, the role of the inhibitory Fc gamma RIIb is unclear. We sought to determine the role of DC-specific Fc gamma RIIb in atherosclerosis. Methods: Bone marrow chimeras were generated by rescuing lethally irradiated Ldlr(-/-) mice with hematopoietic cells from littermate CD11c-Cre(+) or CD11c-Cre-Fcgr2b(fl/fl) donors. Four weeks following transplant, recipients were placed on a Western diet for eight weeks. Various tissues and organs were analyzed for differences in inflammation. Results: Quantitation of atherosclerosis in the proximal aorta demonstrated a 58% increase in female CD11c-Cre(+) Fcgr2b(fl/fl) recipients, but a surprising 44% decrease in male recipients. Hepatic cholesterol and triglycerides were increased in female CD11c-Cre(+) Fcgr2b(fl/fl) recipients. This was associated with an increase in CD36 and MHC Class II expression on hepatic CD11c(+) CD11b(+) DCs in female livers. In contrast, male CD11c-Cre(+) Fcgr2b(fl/fl) recipients had decreased hepatic lipids with a corresponding decrease in CD36 and MHC Class II expression on CD11c(+) cells. Interestingly, both sexes of CD11c-Cre(+) Fcgr2b(fl/fl) recipients had significant decreases in serum cholesterol and TGs with corresponding decreases in liver Fasn transcripts. Conclusions: The absence of Fc gamma RIIb expression on CD11c(+) cells results in sex-dependent alteration in liver inflammation influencing atherogenesis and sex-independent modulation of serum cholesterol and TGs.