FcγRIIB Inhibits the Development of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

Abstract

The immune processes associated with atherogenesis have received considerable attention during recent years. IgG FcRs (FcγR) are involved in activating the immune system and in maintaining peripheral tolerance. However, the role of the inhibitory IgG receptor FcγRIIB in atherosclerosis has not been defined. Bone marrow cells from FcγRIIB-deficient mice and C57BL/6 control mice were transplanted to low-density lipoprotein receptor-deficient mice. Atherosclerosis was induced by feeding the recipient mice a high-fat diet for 8 wk and evaluated using Oil Red O staining of the descending aorta at sacrifice. The molecular mechanisms triggering atherosclerosis was studied by examining splenic B and T cells, as well as Th1 and Th2 immune responses using flow cytometry and ELISA. The atherosclerotic lesion area in the descending aorta was ~5-fold larger in mice lacking FcγRIIB than in control mice (2.75 ± 2.57 versus 0.44 ± 0.42%; p < 0.01). Moreover, the FcγRIIB deficiency resulted in an amplified splenocyte proliferative response to Con A stimulation (proliferation index 30.26 ± 8.81 versus 2.96 ± 0.81%, p < 0.0001) and an enhanced expression of MHC class II on the B cells (6.65 ± 0.64 versus 2.33 ± 0.25%; p < 0.001). In accordance, an enlarged amount of CD25-positive CD4 T cells was found in the spleen (42.74 ± 4.05 versus 2.45 ± 0.31%; p < 0.0001). The plasma Ab and cytokine pattern suggested increased Th1 and Th2 immune responses, respectively. These results show that FcγRIIB inhibits the development of atherosclerosis in mice. In addition, they indicate that absence of the inhibiting IgG receptor cause disease, depending on an imbalance of activating and inhibiting immune cells.

Molecular Biology of Atherosclerosis

“…Inflammatory cytokines in aorta were higher as were plasma IgG directed against modified LDL (1191) Only abdominal aorta area at 12 wk assessed. Increase in anti-oxLDL IgG also seen (2093). Table 6) and may promote T-cell recruitment to lesions (296).…”

An Unexpected Intriguing Effect of Toll-Like Receptor Regulator RP105 (CD180) on Atherosclerosis Formation With Alterations on B-Cell Activation

“…50 Particularly in autoimmune settings, B cells can actively promote atherosclerosis. 51 Using Rituximab would, however, be a difficult therapy for patients with cardiovascular disease because statins may impair its effect by inducing conformational changes on CD20. 52 This would make new therapeutic targets on B cells such as RP105 even more interesting.…”

Enhanced Atherosclerosis in TIPE2-Deficient Mice Is Associated with Increased Macrophage Responses to Oxidized Low-Density Lipoprotein

“…The heart and aorta were dissected and fixed in 4% paraformaldehyde overnight. The cross-sectional area of the atherosclerotic lesions was evaluated in the aortic root by H&E staining, and the en face area of the atherosclerotic lesions was assessed in the entire aorta by Oil Red O (Sigma-Aldrich) staining as previously described (19,20). In addition, sections were stained with Masson's trichrome for evaluation of collagen contents.…”