Germinal Center–Derived Antibodies Promote Atherosclerosis Plaque Size and Stability

Abstract

Background: Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation; however, the existence, origin, and function of putative atherogenic antibodies are controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown. Methods: We addressed the overall contribution of antibodies to atherosclerosis plaque formation, composition, and stability in vivo (1) with mice that displayed a general loss of antibodies, (2) with mice that had selectively ablated germinal center-derived IgG production, or (3) through interruption of T–B-cell interactions and further studied the effects of antibody deficiency on the aorta by transcriptomics. Results: Here, we demonstrate that atherosclerosis-prone mice with attenuated plasma cell function manifest reduced plaque burden, indicating that antibodies promote atherosclerotic lesion size. However, the composition of the plaque was altered in antibody-deficient mice, with an increase in lipid content and decreases in smooth muscle cells and macrophages, resulting in an experimentally validated vulnerable plaque phenotype. Furthermore, IgG antibodies enhanced smooth muscle cell proliferation in vitro in an Fc receptor–dependent manner, and antibody-deficient mice had decreased neointimal hyperplasia formation in vivo. These IgG antibodies were shown to be derived from germinal centers, and mice genetically deficient for germinal center formation had strongly reduced atherosclerosis plaque formation. mRNA sequencing of aortas revealed that antibodies are required for the sufficient expression of multiple signal-induced and growth-promoting transcription factors and that aortas undergo large-scale metabolic reprograming in their absence. Using an elastase model, we demonstrated that absence of IgG results in an increased severity of aneurysm formation. Conclusions: We propose that germinal center–derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B–T-cell interactions because the loss of humoral immunity leads to a smaller but less stable plaque phenotype.

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

“…The two mouse models also differed in their systemic inflammatory responses to dyslipidemia. Our results add further weight for a role of APOE in inhibiting systemic adaptive immune responses typified by GC formation and DC activation 26,[47][48][49] . However, we could not detect splenic GCs in our D374Y strain, consistent with our previous study with Ldlr -/mice 18 .…”

“…Loss of APOE is known to have multiple effects on the immune system, including the formation of splenic germinal centers (GC) 24,25 resulting in increased atherosclerosis 18,26 . Therefore, we wished to determine whether there is a conserved immune response to dyslipidemia itself, by characterizing the immune compartment of our two mouse strains by flow cytometry of spleen cells.…”

B Cell Fcγ Receptor IIb Modulates Atherosclerosis in Male and Female Mice by Controlling Adaptive Germinal Center and Innate B-1-Cell Responses

“…Data from both models suggest that GC-dependent responses may promote atherosclerosis, consistent with previous data implicating the GC as pathogenic. 25,38,39 Overexpression of FcγRIIb led to a decrease in GC B cells and GC-dependent IgG isotypes (Figure 2). More specifically, limiting FcγRIIb upregulation on GC B cells but not plasma cells, B-1 cells or marginal zone B cells led to increased atherosclerosis, associated with an enhanced GC response (Figure 3).…”

Treatment with a Toll‐like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice

“…Whether this is just a reflection of the total IgM increase in the plasma or whether it actively deposited in the lesion is not known. However, regarding IgG-type antibodies against oxLDL a complex picture has emerged with data showing capacity both to promote and to ameliorate disease [51][52][53][54].…”