Departments of Medicine and Center for Molecular Medicine (M.C., H.J., L.H., S.H., A.B., R.B., N.J.V., S.L.E., S.V.B, D.Y.L., C.S., G.K.H., D.F.J.K., F.W., L.M., S.G.M.), Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Molecular Medicine and Surgery (L.P.M., U.H.), Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Circulation. 2019 May 21;139(21):2466-2482. doi: 10.1161/CIRCULATIONAHA.118.038534.
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.
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.
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.
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.
动脉粥样硬化的进展受到与适应性免疫系统相互作用的调节。体液免疫有助于预防动脉粥样硬化形成；然而，潜在的致动脉粥样硬化抗体的存在、来源和功能仍存在争议。这些促进动脉粥样硬化的抗体如何影响斑块的特定组成和稳定性，以及血管系统的一般情况，目前尚不清楚。
我们通过（1）显示出普遍丧失抗体的小鼠、（2）具有选择性地消除生发中心衍生 IgG 产生的小鼠，或（3）通过中断 T-B 细胞相互作用，以及通过转录组学进一步研究抗体缺乏对主动脉的影响，来研究抗体对动脉粥样硬化斑块形成、组成和稳定性的总体贡献。
在这里，我们证明了血浆细胞功能减弱的易患动脉粥样硬化的小鼠斑块负担减少，表明抗体促进动脉粥样硬化病变大小。然而，在抗体缺乏的小鼠中，斑块的组成发生了改变，脂质含量增加，平滑肌细胞和巨噬细胞减少，导致实验验证的易损斑块表型。此外，IgG 抗体以 Fc 受体依赖性的方式增强平滑肌细胞的增殖，并且体内缺乏抗体的小鼠的新生内膜过度增生形成减少。这些 IgG 抗体被证明来自生发中心，并且在生发中心形成基因缺失的小鼠中，动脉粥样硬化斑块的形成明显减少。主动脉的 mRNA 测序表明，抗体是充分表达多种信号诱导和生长促进转录因子所必需的，并且在缺乏抗体的情况下，主动脉经历大规模的代谢重编程。使用弹性蛋白酶模型，我们证明了 IgG 的缺乏会导致动脉瘤形成的严重程度增加。
我们提出，生发中心衍生的 IgG 抗体通过促进动脉平滑肌细胞增殖和维持主动脉的分子特征，促进动脉粥样硬化斑块的大小和稳定性。这些结果可能对针对 B 细胞或 B-T 细胞相互作用的治疗方法具有重要意义，因为体液免疫的丧失会导致斑块表型更小但更不稳定。
