From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, United Kingdom (A.P.S., M.N., J.B.C., S.A.N., A.J.F., L.M., Z.M.); Department of Laboratory Medicine, (D.T., C.J.B.); Medical University of Vienna, Austria (D.T., C.J.B.); CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna (D.T., C.J.B.); INSERM U970, Paris Cardiovascular Research Center, France (Z.M.); and Université Paris Descartes, Sorbonne Paris Cité, France (Z.M.).
Circ Res. 2017 Jul 21;121(3):270-281. doi: 10.1161/CIRCRESAHA.117.310884. Epub 2017 Jun 15.
Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies, and their importance in both humans and mouse models is still unclear.
To specifically target antibody production by plasma cells and determine the impact on atherosclerotic plaque development in mice with and without CD4+ T cells.
We combined a model of specific antibody deficiency, B cell-specific CD79a- x XBP1 (X-box binding protein-1) floxed mice (XBP1-conditional knockout), with antibody-mediated depletion of CD4+ T cells. Ldlr knockout mice transplanted with XBP1-conditional knockout (or wild-type control littermate) bone marrow were fed western diet for 8 weeks with or without anti-CD4 depletion. All groups had similar levels of serum cholesterol. In Ldlr/XBP1-conditional knockout mice, serum levels of IgG, IgE, and IgM were significantly attenuated, and local antibody deposition in atherosclerotic plaque was absent. Antibody deficiency significantly accelerated atherosclerosis at both the aortic root and aortic arch. T cell and monocyte responses were not modulated, but necrotic core size was greater, even when adjusting for plaque size, and collagen deposition significantly lower. Anti-CD4 depletion in Ldlr/wild-type mice led to a decrease of serum IgG1 and IgG2c but not IgG3, as well as decreased IgM, associated with increased atherosclerosis and necrotic cores, and a decrease in plaque collagen. The combination of antibody deficiency and anti-CD4 depletion has no additive effects on aortic root atherosclerosis.
The endogenous T cell-dependent humoral response can be protective. This has important implications for novel vaccine strategies for atherosclerosis and in understanding the impacts of immunotherapies used in patients at high risk for cardiovascular disease.
不同的 B 细胞反应和功能可能与动脉粥样硬化有关。保护性抗体反应，如针对氧化脂质表位的反应，被认为主要来源于 T 细胞非依赖性先天 B 细胞亚群。相比之下，致病性和保护性抗体都与 T 细胞依赖性抗体有关，但其在人类和小鼠模型中的重要性尚不清楚。
专门针对浆细胞的抗体产生，并确定其在有和没有 CD4+T 细胞的小鼠中对动脉粥样硬化斑块发展的影响。
我们结合了特定抗体缺乏的模型，即 B 细胞特异性 CD79a-x XBP1（X 盒结合蛋白-1）敲除小鼠（XBP1 条件性敲除），与 CD4+T 细胞的抗体介导耗竭相结合。用西方饮食喂养 Ldlr 敲除小鼠，移植 XBP1 条件性敲除（或野生型对照同窝仔鼠）骨髓 8 周，并在有或没有抗 CD4 耗竭的情况下进行。所有组的血清胆固醇水平相似。在 Ldlr/XBP1 条件性敲除小鼠中，IgG、IgE 和 IgM 的血清水平明显降低，动脉粥样硬化斑块中的局部抗体沉积也不存在。抗体缺乏显著加速了主动脉根部和弓部的动脉粥样硬化。T 细胞和单核细胞反应没有被调节，但坏死核心的大小更大，即使在调整斑块大小后也是如此，胶原沉积明显减少。在 Ldlr/野生型小鼠中耗竭 CD4 导致血清 IgG1 和 IgG2c 减少，但 IgG3 没有减少，同时 IgM 减少，与动脉粥样硬化和坏死核心增加以及斑块胶原减少相关。抗体缺乏和抗 CD4 耗竭的联合作用对主动脉根部动脉粥样硬化没有累加效应。
内源性 T 细胞依赖性体液反应可能具有保护作用。这对动脉粥样硬化的新型疫苗策略以及理解在心血管疾病高危患者中使用免疫疗法的影响具有重要意义。
