B Cell Subsets in Mouse and Human Atherosclerosis

摘要 B细胞在小鼠动脉粥样硬化中已成为重要的免疫细胞，调节病变的发展， 依赖子集的方式。B-2 B细胞通过不明确的机制促进动脉粥样硬化，而B-1 B 细胞主要通过产生天然IgM抗体（NAb）发挥动脉粥样硬化保护作用。天然IgM至 在动脉粥样硬化中积累的氧化特异性表位（OSE），如丙二醛（MDA）和 存在于氧化低密度脂蛋白上的磷酸胆碱（PC）可以拮抗oxLDL刺激 巨噬细胞限制炎症。B-1细胞是小鼠中循环IgM的主要来源。人类 最近通过其自发产生IgM的能力鉴定了与鼠B-1细胞相当的细胞， 数据表明该细胞产生针对LDL上OSE的IgM。血浆IgM水平与MDA-LDL相关 冠心病和心血管疾病的发病率更低。因此，解开导致B-1细胞 OSE的IgM的产生可能使靶向免疫策略能够支持LDL上OSE的IgM的产生 并防止人类动脉粥样硬化。我们的工作已经确定CXCR 4是B-1 NA B的关键调节因子 在小鼠中生产。此外，用血管内超声（IVUS）分析人类队列以量化 冠状动脉斑块体积，我们证明了B-1细胞上CXCR 4表达与冠状动脉斑块体积显著相关。 血浆IgM对MDA-LDL和低斑块体积的影响。在这个建议中，我们将使用功能研究的损失和增益 在小鼠动脉粥样硬化模型中，并分析充分表征的人类队列，以研究 CXCR 4和其他相关趋化因子受体介导B-1细胞抗动脉粥样硬化作用

Abstract B cells have emerged as important immune cells in murine atherosclerosis, regulating lesion development in a subset-dependent manner. B-2 B cells promote atherosclerosis through poorly defined mechanisms, and B-1 B cells exert atheroprotective effects largely through production of natural IgM antibodies (NAb). Natural IgM to oxidation-specific epitopes (OSE) that accumulate in atherosclerosis such as malondialdehyde (MDA) and phosphorylcholine (PC) present on oxidized low-density lipoprotein can antagonize oxLDL stimulation of macrophages limiting inflammation. B-1 cells are the major source of circulating IgM in mice. A human equivalent to the murine B-1 cell was recently identified through its ability to spontaneously produce IgM and data implicates this cell in producing IgM to OSE on LDL. Plasma levels of IgM to MDA-LDL are associated with less CAD and fewer CV events in humans. As such, unraveling the pathways that lead to B-1 cell production of IgM to OSE may enable targeted immune strategies to bolster production of IgM to OSE on LDL and protect from atherosclerosis in humans. Our work has identified CXCR4 as a key regulator of B-1 NAb production in mice. Moreover, analyzing a human cohort with intravascular ultrasound (IVUS) to quantify coronary artery plaque volume, we demonstrate significant association of CXCR4 expression on B-1 cells with plasma IgM to MDA-LDL and low plaque volume. In this proposal, we will use loss and gain of function studies in murine atherosclerosis models, and analysis of well characterized human cohorts to study the role of CXCR4 and other implicated chemokine receptors in mediating B-1 cell atheroprotection.