B Cell Subsets in Mouse and Human Atherosclerosis

小鼠和人类动脉粥样硬化中的 B 细胞亚群

• 批准号: 10188607
• 负责人: Coleen A McNamara
• 金额: $ 36.65万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188607
• 关键词: Accounting; Adoptive Transfer; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Apolipoprotein E; Atherosclerosis; Attenuated; B-Lymphocyte Subsets; B-Lymphocytes; BLR1 gene; Binding; Bone Marrow; CCR6 gene; CXCL12 gene; CXCR4 gene; Cardiovascular Diseases; Cause of Death; Cell Communication; Cells; Cessation of life; Color; Conflict (Psychology); Coronary artery; Data; Development; Diet; Edetic Acid; Enzyme-Linked Immunosorbent Assay; Epitopes; Event; Flow Cytometry; Genes; Homing; Human; Immune; Immune Targeting; Immunoglobulin M; Individual; Inflammation; Inflammatory; Knowledge; Lead; Lesion; Leukocytes; Link; Low-Density Lipoproteins; Malondialdehyde; Measurement; Measures; Mediating; Modeling; Modification; Mus; Oxides; Participant; Pathway interactions; Patients; Phospholipids; Phosphorylcholine; Plasma; Prevention; Production; Property; Publishing; Risk; Risk Factors; Role; Source; Surface; Testing; Translating; Ultrasonography; Work; atheroprotective; atherosclerosis risk; attenuation; cardiovascular risk factor; chemokine receptor; chronic inflammatory disease; cohort; coronary artery calcium; disorder risk; enzyme linked immunospot assay; feeding; gain of function; high risk; human data; human disease; immunomodulatory therapies; improved; insight; loss of function; macrophage; migration; mouse model; natural antibodies; novel; overexpression; oxidation; oxidized low density lipoprotein; prevent; protein expression; receptor expression; stem cells; transcriptome sequencing; western diet

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.

抽象的 B细胞在鼠动脉粥样硬化中已成为重要的免疫细胞，从而调节A中的病变发育 子集依赖性方式。 B-2 B细胞通过定义较差的机制促进动脉粥样硬化，而B-1 B 细胞在很大程度上通过生产天然IgM抗体（NAB）发挥动脉保护作用。天然IgM 氧化特异性表位（OSE）积聚在动脉粥样硬化中的氧化剂（MDA）和 存在于氧化的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细胞是小鼠循环IgM的主要来源。人类 最近，通过自发产生IgM和 数据暗示该细胞在LDL上产生IgM与OSE。 IgM到MDA-LDL的等离子水平是相关的 在人类中，CAD较少，简历活动较少。因此，揭开导致B-1细胞的途径 生产IgM向OSE的生产可能使靶向免疫策略能够增强IgM的产生，从而在LDL上产生IgM 并防止人类动脉粥样硬化。我们的工作已将CXCR4确定为B-1 NAB的关键调节器 在小鼠中产生。此外，分析与血管内超声（IVU）的人类队列以量化 冠状动脉斑块体积，我们证明了B-1细胞上CXCR4表达显着相关 血浆IgM至MDA-LDL和低斑块体积。在此提案中，我们将使用功能研究的损失和增益 在鼠动脉粥样硬化模型中，以及对人类人群的分析，以研究的作用 CXCR4和其他与介导B-1细胞动脉保护作用中的趋化因子受体。