Id3/B Lymphocytes and Atherosclerosis

动脉粥样硬化是一种以脂质渗透和炎性细胞聚集为特征的慢性疾病。 血管壁促进斑块进展，可能导致严重的临床后果，如 心肌梗塞和中风。而单核细胞和T淋巴细胞募集的机制和 在血管壁的功能已经得到了广泛的研究8-10，B淋巴细胞的作用仍然存在 不完全理解。在易患动脉粥样硬化的小鼠模型中，B细胞的丢失导致显著的 病变面积增加，通过B细胞置换而减轻11.12。B细胞和浆细胞 在斑块的内膜以及人和动物的外膜中都有表达。 ·13-19， 然而，关于调节B细胞归巢到血管壁的因素或B细胞趋化因子的重要性，目前尚不清楚。 血管壁相关B细胞。已在动脉粥样硬化斑块中检测到IgM和IgG抗体 已经描述了针对各种氧化型低密度脂蛋白(OxLDL)表位的抗体效价17 。 19 ·20.这些抗氧化型低密度脂蛋白 抗体已被证明可以减轻动脉粥样硬化2 0- 24个 · 螺旋-环-螺旋因子ID3与B淋巴细胞的生长和分化有关，但 ID3对B细胞归巢、特异性抗体产生、炎症细胞的影响尚不清楚 血管内募集或动脉粥样硬化。来自我们实验室的令人兴奋的初步数据表明 主动脉特异性B细胞数量和循环中特异性IgM对oxPL水平的降低与AN相关 载脂蛋白E-1增加动脉粥样硬化的形成 -与ApoE-I-对照相比，ID3基因的小鼠为零。 ID3+1+ApoE-I-或ID3-1-ApoE-I-小鼠B细胞过继转移至jJMT ApoE-1 -缺乏成熟B蛋白的小鼠 细胞提供证据表明ID3调节主动脉特异的B细胞归巢，并且ID3对B细胞很重要 介导的动脉粥样硬化保护作用。我们的数据进一步提供了ID3调节B细胞表达的证据 特异性趋化因子：CXCR4、CXCR7和CCR6，但不包括CXCR5或CCR7(已知趋化因子受体 以调节B细胞归巢到淋巴组织)，提供了一种潜在的机制，通过ID3可以调节B细胞 细胞定位于大动脉。有趣的是，采用移植研究显示，主动脉内含有 B细胞(来源于ID3+1+ApoE-1 -捐赠者)在总体炎症细胞图谱中表现出差异 与B细胞明显较少的动脉相比(来自ID3-1 -ApoE-I-捐赠者)。此外，通过我们的 与Sam Tsimikas博士合作，我们发现动脉粥样硬化保护性抗oxLDL IgM水平降低(E06) 在西式饮食中产生的ID3-1-ApoE-I-与ID3+1+ApoE-I-相比。因此， 通过与Sam Tsimikas博士、Tim Bender博士和袁庄博士的密切合作，我们不仅有 新发现和新试剂在手，但我们也建立了一支领先的血管专家团队 疾病、ID3、B细胞和免疫球蛋白的产生，使我们能够做出独特的贡献 了解B细胞介导动脉粥样硬化保护的机制

Atherosclerosis is a chronic disease characterized by lipid infiltration and inflammatory cell recruitment in the vessel wall promoting plaque progression that can lead to serious clinical consequences such as myocardial infarction and stroke. While mechanisms of monocyte and T lymphocyte recruitment and function in the vessel wall have been extensively studied 8-10, the role of B lymphocytes remains incompletely understood. In atherosclerosis-prone mouse models, the loss of B cells results in significantly increased lesion size which was attenuated by replacement of B cells 11.12. B cells and plasma cells have been demonstrated in both the intima of plaques as well as in the adventitia of humans and animals7 • 13-19, yet nothing is known about the factors that regulate B cell homing to the vessel wall or the importance of vessel wall-associated B cells. IgM and IgG antibodies have been detected in atherosclerotic plaques and titers of antibodies against various oxidized LDL (oxLDL) epitopes have been described17 . 19 • 20. These antioxLDL antibodies have been shown to attenuate atherosclerosis2 0- 24 • The helix-loop-helix factor, Id3, has been implicated in the growth and differentiation of B lymphocytes, but nothing is known about the effect of Id3 on B cell homing, specific antibody production, inflammatory cell recruitment in the vessel or atherosclerosis. Exciting preliminary data from our laboratory demonstrates an aortic-specific reduction in B cell number and circulating levels of a specific IgM to oxPL correlating with an increase in atherosclerosis fomnation in ApoE-1 - mice null for the Id3 gene compared with ApoE-I- controls. Adoptive transfer of B cells from Id3+1+ ApoE-I- or Id3-1- ApoE-I- mice to jJMT ApoE-1 - mice lacking mature B cells provides evidence that Id3 regulates aortic-specific B cell homing and that Id3 is important for B cell mediated atheroprotection. Our data further provides evidence that Id3 regulates B cell expression of specific chemokines: CXCR4, CXCR7, and CCR6 but not CXCR5 or CCR7 (chemokine receptors known to regulate B cell homing to lymphoid tissue), providing a potential mechanism whereby Id3 may regulate B cell homing specifically to the aorta. Interestingly, adoptive transfer studies revealed that aortas containing B cells (from Id3+1+ ApoE-1 - donors) demonstrated differences in the overall inflammatory cell profile compared with aortas with significantly fewer B cells (from Id3-1 - ApoE-I- donors). Moreover, through our collaboration with Dr. Sam Tsimikas, we show reduced levels of the atheroprotective anti-oxLDL IgM (E06) produced in response to Western diet feeding in the Id3-1- ApoE-I- compared to the Id3+1+ ApoE-I-. Thus, through close collaboration with Drs. Sam TSimikas, Tim Bender and Yuan Zhuang, not only do we have novel findings and novel reagents in hand, but we have also built a team of leading experts in vascular disease, Id3, B cells and immunoglobulin production that uniquely positions us to make contributions toward understanding the mechanisms whereby B cells mediate atheroprotection