Id3/B Lymphocytes and Atherosclerosis

动脉粥样硬化是一种慢性疾病，其特征是脂质浸润和炎性细胞募集， 血管壁促进斑块进展，这可能导致严重的临床后果， 心肌梗塞和中风。虽然单核细胞和T淋巴细胞的募集机制， 虽然已经对血管壁中的功能进行了广泛的研究8-10，但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细胞的损失导致显著的 增加的病变尺寸，其通过替换B细胞而减弱11.12。B细胞和浆细胞 在人和动物的斑块内膜以及外膜中均得到证实7 · 13-19， 然而，对于调节B细胞归巢到血管壁的因子以及 血管壁相关B细胞。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LDL（oxLDL）表位的抗体滴度17 . 19 · 20。这些抗oxLDL 抗体已经显示出减弱动脉粥样硬化2 0- 24 · 螺旋-环-螺旋因子Id 3与B淋巴细胞的生长和分化有关，但 关于Id 3对B细胞归巢、特异性抗体产生、炎性细胞增殖和免疫应答的影响尚不清楚。 血管中的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， B细胞数量和oxPL特异性IgM循环水平的特异性降低与 ApoE-1中动脉粥样硬化形成增加 - 与ApoE-1对照组相比，Id 3基因无效的小鼠。 将B细胞从Id 3 +1+ ApoE-I-或Id 3 -1- ApoE-I-小鼠过继转移至jJMT ApoE-1 - 缺乏成熟B的小鼠 Id 3对肿瘤特异性B细胞归巢的调节以及Id 3对B细胞归巢的重要性 介导的动脉粥样硬化保护作用。我们的数据进一步提供了Id 3调节B细胞表达的证据， 特异性趋化因子：CXCR 4、CXCR 7和CCR 6，但不包括CXCR 5或CCR 7（已知的趋化因子受体 调节B细胞归巢到淋巴组织），提供了Id 3可调节B的潜在机制 细胞归巢到主动脉有趣的是，过继转移研究显示， B细胞（来自Id 3 +1+ ApoE-1 - 供体）在总体炎性细胞谱中表现出差异 与B细胞显著减少的乳腺癌相比（来自Id 3 -1 - ApoE-1-供体）。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（E06）水平降低 与Id 3 +1+ ApoE-I-相比，Id 3 -1- ApoE-I-在响应西方饮食喂养中产生。因此，在本发明中， 通过与Sam TSimikas博士、Tim Bender博士和Yuan Zhuang博士的密切合作，我们不仅拥有 新的发现和新的试剂在手，但我们也建立了一个领先的血管专家团队， 疾病、Id 3、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