Role of B-1 Cells and Natural antibodies in Inflammation and Atherosclerosis

先天免疫在动脉粥样硬化形成中起着重要作用，我们的工作通过证明在氧化损伤的分子复合物（如OxLDL和凋亡细胞）上产生的“氧化特异性表位”（OSE）是先天模式识别受体（如IgM天然抗体（NAb））的主要靶点，提供了对此的更好理解。在第一个周期期间，我们证明了所有IgM NAb中的20-30%在小鼠和人中都与OSE结合，并且我们提出IgM OSE-NAb已经被保守以向健康和疾病中产生的许多OSE提供稳态。相当多的数据支持IgM在鼠模型中的动脉粥样硬化保护作用，并且人中的IgM滴度与心血管疾病（CVD）负相关。在更新中，我们将专注于了解NAb在小鼠和人类中的作用，并定义调节产生NAb的8-1细胞的机制。 特定目标1将定义小鼠和人类中OSE NAb的库和流行率。我们将产生 IgM NAb重链可变（IGHV）CDR 3序列及其在人和小鼠中的相对表达的B-1细胞来源的数据库。然后，我们将对OSE-B-1细胞进行分类以注释OSE NAb，并将在小鼠炎症和动脉粥样硬化实验模型以及人类流行病学研究中检查它们的相对表达。具体目标2将定义OSE NAb和B-1细胞在炎症和动脉粥样硬化形成中的作用。使用表达OSE抗体的转基因小鼠，我们将试图确定OSE抗体影响炎症和动脉粥样硬化的机制。由于这些NAb靶向动脉粥样硬化病变中普遍存在的氧化脂质，因此这些研究应确定这些氧化部分在介导炎症和动脉粥样硬化形成中的重要性。具体目标3将检验以下假设：B-1细胞的生命功能，例如NAb的增殖和分泌由TLR正调控，而核受体GR和LXR负调控B-1细胞。我们将确定这些免疫调节剂的转录调控B-1细胞相比，B-2细胞和巨噬细胞的影响，提供一个更好的理解这些免疫细胞调节剂的综合反应。这些研究应该对先天免疫在炎症和动脉粥样硬化中的重要作用产生新的见解，并可能导致CVD的新诊断和治疗方法。

Innate Immunity plays a fundamental role in atherogenesis and our work has provided an improved understanding of this by demonstrating that "oxidation-specific epitopes" (OSE), which are generated on oxidatively damaged molecular complexes, such as OxLDL and apoptotic cells, are major targets of innate pattern recognition receptors, such as lgM Natural Antibodies (NAbs). During the first cycle, we demonstrated that 20-30% of all lgM NAbs bind to OSE in both mice and humans, and we proposed that lgM OSE-NAbs have been conserved to provide homeostasis to the many OSE generated in both health and disease. Considerable data support an atheroprotective role for lgM in murine models and lgM titers in humans are inversely related to cardiovascular disease (CVD). In the renewal, we will focus on understanding the role of NAbs in mice and humans, and define the mechanisms that regulate 8-1 cells that generate NAbs. Specific Aim 1 will define the repertoire and prevalence of OSE NAbs in mice and humans. We will generate a B-1 cell derived database of lgM NAb heavy chain variable (IGHV) CDR3 sequences and their relative expression in both humans and mice. We will then sort OSE-B-1 cells to annotate OSE NAbs, and will examine their relative expression under experimental models of inflammation and atherosclerosis in mice, and in epidemiological studies in humans. Specific Aim 2 will define the roles of OSE NAbs and B-1 cells in inflammation and atherogenesis. Using transgenic mice expressing OSE antibodies, we will seek to define the mechanisms by which OSE-Abs influence inflammation and atherosclerosis. Because these NAbs target prevalent oxidized lipids in atherosclerotic lesions, these studies should define the importance of these oxidized moieties in mediating inflammation and atherogenesis. Specific aim 3 will test the hypothesis that vital functions of B-1 cells, such as proliferation and secretion of NAbs are positively regulated by TLRs, while the nuclear receptors GRand LXR negatively regulate B-1 cells. We will determine the impact of these immune modulators on transcriptional regulation of B-1 cells in comparison to B-2 cells and macrophages, to provide an improved understanding of the integrated responses to these immune cell regulators. These studies should yield new insights into the important role that innate immunity plays in inflammation and atherosclerosis, and may lead to novel diagnostic and therapeutic approaches for CVD.