B1 B cells in abdominal obesity and diet-accelerated atherosclerosis in SLE

描述（由申请人提供）：高脂肪饮食和持久的肥胖对狼疮患者造成的威胁比一般人群更危险。肥胖的狼疮患者表现出更高的炎症标志物和心脏病发作的风险。高脂肪西方饮食和加速动脉粥样硬化之间的联系在临床上得到了很好的证实。最近的研究还表明，健康的饮食模式可以增强免疫功能，减少肥胖患者的炎症。大量人群无法健康饮食意味着需要探索狼疮患者饮食诱导的心血管疾病的医学干预措施。然而，高脂饮食如何失调免疫系统的分子和细胞机制仍然不清楚，从而阻碍了有效的治疗。B1 B细胞直接存在于腹膜腔和网膜中， 与积聚和发炎的内脏脂肪组织接触。B1 B细胞是天然IgM抗体的来源，该天然IgM抗体通过掩蔽氧化的LDL、抑制巨噬细胞的摄取和防止泡沫细胞形成来防止动脉粥样硬化。饮食对B1 B细胞的影响可能导致动脉粥样硬化的加速，但从未被研究过。基于我们的初步研究，本建议旨在验证高脂肪西方饮食和慢性 肥胖可能会过度刺激和解除B1 B细胞。更糟糕的是，它可能会将保护性的B1 B细胞转化为自我攻击的B细胞。本研究结果将揭示饮食诱导关节硬化症的分子和细胞机制，并为未来设计B细胞靶向免疫治疗提供新的途径。创新：这是一项新的研究，其中B1 B细胞首次被研究为饮食诱导的肥胖和动脉粥样硬化之间的联系。 高脂饮食刺激的B1 B细胞可能改变炎症和调节性T细胞的平衡这一新概念将使用一种新的动物模型进行测试。一种新开发的检测方法将取代传统的基于流式细胞术的B1 B细胞分析，这将彻底改变B1 B细胞研究。 短期高脂西方饮食可能会激活B1 B细胞， 产生抗动脉粥样硬化IgM、细胞因子并促进Treg细胞分化。 然而，长期西方饮食消费和肥胖会将保护性B1细胞的假设：功能转变为促炎反应，导致动脉粥样硬化的恶化。具体目标：目标一：确定饮食诱导的肥胖症失调B1 B细胞功能的程度~目的#2：确定肥胖gld/ApoE-/-小鼠的B1细胞如何影响Treg与Th 17平衡。 影响：我们建议调查一个重要的尚未探索的免疫成分，可能是饮食诱导的肥胖和心脏病之间的关键中介在狼疮患者。本研究的结果将揭示腹腔和网膜乳斑中B1 B淋巴细胞的独特方面，并将提供一种新的机制，以及B细胞介导的保护和发病机制的非静态观点。本研究所获得的知识将为今后B细胞的设计奠定基础 针对不同疾病阶段的亚人群进行风险评估、预防和治疗干预。

DESCRIPTION (provided by applicant): High fat diet and enduring obesity pose a more dangerous threat in lupus patients than in general population. Obese lupus patients show much higher inflammation markers and risk of heart attack. The link between high fat western diet and accelerated atherosclerosis is clinically well established. Recent studies also show evidence that healthy eating patterns enhance immune function and reduce inflammation in obese patients. The inability of a large population to eat healthy signifies the need to explore medical interventions for diet-induced cardiovascular diseases in lupus patients. However the molecular and cellular mechanism of how high fat diet dysregulates the immune system is still unclear and thus hindering efficient therapy. B1 B cells reside in the peritoneal cavity and omentum, in direct contact with accumulated and inflamed visceral adipose tissue. B1 B cells are the source of natural IgM antibodies that protect from atherosclerosis through masking oxidized LDL, inhibiting uptake by macrophage and preventing foam cell formation. Dietary effect on B1 B cells that may lead to accelerated atherosclerosis has never been studied. Based on our preliminary study, this proposal aims to test the hypothesis that high fat western diet and chronic obesity may over-stimulate and disarm B1 B cells. Even worse, it may transform protective B1 B cells into self-attacking B cells. The result of this study will reveal new molecular and cellular mechanisms underlying diet-induced arthrosclerosis and provide new avenues for future design of B cell-targeted immune therapy. INNOVATION: This is a novel study where B1 B cells are for the first time investigated as a link between diet-induced obesity and atherosclerosis. The novel concept that high-fat-diet-stimulated B1 B cells may alter the balance of inflammatory and regulatory T cells will be tested using a novel animal model. A newly developed assay will replace traditional flow cytometry-based analysis of B1 B cells that will revolutionize B1 B cell study. Short-term high fat western diet might activate B1 B cells to produce atheroprotective IgM, cytokines and promote Treg cell differentiation. However chronic western diet consumption and obesity would switch protective B1 cell HYPOTHESIS: functions to pro-inflammatory response leading to the aggravation of atherosclerosis. SPECIFIC AIMS: Aim #1: Determine the extent to which diet-induced obesity dysregulates B1 B cell functions~ Aim #2: Determine how B1 cells from obese gld/ApoE-/- mice may affect Treg vs. Th17 balance. IMPACT: We propose to investigate an important yet unexplored immunologic component that may be the key intermediary between diet-induced obesity and heart disease in lupus patients. The result of this study will unravel unique aspects of B1 B lymphocytes in the abdominal cavity and omental milky spots and will provide a novel mechanism, as well as a non-static view of B cell-mediated protection and pathogenesis. The knowledge obtained from this study will be fundamental for the future design of B cell subpopulation-tailored risk-assessment, prevention and therapeutic intervention at different disease stages.