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

描述(申请人提供)：高脂肪饮食和持久的肥胖对狼疮患者构成比普通人群更危险的威胁。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。高脂肪的西方饮食和加速的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肥胖患者的免疫功能，减少炎症。大量人群无法健康饮食意味着有必要探索狼疮患者饮食引起的心血管疾病的医学干预措施。然而，高脂饮食如何扰乱免疫系统的分子和细胞机制仍不清楚，从而阻碍了有效的治疗。B1B细胞直接存在于腹膜腔和大网膜。 接触积聚和发炎的内脏脂肪组织。B1B细胞是天然IgM抗体的来源，这种抗体通过掩盖氧化的低密度脂蛋白，抑制巨噬细胞的摄取和防止泡沫细胞的形成来保护动脉粥样硬化。饮食对B1B细胞的影响可能导致动脉粥样硬化加速，但从未被研究过。基于我们的初步研究，这项建议旨在检验高脂肪西式饮食和慢性 肥胖可能会过度刺激和解除B1 B细胞的武装。更糟糕的是，它可能会将保护性的B1B细胞转变为自我攻击的B细胞。这项研究的结果将揭示饮食诱导关节硬化的新的分子和细胞机制，并为未来B细胞靶向免疫治疗的设计提供新的途径。创新：这是一项新的研究，首次将B1B细胞作为饮食诱导的肥胖和动脉粥样硬化之间的联系进行了研究。高脂饮食刺激的B1B细胞可能会改变炎症和调节T细胞的平衡这一新概念将通过一个新的动物模型进行测试。一种新开发的分析方法将取代传统的基于流式细胞术的B1 B细胞分析，这将给B1 B细胞的研究带来革命性的变化。短期高脂西方饮食可能激活B1B细胞 产生抗动脉粥样硬化的IgM、细胞因子，促进Treg细胞分化。然而，长期的西方饮食消费和肥胖会将保护性的B1细胞假说转变为促炎反应，从而导致动脉粥样硬化的加重。具体目标：目标1：确定饮食诱导的肥胖在多大程度上失调B1 B细胞功能~目标2：确定肥胖GLD/ApoE-/-小鼠的B1细胞如何影响Treg与Th17的平衡。影响：我们建议调查一个重要但尚未探索的免疫学成分，它可能是狼疮患者饮食诱导肥胖和心脏病之间的关键中介。这项研究的结果将揭开腹部和大网膜乳斑中B1B淋巴细胞的独特之处，并将提供一种新的机制，以及对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。 与公共卫生相关：肥胖会加剧炎症，增加心脏病的风险，从而对狼疮患者构成严重的生命威胁。这一建议旨在验证一种假说，即长期摄入高脂肪的西方饮食，从而导致腹部内脏脂肪的沉积可能会过度刺激腹腔中的B1B细胞，从而失去它们的动脉粥样硬化保护免疫功能。这一研究结果将为未来设计B细胞靶向免疫疗法以减少狼疮患者的炎症性心脏病提供理论基础。

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. PUBLIC HEALTH RELEVANCE: Obesity poses a severe life threat in lupus patients by escalating inflammation and increasing the risk of heart diseases. This proposal aims to test the hypothesis that chronic consumption of high fat western diet and consequently, the deposition of abdominal visceral fat may over- stimulate B1 B cells in the abdominal cavity and as a result, lose their atheroprotective immunologic functions. The result of ths study will provide a rationale for future design of B cell- targeted immune therapy to reduce inflammatory heart diseases in lupus patients.