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

B1 B 细胞在 SLE 患者腹部肥胖和饮食加速动脉粥样硬化中的作用

• 批准号: 8356807
• 负责人: Xuemei Zhong
• 金额: $ 19.01万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356807
• 关键词: Abdomen; Abdominal Cavity; Adipose tissue; Affect; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigens; Apolipoprotein E; Atherosclerosis; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biological Assay; Cardiovascular Diseases; Cell Communication; Cell Death; Cell Differentiation process; Cell physiology; Cells; Central obesity; Chronic; Consumption; Deposition; Diet; Disease; Eating; Epidemiology; Equilibrium; Fatty acid glycerol esters; Flow Cytometry; Foam Cells; Future; General Population; Greater sac of peritoneum; Heart Diseases; Homeostasis; Immune system; Immunity; Immunization; Immunoglobulin Class Switching; Immunoglobulin M; Immunoglobulins; Immunologics; Immunotherapy; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Intervention; Intestines; Keyhole Limpet Hemocyanin; Knock-in Mouse; Knowledge; Lead; Life; Ligands; Link; Lipoproteins; Location; Lupus; Masks; Mediating; Medical; Mesentery; Modeling; Molecular; Monitor; Mus; Myocardial Infarction; Obese Mice; Obesity; Omentum; Pathogenesis; Patients; Pattern; Peritoneal; Phosphorylcholine; Physiological; Play; Population; Prevalence; Prevention therapy; Preventive Intervention; Process; Regulatory T-Lymphocyte; Reporting; Risk; Risk Assessment; Risk Factors; Role; Saturated Fatty Acids; Serological; Site; Source; Spottings; Staging; Surface; Systemic Lupus Erythematosus; T cell differentiation; T-Lymphocyte; TLR2 gene; TLR4 gene; Testing; Therapeutic Intervention; Thymus Gland; Time; Tissues; Toll-like receptors; Undifferentiated; Visceral; Vitamin A; Woman; atheroprotective; base; cytokine; design; feeding; good diet; heart disease risk; high risk; immune function; inflammatory marker; macrophage; migration; novel; oxidized low density lipoprotein; prevent; receptor binding; research study; uptake

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.

描述（由申请人提供）：高脂肪饮食和持续肥胖对狼疮患者构成比一般人群更危险的威胁。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。高脂肪西方饮食与动脉粥样硬化加速之间的联系已在临床上得到充分证实。最近的研究也表明，健康的饮食模式可以增强肥胖患者的免疫功能，减少炎症。大量人口无法健康饮食意味着需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，高脂肪饮食失调免疫系统的分子和细胞机制尚不清楚，因此阻碍了有效的治疗。B1 B细胞直接存在于腹膜腔和网膜中