How do obesity and related inflammation decrease antibody responses in aging?

肥胖和相关炎症如何降低衰老过程中的抗体反应？

基本信息

批准号：
10251000
负责人：
BONNIE B. BLOMBERG
金额：
$ 36.07万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251000
关键词：
Address Adipocytes Adipose tissue Affinity Age Aging Anti-Inflammatory Agents Antibodies Antibody Affinity Antibody Response Antibody-Producing Cells Antigens Antioxidants Autoantibodies Autoantigens Autoimmunity B-Lymphocyte Subsets B-Lymphocytes Cell physiology Cells Chronic Coculture Techniques Conditioned Culture Media Data Defect Disease Elderly Fatty acid glycerol esters Functional disorder High Fat Diet Human Immune Immune response Immune system Immunoglobulin Class Switching Immunoglobulin G Immunoglobulins In Vitro Infection Inflammation Inflammation Mediators Inflammatory Intervention Knowledge Ligands Lymphocyte Malignant Neoplasms Measures Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Morbidity - disease rate Mus Obese Mice Obesity Pathway interactions Phenotype Plant Roots Population Process Public Health Publishing Regulation Serum Signaling Molecule Spleen T-Lymphocyte T-Lymphocyte Subsets TNF gene Testing Thinness Tumor-infiltrating immune cells Vaccination Visceral age effect age related aged base cell age chemokine cytokine diet-induced obesity human old age (65+)humoral immunity deficiency immune system function improved improved functioning in vitro Assay in vivo inflammatory marker lipid biosynthesis mortality receptor recruit response transcription factor vaccine response γδ T cells

项目摘要

Decreases in the immune response with aging, including B lymphocytes and their progeny, antibody- secreting (ASC), are a major contributor to mortality and morbidity in the elderly population. This can be seen by increased infections and lower response to vaccination as well as an increase in various diseases such as cancer and autoimmunity. The age-related decrease in B cell function is associated with chronic low-grade inflammation and associated with an increase in fat, visceral adipose tissue (VAT). Despite its public health importance, the root causes of this decrease in B cell function are not well understood. We have recently shown that aged/old mice have increased VAT associated with lower in vivo antibody response, and adipocyte-derived molecules may not only recruit immune cells but also contribute to the inflammatory process. Our preliminary data in mice show infiltrating immune cells in the VAT, higher percentages of pro- inflammatory B cells (Age-associated B Cells, ABC) and T cells (γδ, gamma-delta), and higher amounts of the IgG2c subclass, associated with autoimmune antibodies. We hypothesize that the VAT is an important generator of inflammatory B (and T) cells which contributes to the dysfunction of the aged immune system. Our preliminary data show that adipocytes secrete chemokines which could attract B cells to the VAT and for which the corresponding receptors are expressed by VAT B cells. In this proposal, Aim 1 will determine if the adipose tissue is contributing to the phenotypic and functional changes in B cell subsets observed in older/obese mice. Included in these studies will be testing for the promotion of pro-inflammatory B cell subsets by co-culture of adipocytes from the VAT with splenic B cells from the same mice. Our preliminary data for this show an increase in the relative percentage of the inflammatory ABC, similar to what we have observed in the VAT. We will also confirm if adipocytes produce several pro-inflammatory chemokines and if there are autoantibodies in the VAT for self-antigens. In Aim 2 we will determine which changes in metabolic pathways are responsible for the reduced antibody responses in mice undergoing DIO (diet-induced obesity) by doing mechanistic studies on mitochondrial function in DIO and controls and associating with an in vitro B cell response. An in vivo response to NP-OVA will also be measured in DIO mice. In Aim 3 we will determine if ABC are making autoimmune antibodies and less protective antibodies (than FO, follicular B cells) in response to in vivo antigen stimulation and do interventions to determine how that might be improved. These studies will help to determine mechanisms for obesity-related changes in inflammation, how these decrease the function of the immune system and if we can restore B cell function in the aged and obese mice. At the conclusion of our studies we will have expanded our knowledge of mechanisms for inflammation generating B cell deficiencies in aging/obesity and identified candidate strategies for their improvement.

随着年龄的增长，免疫反应下降，包括 B 淋巴细胞及其后代、抗体- 分泌（ASC）是老年人群死亡率和发病率的主要原因。由于感染增加和对疫苗接种的反应降低以及各种疾病的增加，例如癌症和自身免疫性与年龄相关的 B 细胞功能下降与慢性低度恶性相关。炎症并与脂肪、内脏脂肪组织（VAT）增加有关，尽管它对公共健康有益。重要性，但我们最近尚不清楚 B 细胞功能下降的根本原因。表明老年小鼠的增值税增加与体内抗体反应较低相关，并且脂肪细胞衍生的分子不仅可以招募免疫细胞，还可以促进炎症我们在小鼠身上的初步数据显示，VAT 中的免疫细胞浸润，亲细胞比例较高。炎症 B 细胞（年龄相关 B 细胞，ABC）和 T 细胞（γδ，gamma-delta），以及更高含量的 IgG2c 亚类，与自身免疫抗体相关。我们认为 VAT 是炎症 B（和 T）细胞的重要产生者，我们的初步数据表明，脂肪细胞会导致衰老的免疫系统功能障碍。分泌趋化因子，可以吸引 B 细胞到 VAT，并且相应的受体是在该提案中，目标 1 将确定脂肪组织是否有助于在老年/肥胖小鼠中观察到 B 细胞亚群的表型和功能变化。研究将通过共培养脂肪细胞来测试促炎 B 细胞亚群的促进作用我们的初步数据表明，来自同一小鼠的脾 B 细胞的 VAT 有所增加。炎症 ABC 的相对百分比，与我们在增值税中观察到的类似。确认脂肪细胞是否产生多种促炎趋化因子以及脂肪细胞中是否存在自身抗体自身抗原的增值税在目标 2 中，我们将确定代谢途径的哪些变化是造成的。通过执行 DIO（饮食诱导肥胖）小鼠的机制，抗体反应减少研究 DIO 和对照中的线粒体功能以及与体外 B 细胞反应的相关性。还将在 DIO 小鼠中测量对 NP-OVA 的体内反应，在目标 3 中，我们将确定 ABC 是否正在产生。自身免疫抗体和保护性较低的抗体（比 FO、滤泡 B 细胞）对体内反应抗原刺激并进行干预以确定如何改进这些研究将有所帮助。确定与肥胖相关的炎症变化的机制，这些变化如何降低炎症的功能免疫系统以及我们能否恢复衰老和肥胖小鼠的 B 细胞功能。我们的研究将扩展我们对 B 细胞炎症生成机制的了解衰老/肥胖方面的缺陷，并确定了改进的候选策略。