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.

随着衰老的衰老，免疫响应减少，包括B淋巴细胞及其进展及其抗体 - 分泌（ASC）是造成古老人口死亡率和发病率的主要贡献者。这可以看见通过增加感染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。 B细胞功能与年龄相关的降低与慢性低级有关炎症，与脂肪，内脏脂肪组织（VAT）的增加有关。尽管有公共卫生重要的是，B细胞功能降低的根本原因尚不清楚。我们最近有表明年龄/旧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能募集免疫细胞，而且有助于炎症过程。我们在小鼠中的初步数据显示，在增值税中浸润的免疫细胞，较高百分比炎性B细胞（与年龄相关的B细胞，ABC）和T细胞（γδ，伽马 - 戴尔塔），以及较高量的 IgG2C亚类，与自身免疫抗体有关。我们假设增值税是炎症B（和T）细胞的重要发生器导致老年免疫系统功能障碍。我们的初步数据表明脂肪细胞秘密趋化因子可以吸引B细胞进入桶，相应的接收器为由增值税B细胞表达。在此提案中，AIM 1将确定脂肪组织是否有助于在老年/肥胖小鼠中观察到的B细胞子集的表型和功能变化。其中包括在其中研究将测试通过从带有来自同一小鼠的脾B细胞的增值税。我们的初步数据显示炎症性ABC的相对百分比，类似于我们在增值税中观察到的。我们也会确认脂肪细胞是否产生几种促炎性趋化因子，并且是否存在自身抗体自我抗原的增值税。在AIM 2中，我们将确定代谢途径的哪些变化负责通过机械性的DIO（饮食引起的肥胖症）的小鼠的抗体反应降低关于DIO和对照中线粒体功能的研究，并与体外B细胞反应相关。一个在DIO小鼠中也将测量对NP-ova的体内反应。在AIM 3中，我们将确定ABC是否正在制作自身免疫性抗体和较少受保护的抗体（而不是fo，follicular b细胞）响应体内抗原刺激并进行干预以确定如何改善。这些研究将有助于为了确定与肥胖相关炎症变化的机制，这些机制如何降低免疫系统以及我们是否可以恢复老年和肥胖小鼠的B细胞功能。结束我们的研究将扩大对产生B细胞炎症机制的知识衰老/肥胖症的缺陷和确定候选策略的改善。