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

随着年龄的增长，免疫反应降低，包括B淋巴细胞及其子代，抗体- 分泌性疾病(ASC)是老年人口死亡率和发病率的主要因素。这是可以看到的 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，如 癌症和自身免疫。年龄相关性B细胞功能下降与慢性低度恶性疾病有关 炎症并与脂肪、内脏脂肪组织(VAT)的增加相关。尽管它的公共卫生 重要的是，B细胞功能下降的根本原因尚不清楚。我们最近做了 结果表明，衰老/老龄小鼠体内抗体反应较低时，VAT增加，且 脂肪细胞衍生的分子不仅可能招募免疫细胞，还可能参与炎症反应 进程。我们在小鼠身上的初步数据显示，免疫细胞在VAT中渗透，更高比例的PRO- 炎性B细胞(年龄相关的B细胞，ABC)和T细胞(γδ，γ-增量)，以及更高数量的 IgG2c亚类，与自身免疫抗体相关。 我们假设增值税是炎性B(和T)细胞的重要生成者 导致老年人免疫系统功能障碍。我们的初步数据显示，脂肪细胞 分泌趋化因子，可吸引B细胞进入增值税，其相应的受体是 由VAT B细胞表达。在这项提案中，目标1将确定脂肪组织是否对 观察到老年/肥胖小鼠B细胞亚群的表型和功能变化。包括在这些文件中 研究将测试促进促炎性B细胞亚群通过与来自 用同一只小鼠的脾B细胞进行增值税。我们的初步数据显示， 炎症性ABC的相对百分比，与我们在增值税中观察到的类似。我们还将 确认脂肪细胞是否产生几种促炎趋化因子，以及是否存在自身抗体 自身抗原的增值税。在目标2中，我们将确定代谢途径中的哪些变化是导致 机械性肥胖对饮食诱导肥胖小鼠抗体反应的影响 DIO患者和对照组线粒体功能的研究及其与体外B细胞反应的关系。An In 对NP-OVA的活体反应也将在DIO小鼠中进行测量。在目标3中，我们将确定ABC是否正在制作 自身免疫抗体和较少保护性抗体(比滤泡B细胞)对体内的反应 抗原刺激并进行干预，以确定如何改善这一点。这些研究将会有所帮助 为了确定肥胖相关炎症变化的机制，这些变化如何降低 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。在……结束时 我们的研究将扩大我们对炎症产生B细胞的机制的了解 老龄化/肥胖方面的不足，并确定了改善这些缺陷的候选战略。

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.