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

随着年龄的增长，免疫反应减少，包括B淋巴细胞及其后代，抗体- 分泌型糖尿病（ASC）是老年人群死亡率和发病率的主要原因。这可以看作 感染增加，对疫苗接种的反应降低，以及各种疾病的增加， 癌症和自身免疫与年龄相关的B细胞功能下降与慢性低级别 炎症，并与脂肪，内脏脂肪组织（VAT）的增加有关。尽管它的公共卫生 重要的是，这种B细胞功能下降的根本原因还没有很好地理解。我们最近 显示老龄/老年小鼠具有与较低的体内抗体应答相关的增加的VAT，并且 脂肪细胞衍生的分子不仅可以募集免疫细胞， 过程我们在小鼠中的初步数据显示，VAT中浸润的免疫细胞， 炎性B细胞（炎症相关B细胞，ABC）和T细胞（γ δ，γ-δ），以及更高量的 IgG2c亚类，与自身免疫抗体相关。 我们假设VAT是炎症B（和T）细胞的重要产生者， 会导致老年人免疫系统的功能障碍。我们的初步数据显示脂肪细胞 分泌趋化因子，其可以将B细胞吸引到VAT，并且相应的受体是 由VAT B细胞表达。在该提案中，目标1将确定脂肪组织是否有助于 在老年/肥胖小鼠中观察到的B细胞亚群的表型和功能变化。列入这些 研究将测试通过共培养脂肪细胞促进促炎性B细胞亚群， 用来自相同小鼠的脾B细胞进行VAT。我们的初步数据显示， 炎性ABC的相对百分比，与我们在VAT中观察到的相似。我们还将 确认脂肪细胞是否产生几种促炎趋化因子， 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 通过进行机械性免疫抑制， DIO和对照中线粒体功能的研究以及与体外B细胞应答的相关性。的in 还将在DIO小鼠中测量对NP-OVA的体内应答。在目标3中，我们将确定ABC是否正在 自身免疫抗体和较少的保护性抗体（比FO，滤泡B细胞），以响应体内 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 免疫系统以及我们是否能恢复老年和肥胖小鼠的B细胞功能。结束时 我们的研究将扩大我们对炎症产生B细胞的机制的认识 衰老/肥胖的缺陷，并确定了改善这些缺陷的候选策略。

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.