SPMs, linoleic acid, and antibody levels in obesity

项目总结 许多研究已经定义了肥胖如何损害慢性炎症。相比之下，人们对此知之甚少。 肥胖如何损害体液免疫，体液免疫是产生抗体的罪魁祸首。建立基础 考虑到肥胖者的增加，将肥胖与抗体产生受损联系起来的因素是至关重要的 对病毒/细菌感染的敏感性和对不同疫苗的不良反应。在分子水平上， 抗体的产生在一定程度上受到专门的亲解介体(SPM)的调节。SPM是强大的 由多不饱和脂肪酸合成的免疫拆分剂，如二十二碳六烯酸(DHA)。我们和 其他人发现，从DHA合成的SPM可以促进流感感染时抗体的产生，并 接种疫苗。此外，DHA衍生的SPM在肥胖方面存在缺陷，并与 肥胖小鼠体内的亚油酸。亚油酸在西方饮食中含量极其丰富，这可能是一个主要原因 为什么肥胖者的SPM不足。总而言之，我们的数据让我们检验了肥胖的中心假设 在接种流感疫苗时不能有效产生抗体的受试者减少了循环。 DHA衍生的SPM水平和亚油酸水平的增加。为了解决这一假设，我们将依靠 对一项大型临床研究中储存的血液样本的分析，在该研究中，受试者被分层为应答者 (即产生抗体的瘦和肥胖个体)和无反应者(即产生抗体的瘦和肥胖受试者 没有有效地产生抗体)的季节性三价灭活流感疫苗。该方法 将依赖于基于质谱学的代谢物脂肪分析，火焰离子化的气相色谱 检测和ELISA。影响：这项提案将在受损的抗体产生之间建立关键联系 和人类水平的肥胖症。这将为今后SPM的机理研究和研究奠定基础 和亚油酸作为人类潜在的可修改变量来改善对病毒的反应结果 感染/疫苗接种。这项提案的完成将使人们对一个主要的公共卫生负担有了深入的了解， 这是一种传染病(流感)和一种非传染性疾病(肥胖症)的融合。

PROJECT SUMMARY Numerous studies have defined how obesity impairs chronic inflammation. In contrast, far less is known about how obesity impairs humoral immunity, which is responsible for antibody production. Establishing underlying factors that link obesity with impaired antibody production is critical given that obese individuals have increased susceptibility to viral/bacterial infections and poor responses to differing vaccinations. At a molecular level, antibody production is regulated, in part, by specialized pro-resolving mediators (SPMs). SPMs are potent immunoresolvants synthesized from polyunsaturated fatty acids such as docosahexaenoic acid (DHA). We and others have found that SPMs synthesized from DHA boost antibody production upon influenza infection and vaccination. Furthermore, DHA-derived SPMs are deficient in obesity and associated with an elevation in linoleic acid in obese mice. Linoleic acid is extremely abundant in the western diet and may be a major reason why SPMs are deficient in the obese. Collectively, our data lead us to test the central hypothesis that obese subjects that do not effectively produce antibodies upon influenza vaccination have decreased circulating levels of DHA-derived SPMs and increased levels of linoleic acid. To address this hypothesis, we will rely on analyses of blood samples stored from a large clinical study in which subjects were stratified as responders (i.e. lean and obese individuals that produced antibody) and non-responders (i.e. lean and obese subjects that did not effectively produce antibody) upon the seasonal trivalent inactivated influenza vaccine. The approach will rely on mass spectrometry based metabololipidomic analyses, gas chromatography with flame ionization detection, and ELISAs. Impact: This proposal will establish key links between impaired antibody production and obesity at the human level. This will set the basis for future mechanistic studies and investigation of SPMs and linoleic acid as potential modifiable variables in humans to improve outcomes in response to viral infections/vaccinations. Completion of this proposal will had provided insight into a major public health burden, which is the convergence of an infectious disease (influenza) with a noncommunicable disease (obesity).