Regulation of primary and memory B cell vaccine responses in the elderly

 描述(由申请人提供)：衰老与个体建立保护性免疫反应的能力下降有关。尽管随着年龄的增长，T细胞和抗原提呈细胞的功能明显下降，但我们已经证明，老年人的B细胞存在固有缺陷，影响了他们对疫苗的反应。这些缺陷包括激活诱导型胞苷脱氨酶(AID)的减少，AID是类切换重组所必需的，而体细胞超突变是产生最佳抗体反应和免疫记忆所必需的。我们之前已经确定了B细胞特异性生物标记物，能够监测或预测个体对流感疫苗的反应。具体地说，免疫前测量的CpG应答AID、体外开关记忆B细胞百分率和B细胞胞浆肿瘤坏死因子-α与体内血清应答显著相关，因此我们提出将这些指标作为应答的预测标记物。在这笔赠款中，我们将测试老年人、接种疫苗无效的年轻个体以及感染呼吸道感染的人的B细胞功能、上述特异性标志物以及特殊的B和T细胞亚群是否受损。我们最近出人意料地发现，老年人对流感疫苗的B记忆反应可能不会减少，至少对重复接种疫苗是如此，目前的竞争性更新将通过探索老年人和年轻人B记忆和/或浆母细胞和浆细胞功能下降的机制来扩展我们之前对疫苗反应的研究。这项R01竞争性更新应用的目的是确定哪些B细胞亚群和B细胞特异性生物标志物负责和预测年轻人和老年人对流感疫苗的初级和体内记忆反应，以及特定T细胞亚群对此的贡献。我们将进一步确定导致老年人初级和记忆抗体反应下调的分子机制，包括候选转录因子和信号通路，炎症和血清微生物组和miRNAs的作用。最后，我们将继续我们的新的小分子研究，以改善老年人体外受损的B细胞反应。这些研究的重点是流感疫苗的反应，但应该与其他疫苗反应以及老年人和成人对照组的免疫反应的一般状态相关。这些研究的结果应该有助于预防传染病和改善生物生活质量。 在老年人身上。

 DESCRIPTION (provided by applicant): Aging is associated with a decline in the ability of the individual to mount protective immune responses. Although it is clear that T cells and antigen-presenting cells have decreased function with age, we have shown that elderly individuals have intrinsic defects in B cells, compromising their responses to vaccines. These defects include the reduction in activation-induced cytidine deaminase (AID), necessary for class switch recombination and somatic hypermutation which are both required for the generation of optimal antibody responses and immunological memory. We have previously identified B cell-specific biomarkers able to either monitor or predict the response of an individual to the influenza vaccine. Specifically, AID in response to CpG, the ex vivo percentage of switch memory B cells and B cell cytoplasmic TNF-a, all measured before vaccination, significantly correlate with the in vivo serum response and therefore we have proposed these as predictive markers of response. In this grant we will test whether B cell function, the specific markers above, and particulat B and T cell subsets are impaired in the elderly, in young individulas which do not respond to vaccination and in those that contract respiratory tract infections. We have recently unexpectedly found that the B memory response to the influenza vaccine may not be reduced in the elderly, at least to a repeated vaccine and the current competing renewal will extend our previous studies on the vaccine response by pursuing mechanisms for decrease in B memory and/or plasmablast and plasma cell function in elderly and younger individuals. Objectives of this R01 competing renewal application are to determine which B cell subsets and B cell-specific biomarkers are responsible for and predictive of the primary and memory in vivo responses to the influenza vaccine in young and elderly and the contribution of particular T cell subsets to this. We will determine further molecular mechanisms responsible for the down- regulation of primary and memory antibody responses in aged individuals, including candidate transcription factors and signaling pathways, contribution of inflammation and the serum microbiome and miRNAs. Lastly, we will continue our novel studies with small molecules to improve the impaired in vitro B cell responses in the elderly. These studies are focused on the influenza vaccine response but should be relevant for other vaccine responses as well as the general state of immune responsiveness in the elderly and the adult controls. The results of these studies should help to prevent infectious diseases and improve the biological quality of life in the elderly.