滤泡辅助性T细胞通过ICOS途径介导的B细胞活化在年龄相关性黄斑变性中的作用和机制研究

Inflammatory response of the immune system is an important factor involved in the occurrence and development of age-related macular degeneration (AMD), but the relationship between B cell-mediated humoral immunity and AMD is still unknown. Our previous study found that B cells in patients with AMD showed activated status, and IgA level in tears and serum was elevated. Further analyses revealed that AMD patients presented follicular T helper T cells (Tfh) subtype disorder, whereas Tfh cells play an important role in regulating the function of B cells. In addition, recent studies have confirmed that the ICOS pathway is a critical factor in the regulation of Tfh cells. Therefore, we hypothesize that Tfh-induced B cell activation through ICOS pathway involves in the pathogenesis and progression of AMD. In this study, we will comprehensively investigate the function of B cells in AMD patients through the detection of B-cell related factors in aqueous humor and peripheral blood and cell experiments in vitro. We will examine the changes of Tfh cell number in AMD patients and the regulation of Tfh cells on B cells through flow cytometry and cell culture experiments. We will determine the regulatory mechanism of ICOS signaling pathway on Tfh cells through pathway stimulation and blocking experiments. Based on this research, we plan to identify the mechanism of Tfh modulating B cell activation through ICOS in AMD. This study will provide theoretical and scientific evidence for developing novel immunotherapies of AMD.

免疫炎症是参与年龄相关性黄斑变性（AMD）发生发展的重要因素，但B细胞介导的体液免疫与AMD的关系尚不明了。课题组前期研究发现：AMD患者体内B细胞呈现激活状态，泪液及血清中IgA水平上升；进一步研究发现AMD患者滤泡辅助性T细胞（Tfh）的亚型紊乱，而Tfh对B细胞的功能起重要调控作用。此外，近年研究证实，ICOS通路对Tfh有重要调控作用。因此我们提出科学假设：Tfh通过ICOS途径介导的B细胞活化参与AMD的发生发展。本课题拟通过房水及外周血B细胞相关因子检测与体外细胞实验，全面了解AMD患者B细胞的功能；采用流式细胞和细胞培养等实验，探究AMD患者Tfh的数量改变以及Tfh对B细胞的调控作用；利用通路刺激与阻断实验，明确ICOS信号通路对Tfh的调控机理。通过以上研究，全面探明Tfh通过ICOS途径介导的B细胞活化在AMD中的作用机制，为开发新型免疫疗法提供理论基础和科学依据。

免疫炎症是参与年龄相关性黄斑变性（AMD）发生发展的重要因素，但B细胞介导的体液免疫与AMD的关系尚不明确。本课题首先通过泪液及外周血抗体检测和体外细胞实验，发现AMD患者泪液及血清中IgA水平明显升高、外周血浆母细胞比例也显著升高，且与AMD严重程度呈正相关，表明AMD患者体内B细胞呈现激活状态；其次，基于Tfh对B细胞功能的重要调控作用，全面检测了AMD患者外周血Tfh细胞的数量、亚型及其功能，发现AMD患者体内Tfh细胞数量显著增多且功能紊乱，同时Tfh细胞高表达ICOS、PD-1及细胞因子IL-21与IL-17，表明AMD患者的Tfh细胞处于活化的状态；最后，通过细胞共培养与细胞因子中和等实验，证实Tfh细胞的活化通过IL-21途径促进B细胞产生过量抗体，导致AMD的发生发展。通过以上研究，全面探明了Tfh调控B细胞活化诱导AMD的作用及机制，为开发新型免疫疗法提供理论基础和科学依据。