PD-1+Tfh细胞在IgG4相关性疾病中的作用机制探究

The typical immunological and pathological mechanism of IgG4 related disease(IgG4-RD)were the aberrant processes of GCs formation, B cell subsets, differentiation and antibodies secretion. Tfh cells provide critical ‘helper’ function in the process of inducing the activation and differentiation of B cells, promoting B cell activation, clonal expansion, Ig heavy chain isotype switching and somatic hypermutation. Our previous studies have found that the PD-1+Tfh cell subsets positively correlated to the serum levels of IgG and IgG4, the IgG4/IgG ratio, the number of involved organs and the frequency of (CD19+CD24-CD38hi) plasmablast/plasma cells, which could highly secret IgG4 antibodies, and these results were more prominent in involved tissues of IgG4-RD. Therefore, we speculated the important role of PD-1+Tfh cells in the pathgenesis of IgG4-RD, especially in the process of promoting GC B cells switched into plasmablast/plasma cells. While the specific function and mechanism were still not clear, urgently need us to further explore. In this study, we will deeply discuss the characteristic, related mechanism and function of PD-1+Tfh cell subsets from various aspects, including cell expression, singal pathway, gene expression profiles, transcriptional regulation, and function, which could provide betterunderstanding of the pathogenesis of IgG4-RD.

IgG4相关性疾病的主要免疫和病理学机制为生发中心B细胞增殖、分化、抗体分泌过程中的异常，而Tfh细胞主要功能为诱导B细胞分化浆细胞，在B细胞分泌抗体、抗体类别转换及体细胞高频突变过程中提供重要活化信号。我们前期研究发现PD-1+Tfh细胞亚群与患者血清IgG4，IgG，IgG4/IgG%，器官受累数目，以及异常高表达IgG4的（CD19+CD24-CD38hi）浆母细胞间均呈显著正相关性，且在受累组织中的表达尤为明显，从而推测PD-1+ Tfh细胞在IgG4-RD的发病机制中，尤其对促进GC中B细胞向分泌IgG4为主的浆细胞分化过程中可能起着关键的作用；但具体作用及相关机制并不清楚，亟待进一步研究，本课题将围绕PD-1+Tfh细胞，拟从细胞表达、信号通路、基因谱、转录调控、功能特性等各个方面进一步探索其在IgG4-RD中的作用机制，从而为IgG4-RD的发病机制提供新的思路。

本次研究通过流式细胞术检测发现IgG4-RD患者外周血Th1与Th2型细胞显著增多，Th1与Th2型细胞占比均升高的IgG4-RD患者疾病相对较重。通过组织水平以及单细胞水平的转录组测序技术并结合免疫组库信息，首次探究IgG4-RD受累局部的免疫学特征，深入解析IgG4-RD受累组织中T-B细胞间的相互作用，发现在IgG4-RD的受累组织中存在强烈的生发中心反应，同时可观察到显著增强的Th-2型应答相关信号，Th-1和Th2型反应的协同作用能促进IgG4-RD中促炎因子及胶原成分相关基因的表达，进而影响受累组织局部的免疫微环境，并促进纤维化。此外，通过单臂单中心研究，首次探索泰他西普治疗IgG4-RD患者的疗效，并基于患者的临床指标与免疫细胞亚群的变化趋势分析泰他西普在IgG4-RD中的具体作用机制，研究结果显示，泰他西普治疗IgG4-RD有一定的作用，但对非浆母细胞优势型患者疗效有限,为IgG4-RD的治疗提供新的选择。