滤泡性辅助性T细胞与寻常型银屑病免疫致病机制及疾病进展的关系研究

It is generally accepted that psoriasis is a T cell-mediated disease. Follicular helper T (Tfh) cells, a recently-identified subset of CD4+ T cells, have distinct functions from those of other T cell subsets. Previous studies have shown that IL-21 is the main functional cytokine of Tfh cells. We previously found that the frequency of Tfh cells was significantly increased in patients with psoriasis vulgaris, and the function of Tfh cells was activated; besides, the frequency of Tfh cells was also correlated with disease severity of psoriasis vulgaris. In addition, alterations in circulating Tfh cell subsets have significant effects on the progression of psoriasis vulgaris. Our data also showed that the level of IL-21 in serum was increased and correlated with disease severity of psoriasis vulgaris. However, how Tfh cells cause the progression of psoriasis remains unclear. Thus, we hypothesize that the activated Tfh cells secrete high level of IL-21, which subsequently may contribute to the proliferation and activation of keratinocytes, thus leading to the progression of psoriasis. We are currently demonstrating the hypothesis though using a longitudinal design to observe the dynamics of Tfh cell frequency, functions, subsets and their correlations with disease progression in patients with psoriasis. Then, we will confirm above hypothesis in vitro assay. Our study will shed new light on the immune pathogenesis of psoriasis and provide new targets for therapy.

滤泡性辅助性T细胞（Tfh）是一种新型CD4+T细胞亚群，与其他CD4+T细胞功能明显不同，主要功能性细胞因子为IL-21。我们已发表的多项前期研究分别显示：（1）银屑病患者中Tfh细胞频率明显升高，功能活化，与疾病严重程度密切相关；（2）银屑病患者中存在Tfh细胞亚群失衡现象，Tfh17细胞显著升高；（3）银屑病患者中IL-21水平显著升高，与疾病严重程度正相关。但目前尚不清楚Tfh细胞如何导致银屑病的发生发展。因此，我们假设在银屑病中活化的Tfh细胞通过分泌大量IL-21作用于角质形成细胞，导致其过度增殖和活化，进而引起银屑病的发生发展。目前我们正通过建立银屑病患者长期随访队列，分析Tfh细胞频率、功能、亚群与疾病进展的关系；再通过体外功能实验，阐明IL-21在Tfh细胞和角质形成细胞间相互作用的关键机制。旨在从T细胞层面补充银屑病免疫发病机制，为银屑病治疗提供新靶点。

滤泡性辅助性T细胞（Tfh）是一种新型CD4+T细胞亚群，与其他CD4+T细胞功能明显不同，主要功能性细胞因子为IL-21，目前在银屑病中研究尚少。为探讨Tfh细胞是否介导银屑病的发生发展，我们通过建立断面研究和随访研究，分析银屑病患者中Tfh细胞频率、功能、亚群的特征及其与疾病进展的关系；再通过细胞实验和动物实验，阐明Tfh细胞参与银屑病发病的关键机制。我们的研究结果显示：（1）银屑病患者中Tfh细胞频率明显升高，功能活化，且存在Tfh细胞亚群失衡现象，Tfh17细胞显著升高；（2）Tfh细胞与疾病严重程度密切相关，银屑病患者经有效治疗后，PASI评分降低，Tfh细胞频率降低，功能性分子表达降低；（3）Tfh细胞可通过IL-21促进角质形成细胞增殖，阻断IL-21后可抑制这种促进作用；（4）IL-21不仅可促进角质形成细胞增殖，并可上调IL-17A表达，加重银屑病炎症反应。因此，我们的研究从T细胞层面补充了银屑病免疫发病机制，为银屑病治疗提供了新型靶点。