TIGIT通过上调Tph细胞IL-21促进IgG4相关性疾病浆细胞分化的机制研究

IgG4相关性疾病(IgG4-RD)是以多发脏器肿大和功能衰竭为表现的自身免疫疾病。IgG4+浆细胞异常分化是疾病发生的关键，该过程受CD4+T细胞及其细胞因子调控，但具体机制不清。我们通过IgG4-RD后腹膜组织单细胞转录组测序，发现组织中外周辅助T(Tph)细胞比例显著升高伴免疫调节受体TIGIT和IL21高表达；外周血TIGIT+Tph比例与疾病活动性密切相关；CD4+T细胞敲减TIGIT后IL21表达降低、且抑制浆细胞分化。因此，我们推测TIGIT通过上调Tph细胞IL21介导浆细胞分化，促进IgG4-RD发生。本研究拟在组织和外周血中明确TIGIT+Tph与疾病活动性、IL21及IgG4水平的相关性；细胞水平明确TIGIT上调Tph细胞IL21促进浆细胞分化的分子机制；明确TIGIT单抗抑制IgG4-RD浆细胞分化的作用，为明确IgG4-RD的发病机制及探索新型治疗靶点提供依据。

IgG4-related disease (IgG4-RD) is an autoimmune disease characterized by multiple organ enlargement and organ failure. Abnormal differentiation of IgG4+ plasma cells is the key to the occurrence and development of the disease. This process is regulated by CD4+ T cells, but the specific mechanism is unclear. Through Single-cell RNA-sequencing (scRNA-seq) of human IgG4-RD retroperitoneal tissue, we found that the proportion of peripheral helper T (Tph) cells in the tissue was significantly increased with high expression of immune regulatory receptors TIGIT and cytokine IL21. The proportion of TIGIT+Tph in the peripheral blood was found to be positively correlated with the disease activity of IgG4-RD. After TIGIT knockdown, the IL21 expression of CD4+T cells was reduced, and the ability of CD4+T cell to promote plasma cell differentiation was weakened. Therefore, we speculate that TIGIT mediates plasma cell differentiation by upregulating IL21 in Tph cells, therefore promoting the occurrence of IgG4-RD. This study intends to determine the correlation between the proportion of TIGIT+Tph cell and the disease activity, the IgG4 level, and the IL21 level in both the tissues and the peripheral blood; in vitro, we aim to clarify the molecular mechanism that TIGIT up-regulates the expression of IL21 in Tph cell leading to plasma cell differentiation; we aim to clarify that TIGIT monoclonal antibody inhibits plasma cell differentiation in IgG4-RD, in order to provide a basis for clarifying the pathogenesis of IgG4-RD and new targeted therapy.