NK-like B细胞（NKB）在类风湿关节炎发病中的作用及机制研究

类风湿关节炎（RA）是一种高致残性自身免疫病，B细胞异常活化是其发病核心环节。除了经典B细胞，新的B细胞亚群不断被发现。本课题组长期从事B细胞在RA发病中的作用及机制研究，证实了数种新型B细胞亚群功能异常促进RA发病。免疫学家最新研究发现了一群同时具有NK和B细胞表型的细胞-NK-like B细胞（NKB），参与天然免疫反应。我们预实验发现，RA状态下人和小鼠NKB细胞均明显扩增，过继转移NKB细胞加重关节炎小鼠的症状，提示其参与RA发病。作为一类重要的新型天然样B细胞，NKB细胞在RA发病中的具体作用及机制亟待深入。在此基础上，本项目拟利用RA患者标本和胶原诱导性关节炎模型小鼠，系统性研究NKB细胞在RA中的致病作用及机制，揭示其数量、免疫学表型、转录组、代谢组、BCR repertoire及功能的变化，并探讨潜在分子机制和信号通路，从而为深入理解RA发病机制和寻找新的治疗策略进行探索。

Rheumatoid arthritis (RA) is a kind of disease that causes highly progressive disability. B cells play crucial roles in the pathogenesis of RA. Besides classic subsets, new B cell subsets have also been recognized gradually. Our team has long been studying the role of B cells in the pathogenesis of RA, proving that the functional abnormality of kinds of new B cell subsets promoted RA initiation and progression. Just recently, a new cell subset demonstrating both the phenotype of NK cells and B cells was identified, namely natural killer-like B cells (NKB), and was proved to be involved in the anti-microbial innate immunity. Our preliminary results showed that under RA circumstance, both human and mouse NKB cells expanded dramatically, and adoptive transfer of NKB cells exacerbated the severity of the arthritic mice, indicating their pathogenic roles in RA pathogenesis. As an essential novel innate-like B cell subset, the detailed functions of NKB cells in RA pathogenesis and the underlying mechanism need to be studied. In this study, using RA patient specimens as well as arthritis mice, we will systemically explore the role of NKB cells in RA pathogenesis. The frequencies, the immune phenotypes, the transcriptome, the metabonome, the BCR repertoire as well as the pathogenic functions of NKB cells will be studied, and the potential underlying molecular mechanisms and signaling pathways will be discussed. This will not only help us better understand the pathogenesis mechanism of RA, but also assist us finding novel therapeutic strategies for the disease.