南京医科大学Xiaoming Wang,Jingjing Chen和Nan Che共同合作近期取得重要工作进展，他们研究发现Jmjd1c能够使STAT3去甲基化以抑制浆细胞分化和类风湿性关节炎。相关论文2022年8月22日在线发表于《自然—免疫学》杂志上。

研究人员发现Jmjd1c（JmjC 结构域组蛋白去甲基化酶的成员）在B细胞中而非在其他免疫细胞中的表达保护小鼠免受类风湿性关节炎（RA）的侵害。在患有RA的人类中，B细胞中JMJD1C的表达水平与浆细胞频率和疾病严重程度呈负相关。从机制上讲，Jmjd1c去甲基化STAT3，而不是组蛋白底物，以抑制浆细胞分化。Jmjd1c缺失引起的STAT3 Lys140高甲基化抑制与磷酸酶Ptpn6的相互作用，导致异常持续的STAT3磷酸化和激活，进而促进浆细胞生成。缺乏Jmjd1c的生发中心B细胞也获得了显著增加的分化为浆细胞的倾向。STAT3 Lys140Arg点突变完全消除了Jmjd1c丢失引起的影响。B细胞中Jmjd1c过表达的小鼠表现出与Jmjd1c缺陷小鼠相反的表型。

总体而言，他们的研究揭示了Jmjd1c作为浆细胞分化和RA的关键调节因子，并且还强调了去甲基化修饰对B细胞中STAT3的重要性。

据介绍，适当调控B细胞向浆细胞分化对体液免疫至关重要，同时防止抗体介导的自身免疫。然而，潜在的机制，尤其是那些具有病理后果的机制，仍不清楚。

附：英文原文

Title: Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis

Author: Yin, Yuye, Yang, Xinyi, Wu, Shusheng, Ding, Xinyu, Zhu, Huamin, Long, Xuehui, Wang, Yuliang, Zhai, Sulan, Chen, Yun, Che, Nan, Chen, Jingjing, Wang, Xiaoming

Issue&Volume: 2022-08-22

Abstract: Appropriate regulation of B cell differentiation into plasma cells is essential for humoral immunity while preventing antibody-mediated autoimmunity; however, the underlying mechanisms, especially those with pathological consequences, remain unclear. Here, we found that the expression of Jmjd1c, a member of JmjC domain histone demethylase, in B cells but not in other immune cells, protected mice from rheumatoid arthritis (RA). In humans with RA, JMJD1C expression levels in B cells were negatively associated with plasma cell frequency and disease severity. Mechanistically, Jmjd1c demethylated STAT3, rather than histone substrate, to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibited the interaction with phosphatase Ptpn6 and resulted in abnormally sustained STAT3 phosphorylation and activity, which in turn promoted plasma cell generation. Germinal center B cells devoid of Jmjd1c also acquired strikingly increased propensity to differentiate into plasma cells. STAT3 Lys140Arg point mutation completely abrogated the effect caused by Jmjd1c loss. Mice with Jmjd1c overexpression in B cells exhibited opposite phenotypes to Jmjd1c-deficient mice. Overall, our study revealed Jmjd1c as a critical regulator of plasma cell differentiation and RA and also highlighted the importance of demethylation modification for STAT3 in B cells.

DOI: 10.1038/s41590-022-01287-y

Source: https://www.nature.com/articles/s41590-022-01287-y