Interleukin-35 Promotes Th9 Cell Differentiation in IgG4-Related Disorders: Experimental Data and Review of the Literature

作者：Zhang, Jun; Lian, Min; Li, Bo; Gao, Lixia; Tanaka, Toshihiro; You, Zhengrui; Wei, Yiran; Chen, Yong; Li, Yikang; Li, You; Huang, Bingyuan; Tang, Ruqi; Wang, Qixia; Miao, Qi; Peng, Yanshen; Fang, Jingyuan; Lian, Zhexiong; Okazaki, Kazuichi; Xiao, Xiao^*; Zhang, Weici^*; Ma, Xiong^*

来源：Clinical Reviews in Allergy and Immunology, 2021, 60(1): 132-145.

DOI：10.1007/s12016-020-08803-8

• Interleukin-35
• Th9 cell
• IgG4-related disease

IgG4-related disease (IgG4-RD) is characterized by intense infiltration of IgG4-positive plasma cells in affected organs. However, the mechanisms acting in the immune responses in IgG4-RD are not fully understood. The aim of this study was to dissect the mechanism underlying the immunoglobulin class switch in IgG4-RD by addressing the crosstalk between IL-35-producing and Th9 cells. The expression level of IL-35 was examined in plasma samples from patients with hepatobiliary and/or pancreatic manifestations of IgG4-RD. Our data demonstrate that IgG4-RD patients exhibit significantly high-level productions of IL-35 as compared to disease and healthy controls. We detected the two subunits of IL-35, EBI3 and IL-12p35, in the two major affected organs, liver and pancreatic tissue, from IgG4-RD. The EBI3- and IL-12p35-positive cells were significantly higher in affected organs in IgG4-RD as compared to disease controls. The colocalization of EBI3 with CD19 and CD38, markers for B cells, suggest the presence of IL-35-producing B cells in affected organs in IgG4-RD. The effects of IL-35 in Th9 differentiation and IL-9 in production of immunoglobulin were then assessed. Surprisingly, IL-35 treatment promoted naive CD4 T cell differentiating towards Th9 cells through IRF4 signaling. As a consequence, IL-9 secreted by Th9 cells promoted the differentiation of plasma cells and production of IgG1 and IgG4, predominantly IgG4. In conclusion, our data demonstrate that IL-35 actively participates in the process of inflammation and plays an important role in Th9 differentiation resulting in an immunoglobulin class switch towards IgG4.

• 单位
  1; 河北医科大学; 上海交通大学