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

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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 naïve 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.

Original languageEnglish (US)
JournalClinical Reviews in Allergy and Immunology
StateAccepted/In press - 2020


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

ASJC Scopus subject areas

  • Immunology and Allergy


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