TY - JOUR
T1 - Interleukin-35 Promotes Th9 Cell Differentiation in IgG4-Related Disorders
T2 - Experimental Data and Review of the Literature
AU - Zhang, Jun
AU - Lian, Min
AU - Li, Bo
AU - Gao, Lixia
AU - Tanaka, Toshihiro
AU - You, Zhengrui
AU - Wei, Yiran
AU - Chen, Yong
AU - Li, Yikang
AU - Li, You
AU - Huang, Bingyuan
AU - Tang, Ruqi
AU - Wang, Qixia
AU - Miao, Qi
AU - Peng, Yanshen
AU - Fang, Jingyuan
AU - Lian, Zhexiong
AU - Okazaki, Kazuichi
AU - Xiao, Xiao
AU - Zhang, Weici
AU - Ma, Xiong
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - IgG4-related disease
KW - Interleukin-35
KW - Th9 cell
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UR - http://www.scopus.com/inward/citedby.url?scp=85088561048&partnerID=8YFLogxK
U2 - 10.1007/s12016-020-08803-8
DO - 10.1007/s12016-020-08803-8
M3 - Article
AN - SCOPUS:85088561048
JO - Clinical Reviews in Allergy and Immunology
JF - Clinical Reviews in Allergy and Immunology
SN - 1080-0549
ER -