%0 Journal Article
%T Interleukin-35 Promotes Th9 Cell Differentiation in IgG4-Related Disorders: Experimental Data and Review of the Literature.
%A Zhang J
%A Lian M
%A Li B
%A Gao L
%A Tanaka T
%A You Z
%A Wei Y
%A Chen Y
%A Li Y
%A Li Y
%A Huang B
%A Tang R
%A Wang Q
%A Miao Q
%A Peng Y
%A Fang J
%A Lian Z
%A Okazaki K
%A Xiao X
%A Zhang W
%A Ma X
%J Clin Rev Allergy Immunol
%V 60
%N 1
%D Feb 2021
%M 32712804
%F 10.817
%R 10.1007/s12016-020-08803-8
%X 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.