{Reference Type}: Journal Article
{Title}: Interleukin-35 Promotes Th9 Cell Differentiation in IgG4-Related Disorders: Experimental Data and Review of the Literature.
{Author}: Zhang J;Lian M;Li B;Gao L;Tanaka T;You Z;Wei Y;Chen Y;Li Y;Li Y;Huang B;Tang R;Wang Q;Miao Q;Peng Y;Fang J;Lian Z;Okazaki K;Xiao X;Zhang W;Ma X;
{Journal}: Clin Rev Allergy Immunol
{Volume}: 60
{Issue}: 1
{Year}: Feb 2021
{Factor}: 10.817
{DOI}: 10.1007/s12016-020-08803-8
{Abstract}: 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.