Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
Department of Rheumatology and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.
Clin Rev Allergy Immunol. 2021 Feb;60(1):132-145. doi: 10.1007/s12016-020-08803-8.
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.
IgG4 相关疾病（IgG4-RD）的特征是受影响器官中 IgG4 阳性浆细胞的强烈浸润。然而，IgG4-RD 中免疫反应的机制尚不完全清楚。本研究旨在通过研究 IL-35 产生细胞和 Th9 细胞之间的串扰，剖析 IgG4-RD 中免疫球蛋白类别转换的机制。在患有肝胆和/或胰腺 IgG4-RD 表现的患者的血浆样本中检查了 IL-35 的表达水平。我们的数据表明，与疾病和健康对照相比，IgG4-RD 患者表现出明显高水平的 IL-35 产生。我们在 IgG4-RD 的两个主要受影响的器官，肝和胰腺组织中检测到了 IL-35 的两个亚基，EBI3 和 IL-12p35。与疾病对照相比，在 IgG4-RD 的受影响器官中，EBI3 和 IL-12p35 阳性细胞明显更高。EBI3 与 CD19 和 CD38 的共定位，CD19 和 CD38 是 B 细胞的标志物，表明在 IgG4-RD 的受影响器官中存在产生 IL-35 的 B 细胞。然后评估了 IL-35 在 Th9 分化和 IL-9 在免疫球蛋白产生中的作用。令人惊讶的是，IL-35 通过 IRF4 信号促进幼稚 CD4 T 细胞向 Th9 细胞分化。结果，Th9 细胞分泌的 IL-9 促进了浆细胞的分化和 IgG1 和 IgG4 的产生，主要是 IgG4。总之，我们的数据表明，IL-35 积极参与炎症过程，并在 Th9 分化中发挥重要作用，导致 IgG4 免疫球蛋白类别转换。
