IgG4相关硬化性胆管炎中浆细胞来源的白介素-35调控巨噬细胞极化的机制研究

As the most common extra-pancreatic involvement of IgG4-RD, IgG4-related Sclerosing Cholangitis (IgG4-SC) is one of autoimmune liver diseases, characterized with the cytokine profile mainly represented by the T helper type 2(Th2) pattern and persistent mature B cell activation and IgG4 secretion. Interleukin-35 (lL-35) is a newly member of IL-12 cytokine family and play a role of regulatory immune modulation in inflammatory diseases. In our previous study, we investigated the dramatic increase of Interleukin-35 (IL-35) expression in the liver of IgG4-SC, which was mainly produced by plasma cells in the liver and colocalized with IgG4 positive plasma cell. Then, we found the elevated expression of IL-35 receptor gp130/IL12Rβ2 on macrophage of IgG4-SC patients. Furthermore, in vitro culture experiments confirmed that IL-35 regulated the polarization of macrophages towards M2. Therefore, we hypothesize that IL-35 may serve as biological characteristics and effector cytokine of IgG4 positive plasma cell. It binds to the receptor gp130/IL12Rβ2 specifically, modulating the polarization of macrophage, participating in the regulation of immune microenvironment of IgG4-SC. Our study may elucidate the biological characteristics and function of disease-specific IgG4 positive plasma in IgG4-SC, and explore the promising immunotherapy strategy in autoimmune liver diseases.

IgG4相关硬化性胆管炎（IgG4-SC）是一类以Th2型细胞免疫主导、成熟B细胞持续活化并分泌IgG4为特征的自身免疫性疾病。白介素-35（IL-35）作为IL-12家族的细胞因子之一，在炎症性疾病中发挥负性免疫调控作用。我们前期研究发现，在IgG4-SC患者肝内免疫微环境中浆细胞分泌的IL-35显著升高，且与IgG4阳性的浆细胞存在共定位，而IgG4-SC肝内巨噬细胞表面的gp130/IL12Rβ2受体表达显著升高。体外诱导实验提示，IL-35可调控巨噬细胞极化并促进其向M2型极化。因此，我们提出假设：IL-35是IgG4阳性浆细胞的重要生物学特征和效应分子，通过与受体gp130/IL12Rβ2特异性结合调控巨噬细胞M1/M2型极化，从而影响IgG4-SC肝内免疫微环境。本研究旨在阐明IgG4-SC中疾病特异性B细胞的生物学特征和功能，并为发现更有效的免疫治疗新靶点提供依据。

IgG4相关硬化性胆管炎（IgG4-SC）是一类以Th2型细胞免疫主导、成熟B细胞持续活化并分泌IgG4为特征的自身免疫性疾病。白介素-35（IL-35）作为IL-12家族的细胞因子之一，在炎症性疾病中发挥负性免疫调控作用。本研究发现，与疾病对照和健康对照组相比，IgG4相关肝胆胰疾病患者血浆 IL-35 表达水平显著升高，病变组织中EBI3和IL-12p35阳性细胞数量显著升高。EBI3、IL-12p35分别与B细胞标志物CD19和CD38存在共定位，表明IgG4相关肝胆胰疾病患者病变组织中B细胞可以分泌IL-35。 有趣的是，体外诱导实验表明IL-35通过激活IRF4促进了幼稚的CD4阳性T细胞向Th9细胞分化。IgG4相关肝胆胰疾病患者外周血和病变组织中Th9细胞显著升高， 由Th9细胞分泌的IL-9促进了浆细胞的分化以及IgG1和IgG4的产生，且主要促进了浆细胞分泌IgG4，使IgG1/IgG4比值显著降低。因此，IgG4相关肝胆胰疾病患者IL-35显著升高，并且在Th9细胞分化中发挥重要作用，从而进一步促进了IL-9介导的浆细胞分化和IgG4型免疫球蛋白类别转换。 本研究以IL-35为切入点，探索IgG4-SC肝脏自身免疫微环境下的细胞免疫和细胞分化平衡的调控机制，明确分泌IL-35的IgG4阳性浆细胞参与IgG4-SC疾病进展的作用和机制，并且为调控浆细胞分泌IgG4型免疫球蛋白的生物学行为提供新策略和免疫新靶点。