OBJECTIVES Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) and autoimmune pancreatitis (AIP) are characterized by an abundance of circulating and tissue IgG4-positive plasma cells. T-follicular helper (Tfh) cells are necessary for B-cell differentiation into plasma cells. We aimed at elucidating the presence and phenotype of Tfh cells and their relationship with disease activity in IgG4-SC/AIP. METHODS Circulating Tfh-cell subsets were characterized by multiparametric flow cytometry in IgG4-SC/AIP (n = 18), disease controls with primary sclerosing cholangitis (n = 8), and healthy controls (HCs, n = 9). Tissue Tfh cells were characterized in IgG4-SC/AIP (n = 12) and disease control (n = 10) specimens. Activated PD1+ Tfh cells were cocultured with CD27+ memory B cells to assess their capacity to support B-cell differentiation. Disease activity was assessed using the IgG4-responder index and clinical parameters. RESULTS Activated circulating PD-1+CXCR5+ Tfh cells were expanded in active vs inactive IgG4-SC/AIP, primary sclerosing cholangitis, and HC (P < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1, P = 0.003; Tfh2, P = 0.0006; Th17, P = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (P = 0.01) correlated with the PD-1+ Tfh2 subset (r = 0.69, P = 0.03). Increased IL-4 and IL-21 cytokine production from stimulated cells of IgG4-SC/AIP, important in IgG4 class switch and proliferation, correlated with PD-1+ Tfh2 (r = 0.89, P = 0.02) and PD-1+ Tfh17 (r = 0.83, P = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1- Tfh (P = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (r = 0.70, P = 0.002), sIgE (r = 0.66, P = 0.006), and IgG4-responder index (r = 0.60, P = 0.006). Activated CXCR5+ Tfh cells homed to lymphoid follicles in IgG4-SC/AIP tissues. CONCLUSIONS Circulating and tissue-activated Tfh cells are expanded in IgG4-SC/AIP, correlate with disease activity, and can drive class switch and proliferation of IgG4-committed B cells. PD1+ Tfh2 cells may be a biomarker of active disease and a potential target for immunotherapy.

中文翻译：

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活化的 T 滤泡辅助 2 细胞与 IgG4 相关的硬化性胆管炎和胰腺炎的疾病活动有关。

目的 免疫球蛋白 G4 相关硬化性胆管炎 (IgG4-SC) 和自身免疫性胰腺炎 (AIP) 的特征是循环和组织中大量 IgG4 阳性浆细胞。T 滤泡辅助 (Tfh) 细胞是 B 细胞分化为浆细胞所必需的。我们旨在阐明 Tfh 细胞的存在和表型及其与 IgG4-SC/AIP 疾病活动的关系。方法循环 Tfh 细胞亚群通过多参数流式细胞术在 IgG4-SC/AIP (n = 18)、原发性硬化性胆管炎疾病对照 (n = 8) 和健康对照 (HCs, n = 9) 中进行表征。组织 Tfh 细胞在 IgG4-SC/AIP (n = 12) 和疾病控制 (n = 10) 标本中进行了表征。将活化的 PD1+ Tfh 细胞与 CD27+ 记忆 B 细胞共培养，以评估它们支持 B 细胞分化的能力。使用 IgG4 反应指数和临床参数评估疾病活动性。结果 活化的循环 PD-1+CXCR5+ Tfh 细胞在活性与非活性 IgG4-SC/AIP、原发性硬化性胆管炎和 HC 中扩增（P < 0.01），所有 Tfh 细胞亚群上 PD-1 表达增强（Tfh1、P = 0.003；Tfh2，P = 0.0006；Th17，P = 0.003）。CD27+CD38+CD19lo 浆母细胞在活动性疾病与 HC 中的扩增（P = 0.01）与 PD-1+ Tfh2 亚群相关（r = 0.69，P = 0.03）。受刺激的 IgG4-SC/AIP 细胞产生的 IL-4 和 IL-21 细胞因子增加，在 IgG4 类别转换和增殖中很重要，与 PD-1+ Tfh2 (r = 0.89, P = 0.02) 和 PD-1+ Tfh17 相关(r = 0.83, P = 0.03) 子集。PD1+ Tfh 与 CD27+ B 细胞的共培养诱导的 IgG4 表达高于 PD1- Tfh (P = 0.008)。PD-1+ Tfh2 细胞与疾病活动的临床标志物密切相关：sIgG4 (r = 0.70, P = 0.002)、sIgE (r = 0.66, P = 0.006) 和 IgG4 反应指数 (r = 0.60, P = 0.006)。活化的 CXCR5+ Tfh 细胞归巢于 IgG4-SC/AIP 组织中的淋巴滤泡。结论 循环和组织激活的 Tfh 细胞在 IgG4-SC/AIP 中扩增，与疾病活动相关，并且可以驱动 IgG4 定向 B 细胞的类别转换和增殖。PD1+ Tfh2 细胞可能是活动性疾病的生物标志物和免疫治疗的潜在靶点。结论 循环和组织激活的 Tfh 细胞在 IgG4-SC/AIP 中扩增，与疾病活动相关，并且可以驱动 IgG4 定向 B 细胞的类别转换和增殖。PD1+ Tfh2 细胞可能是活动性疾病的生物标志物和免疫治疗的潜在靶点。结论 循环和组织激活的 Tfh 细胞在 IgG4-SC/AIP 中扩增，与疾病活动相关，并且可以驱动 IgG4 定向 B 细胞的类别转换和增殖。PD1+ Tfh2 细胞可能是活动性疾病的生物标志物和免疫治疗的潜在靶点。