Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
Sanquin Research, Department of Immunopathology, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
J Gastroenterol Hepatol. 2019 Oct;34(10):1878-1886. doi: 10.1111/jgh.14512. Epub 2018 Nov 22.
Immunoglobulin subclass G4-related disease (IgG4-RD) is characterized by an abundance of IgG4 antibodies in the serum and tissue. Glycosylation status of antibodies can impact on immune effector functions and disease pathophysiology. We sought to establish glycosylation patterns in a prospective cohort of patients with IgG4-RD and the relationship with disease activity and response to treatment.
We assessed IgG Fc-tail and Fab-arm glycosylation status in patients with IgG4-RD (n = 22), disease controls with primary sclerosing cholangitis (PSC) (n = 22), and healthy controls (n = 22). Serum IgG and subclasses were quantified using ELISA. Fc and Fab glycosylation were analyzed by mass spectrometry and lectin affinity chromatography, respectively. Disease activity, organ damage, and response to treatment were assessed using the IgG4 Responder Index.
Immunoglobulin G Fab sialylation was increased in IgG4-RD compared with PSC and healthy control (P = 0.01), with a preferential increase in IgG4-specific Fab sialylation, which was independent of IgG4 Fab-arm exchange. There was a reduction in IgG1-specific Fc bisection and hybrid structures in IgG4-RD (P < 0.01), which recovered upon steroid treatment and correlated with disease activity. Overall, IgG Fc galactosylation was reduced in both IgG4-RD and PSC (P < 0.01), with a preferential reduction in IgG1-specific sialylation and enhancement of IgG4-specific bisection in PSC. IgG4 fucosylation and IgG1/2/3 hybrid structures negatively correlated with complement C3 and C4 levels in IgG4-RD (P < 0.01), but not PSC.
We report the first study showing unique antibody glycosylation status in a prospective cohort of IgG4-RD and PSC patients, which may determine modulation of the immune system and contribute to disease pathophysiology.
免疫球蛋白 G4 相关疾病（IgG4-RD）的特征是血清和组织中存在大量 IgG4 抗体。抗体的糖基化状态会影响免疫效应功能和疾病病理生理学。我们旨在建立 IgG4-RD 患者前瞻性队列的糖基化模式，并研究其与疾病活动度和治疗反应的关系。
我们评估了 IgG4-RD 患者（n=22）、原发性硬化性胆管炎（PSC）患者（n=22）和健康对照者（n=22）的 IgG Fc 尾部和 Fab 臂糖基化状态。使用 ELISA 定量检测血清 IgG 和亚类。分别通过质谱分析和凝集素亲和层析分析 Fc 和 Fab 糖基化。使用 IgG4 应答指数评估疾病活动度、器官损伤和治疗反应。
与 PSC 和健康对照组相比，IgG4-RD 患者的 IgG Fab 唾液酸化增加（P=0.01），并且 IgG4 特异性 Fab 唾液酸化呈优先增加，这与 IgG4 Fab 臂交换无关。IgG4-RD 患者 IgG1 特异性 Fc 二分叉和杂交结构减少（P<0.01），在类固醇治疗后恢复，与疾病活动度相关。总的来说，IgG4-RD 和 PSC 患者的 IgG Fc 半乳糖基化均降低（P<0.01），其中 IgG1 特异性唾液酸化优先降低，PSC 中 IgG4 特异性二分叉增加。IgG4-RD 患者 IgG4 岩藻糖基化和 IgG1/2/3 杂交结构与补体 C3 和 C4 水平呈负相关（P<0.01），而 PSC 患者则无相关性。
我们报告了首例 IgG4-RD 和 PSC 患者前瞻性队列中独特的抗体糖基化状态研究，这可能决定了免疫系统的调节，并有助于疾病病理生理学。
