Genos Ltd, Glycoscience Research Laboratory, Zagreb, Croatia.
Injury, Inflammation and Recovery Unit, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
EBioMedicine. 2022 Jul;81:104101. doi: 10.1016/j.ebiom.2022.104101. Epub 2022 Jun 27.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a respiratory illness named coronavirus disease 2019 (COVID-19), which is one of the main global health problems since 2019. Glycans attached to the Fc portion of immunoglobulin G (IgG) are important modulators of IgG effector functions. Fc region binds to different receptors on the surface of various immune cells, dictating the type of immune response. Here, we performed a large longitudinal study to determine whether the severity and duration of COVID-19 are associated with altered IgG glycosylation.
Using ultra-high-performance liquid chromatography analysis of released glycans, we analysed the composition of the total IgG N-glycome longitudinally during COVID-19 from four independent cohorts. We analysed 77 severe COVID-19 cases from the HR1 cohort (74% males, median age 72, age IQR 25-80); 31 severe cases in the HR2 cohort (77% males, median age 64, age IQR 41-86), 18 mild COVID-19 cases from the UK cohort (17% males, median age 50, age IQR 26-71) and 28 mild cases from the BiH cohort (71% males, median age 60, age IQR 12-78).
Multiple statistically significant changes in IgG glycome composition were observed during severe COVID-19. The most statistically significant changes included increased agalactosylation of IgG (meta-analysis 95% CI [0.03, 0.07], adjusted meta-analysis P= <0.0001), which regulates proinflammatory actions of IgG via complement system activation and indirectly as a lack of sialylation and decreased presence of bisecting N-acetylglucosamine on IgG (meta-analysis 95% CI [-0.11, -0.08], adjusted meta-analysis P= <0.0001), which indirectly affects antibody-dependent cell-mediated cytotoxicity. On the contrary, no statistically significant changes in IgG glycome composition were observed in patients with mild COVID-19.
The IgG glycome in severe COVID-19 patients is statistically significantly altered in a way that it indicates decreased immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the severity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in COVID-19.
This work has been supported in part by Croatian Science Foundation under the project IP-CORONA-2020-04-2052 and Croatian National Centre of Competence in Molecular Diagnostics (The European Structural and Investment Funds grant #KK.01.2.2.03.0006), by the UKRI/MRC (Cov-0331 - MR/V027883/1) and by the National Institutes for Health Research Nottingham Biomedical Research Centre and by Ministry Of Science, Higher Education and Youth Of Canton Sarajevo, grant number 27-02-11-4375-10/21.
严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）导致了一种名为 2019 年冠状病毒病（COVID-19）的呼吸道疾病，这是自 2019 年以来全球主要的健康问题之一。免疫球蛋白 G（IgG）Fc 部分附着的聚糖是调节 IgG 效应功能的重要调节剂。Fc 区域与各种免疫细胞表面的不同受体结合，决定了免疫反应的类型。在这里，我们进行了一项大型的纵向研究，以确定 COVID-19 的严重程度和持续时间是否与 IgG 糖基化的改变有关。
使用超高效液相色谱分析释放的聚糖，我们在四个独立的队列中分析了 COVID-19 期间 IgG N-聚糖的总组成。我们分析了来自 HR1 队列的 77 例严重 COVID-19 病例（74%为男性，中位年龄 72 岁，年龄 IQR 25-80 岁）；来自 HR2 队列的 31 例严重病例（77%为男性，中位年龄 64 岁，年龄 IQR 41-86 岁），来自英国队列的 18 例轻度 COVID-19 病例（17%为男性，中位年龄 50 岁，年龄 IQR 26-71 岁）和来自波黑队列的 28 例轻度病例（71%为男性，中位年龄 60 岁，年龄 IQR 12-78 岁）。
在严重 COVID-19 期间，观察到 IgG 糖基组成发生了多个统计学上显著的变化。最显著的变化包括 IgG 的agalactosylation 增加（荟萃分析 95%CI [0.03，0.07]，调整后的荟萃分析 P<0.0001），这通过补体系统激活调节 IgG 的促炎作用，间接作为缺乏唾液酸化和减少双分支 N-乙酰葡萄糖胺的存在在 IgG 上（荟萃分析 95%CI [-0.11，-0.08]，调整后的荟萃分析 P<0.0001），这间接影响抗体依赖性细胞介导的细胞毒性。相反，在轻度 COVID-19 患者中未观察到 IgG 糖基组成的统计学显著变化。
严重 COVID-19 患者的 IgG 糖基在统计学上发生了显著变化，表明循环免疫球蛋白的免疫抑制作用降低。观察到的变化幅度与疾病的严重程度相关，表明异常的 IgG 糖基组成或 IgG 糖基化的变化可能是 COVID-19 的一个重要分子机制。
这项工作得到了克罗地亚科学基金会部分支持，项目号为 IP-CORONA-2020-04-2052 和克罗地亚国家分子诊断能力中心（欧洲结构和投资基金资助 #KK.01.2.2.03.0006），英国研究与创新署/医学研究理事会（Cov-0331 - MR/V027883/1）和英国诺丁汉生物医学研究中心和萨拉热窝州科学、高等教育和青年部，资助号为 27-02-11-4375-10/21。
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