University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
J Infect Dis. 2020 Nov 13;222(12):2093-2102. doi: 10.1093/infdis/jiz643.
Mycobacterium tuberculosis remains a global health problem and clinical management is complicated by difficulty in discriminating between latent infection and active disease. While M. tuberculosis-reactive antibody levels are heterogeneous, studies suggest that levels of IgG glycosylation differ between disease states. Here we extend this observation across antibody domains and M. tuberculosis specificities to define changes with the greatest resolving power.
Capillary electrophoretic glycan analysis was performed on bulk non-antigen-specific IgG, bulk Fc domain, bulk Fab domain, and purified protein derivative (PPD)- and Ag85A-specific IgG from subjects with latent (n = 10) and active (n = 20) tuberculosis. PPD-specific isotype/subclass, PPD-specific antibody-dependent phagocytosis, cellular cytotoxicity, and natural killer cell activation were assessed. Discriminatory potentials of antibody features were evaluated individually and by multivariate analysis.
Parallel profiling of whole, Fc, and Fab domain-specific IgG glycosylation pointed to enhanced differential glycosylation on the Fc domain. Differential glycosylation was observed across antigen-specific antibody populations. Multivariate modeling highlighted Fc domain glycan species as the top discriminatory features, with combined PPD IgG titers and Fc domain glycans providing the highest classification accuracy.
Differential glycosylation occurs preferentially on the Fc domain, providing significant discriminatory power between different states of M. tuberculosis infection and disease.
结核分枝杆菌仍然是一个全球性的健康问题，临床管理因难以区分潜伏感染和活动性疾病而变得复杂。虽然结核分枝杆菌反应性抗体水平存在异质性，但研究表明疾病状态下 IgG 的糖基化水平存在差异。在这里，我们将这一观察结果扩展到抗体结构域和结核分枝杆菌特异性，以确定具有最大分辨率的变化。
对潜伏（n=10）和活动性（n=20）结核病患者的非抗原特异性 IgG 总量、Fc 结构域总量、Fab 结构域总量和纯化蛋白衍生物（PPD）和 Ag85A 特异性 IgG 进行毛细管电泳糖基化分析。评估了 PPD 特异性同种型/亚类、PPD 特异性抗体依赖性吞噬作用、细胞毒性和自然杀伤细胞激活。单独和通过多元分析评估了抗体特征的鉴别潜力。
对整个、Fc 和 Fab 结构域特异性 IgG 糖基化的平行分析表明 Fc 结构域的差异糖基化增强。在抗原特异性抗体群体中观察到差异糖基化。多元模型突出了 Fc 结构域聚糖种类作为最佳鉴别特征，PPD IgG 滴度和 Fc 结构域聚糖联合提供了最高的分类准确性。
差异糖基化主要发生在 Fc 结构域，为结核分枝杆菌感染和疾病的不同状态提供了重要的鉴别能力。
