美国埃默里大学Eric J. Sundberg等研究人员合作揭示靶向IgG介导病理的IgG特异性内糖苷酶的强效效果。相关论文于2024年10月21日在线发表在《细胞》杂志上。
研究人员表示，特异性水解免疫球蛋白G（IgG）抗体上与Asn297连接糖基的内β-N-乙酰氨基葡萄糖苷酶（ENGase）极为稀有，这是片段结晶可变（Fc）γ受体（FcγR）结合的主要分子决定因素。所有先前表征的IgG特异性ENGase都是由化脓性链球菌菌株分泌的多结构域蛋白，进而作为一种免疫逃逸策略。
通过计算机分析和质谱技术，研究人员识别出了一组由致病性棒状杆菌分泌的单结构域ENGase，展现出对IgG抗体的严格特异性。通过X射线晶体学和表面等离子体共振分析，研究人员发现最具催化效率的IgG特异性ENGase家族成员能够识别IgG的蛋白和糖基成分。
通过体内模型，研究人员证明了这种IgG特异性ENGase在减轻多种依赖于FcγR介导的效应功能的病理（包括T和B淋巴细胞耗竭、自身免疫性溶血性贫血和抗体依赖性登革热疾病增强）中的显著功效，并揭示了其治疗和/或预防广泛IgG介导疾病的潜力。
附：英文原文
Title: Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies
Author: Diego E. Sastre, Stylianos Bournazos, Jonathan Du, E. Josephine Boder, Julia E. Edgar, Tala Azzam, Nazneen Sultana, Maros Huliciak, Maria Flowers, Lea Yoza, Ting Xu, Tatiana A. Chernova, Jeffrey V. Ravetch, Eric J. Sundberg
Issue&Volume: 2024-10-21
Abstract: Endo-β-N-acetylglucosaminidases (ENGases) that specifically hydrolyze the Asn297-linked glycan on immunoglobulin G (IgG) antibodies, the major molecular determinant of fragment crystallizable (Fc) γ receptor (FcγR) binding, are exceedingly rare. All previously characterized IgG-specific ENGases are multi-domain proteins secreted as an immune evasion strategy by Streptococcus pyogenes strains. Here, using in silico analysis and mass spectrometry techniques, we identified a family of single-domain ENGases secreted by pathogenic corynebacterial species that exhibit strict specificity for IgG antibodies. By X-ray crystallographic and surface plasmon resonance analyses, we found that the most catalytically efficient IgG-specific ENGase family member recognizes both protein and glycan components of IgG. Employing in vivo models, we demonstrated the remarkable efficacy of this IgG-specific ENGase in mitigating numerous pathologies that rely on FcγR-mediated effector functions, including T and B lymphocyte depletion, autoimmune hemolytic anemia, and antibody-dependent enhancement of dengue disease, revealing its potential for treating and/or preventing a wide range of IgG-mediated diseases in humans.
DOI: 10.1016/j.cell.2024.09.038
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01135-8