Li Huixian, Lu Wanhong, Jin Qian, Sun Jiping, Gao Li, Hu Juanjuan, Ling Yingying, Zhao Wenyu, Zhang Yong, Xie Xinfang
Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
J Proteome Res. 2025 May 2;24(5):2553-2563. doi: 10.1021/acs.jproteome.5c00253. Epub 2025 Apr 9.
Serum glycoprotein glycosylation changes can indicate disease onset and progression. However, the site-specific N-glycosylation of monoclonal immunoglobulins (M-proteins) in multiple myeloma (MM) and its clinical implications are unclear. In this study, we isolated pathogenic micromonoclonal IgA or IgG (approximately 2 μg) from IgA-MM patients ( = 22) and IgG-MM patients ( = 30), and normal polyclonal IgA and IgG from healthy controls (HCs) ( = 16). Using EThcD-sceHCD-MS/MS, the N-glycosylation dynamics of serum M-proteins in MM were determined. Compared with polyclonal IgA1 from HCs, monoclonal IgA1 from IgA-MM patients had higher fucosylation (58.1% vs 32.1%, < 0.001), sialylation (68.0% vs 50.8%, = 0.011), and mannosylation (1.5% vs 0.3%, < 0.001). While, monoclonal IgG1 from IgG-MM patients had higher fucosylation (97.8% vs 95.3%, < 0.001). In addition, specific N-glycan abundances correlated with MM clinical features: for IgA1, HexNAc5Hex5Fuc1NeuAc1 was associated with hypocomplementemia; for IgG1, HexNAc4Hex3Fuc1 was associated with the serum albumin level ( = -0.363, = 0.049) and estimated glomerular filtration rate ( = -0.433, = 0.017); and HexNAc4Hex5 was associated with therapeutic prognosis. In conclusion, monoclonal IgA1 and IgG1 in MM patients and their polyclonal isotypes in HCs have distinct N-glycosylation profiles, and specific N-glycans of M-proteins are associated with MM characteristics and therapeutic prognosis.
血清糖蛋白糖基化变化可指示疾病的发生和进展。然而，多发性骨髓瘤（MM）中单克隆免疫球蛋白（M蛋白）的位点特异性N-糖基化及其临床意义尚不清楚。在本研究中，我们从22例IgA-MM患者和30例IgG-MM患者中分离出致病性微单克隆IgA或IgG（约2μg），并从16例健康对照（HC）中分离出正常多克隆IgA和IgG。使用EThcD-sceHCD-MS/MS测定MM患者血清M蛋白的N-糖基化动力学。与HC中的多克隆IgA1相比，IgA-MM患者的单克隆IgA1具有更高的岩藻糖基化（58.1%对32.1%，P<0.001）、唾液酸化（68.0%对50.8%，P = 0.011）和甘露糖基化（1.5%对0.3%，P<0.001）。而IgG-MM患者的单克隆IgG1具有更高的岩藻糖基化（97.8%对95.3%，P<0.001）。此外，特定N-聚糖丰度与MM临床特征相关：对于IgA1，HexNAc5Hex5Fuc1NeuAc1与低补体血症相关；对于IgG1，HexNAc4Hex3Fuc1与血清白蛋白水平（r = -0.363，P = 0.049）和估计肾小球滤过率（r = -0.433，P = 0.017）相关；HexNAc4Hex5与治疗预后相关。总之，MM患者的单克隆IgA1和IgG1及其在HC中的多克隆同种型具有不同的N-糖基化谱，并且M蛋白的特定N-聚糖与MM特征和治疗预后相关。
