O-glycoforms of polymeric immunoglobulin A1 in the plasma of patients with IgA nephropathy are associated with pathological phenotypes
O-glycoforms of polymeric immunoglobulin A1 in the plasma of patients with IgA nephropathy are associated with pathological phenotypes
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DOI：
10.1093/ndt/gfab204
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发表时间：
2021-06-21
影响因子：
6.1
通讯作者：
Zhang, Hong
中科院分区：
文献类型：
--
作者：
Yu, Guizhen;Zhang, Yong;Zhang, Hong
背景。免疫球蛋白A1 (IgA1) o -糖基化在IgA肾病（IgAN）的发病机制中起重要作用。然而，IgA1 o -糖型的变异尚未被探索。我们旨在研究聚合IgA1 （pIgA1）铰链区（HR）的IgA1 o -糖型，并评估IgA1 o -糖型与igan中新月形成的关系。发现队列（队列1）包括11名月牙形IgAN患者、10名非月牙形IgAN患者和10名健康对照；验证队列（队列2）包括11名月牙形IgAN患者、9名非月牙形IgAN患者和9名健康对照。共纳入143例不同月牙比例的IgAN患者（队列3）。从参与者的血浆中纯化出pIgA1。在电子转移/高能碰撞解离破碎模式下，通过反相液相色谱和串联质谱法估计IgA1铰链糖肽的分子量来评估o -糖型的变化。在发现队列（队列1）中，IgAN患者与一个HR结合的n -乙酰半乳糖胺（GalNAc）的数量较低。GalNAc3（定义为在三个位点与一个HR结合的o -聚糖）和GalNAc4的比例在新月体IgAN患者中最高，其次是非新月体IgAN患者，而在健康对照组中最低[GalNAc 3: 9.92 +/- 3.37% vs 6.65 +/- 1.53% vs 4.05 +/- 1.24% (P < 0.001)；GalNAc4: 45.91 +/- 4.75% vs 41.13 +/- 2.95% vs 40.98 +/- 2.95% （P = 0.004）。GaINAc5和GalNAc6的比例在月牙期IgAN患者中最低，其次是非月牙期IgAN患者，而在健康对照组中最高[GalNAc5: 50.15 +/- 4.27% vs 47.92 +/- 4.09% vs 45.87 +/- 3.79% (P = 0.028)；GalNAc6: 6.58 +/- 2.53% vs . 6.04 +/- 1.35% vs . 4.65 +/- 2.27% （P = 0.034）。这些结果在验证队列（队列2）中是一致的。在另一组143例不同月牙百分比的患者（队列3）中，pIgA 1中GalNAc的数量随着月牙百分比的增加而减少。IgAN患者中IgA1 hr中GalNAc的数量较低，尤其是新月形IgAN患者，这可能与严重的IgAN表型有关。
Background. Immunoglobulin A1 (IgA1) O-glycosylation plays an important role in the pathogenesis of IgA nephropathy (IgAN). However, variations in IgA1 O-glycoforms have not been explored. We aimed to investigate the IgA1 O-glycoforms in the hinge region (HR) of polymeric IgA1 (pIgA1) and then evaluate the association between IgA1 O-glycoforms and crescent formation in IgAN.Methods. The discovery cohort (Cohort 1) comprised 11 crescentic IgAN patients, 10 noncrescentic IgAN patients and 10 healthy controls and the validation cohort (Cohort 2) comprised 11 crescentic IgAN patients, 9 noncrescentic IgAN patients and 9 healthy controls. A total of 143 IgAN patients with different crescent percentages (Cohort 3) were also included. pIgA1 was purified from the plasma of the participants. The variation in O-glycoforms was evaluated by estimating the molecular weights of IgA1 hinge glycopeptides using reversedphase liquid chromatography and tandem mass spectrometry under electron-transfer/higher-energy collision dissociation fragmentation mode.Results. In the discovery cohort (Cohort 1), the number of N-acetylgalactosamine (GalNAc) bound to one HR was lower in IgAN patients. The proportions of GalNAc3 (defined as O-glycans bound to one HR at three sites) and GalNAc4 were highest in crescentic IgAN patients, followed by noncrescentic IgAN patients, and were lowest in healthy controls [GalNAc 3: 9.92 +/- 3.37% versus 6.65 +/- 1.53% versus 4.05 +/- 1.24% (P < 0.001); GalNAc4: 45.91 +/- 4.75% versus 41.13 +/- 2.95% versus 40.98 +/- 2.95% (P = 0.004), respectively]. The proportions of GaINAc5 and GalNAc6 were lowest in crescentic IgAN patients followed by noncrescentic IgAN patients and were highest in healthy controls [GalNAc5: 50.15 +/- 4.27% versus 47.92 +/- 4.09% versus 45.87 +/- 3.79% (P = 0.028); GalNAc6: 6.58 +/- 2.53% versus 6.04 +/- 1.35% versus 4.65 +/- 2.27% (P = 0.034), respectively]. These results were consistent in the validation cohort (Cohort 2). In another cohort with 143 patients with different crescent percentages (Cohort 3), the number of GalNAc in pIgA 1 decreased with an increasing percentage of crescents.Conclusions. The number of GalNAc in IgA1 HRs was lower in IgAN patients, especially in crescentic IgAN patients, and may be associated with a severe IgAN phenotype.