Protein Mannosylation as a Diagnostic and Prognostic Biomarker of Lupus Nephritis: An Unusual Glycan Neoepitope in Systemic Lupus Erythematosus
Protein Mannosylation as a Diagnostic and Prognostic Biomarker of Lupus Nephritis: An Unusual Glycan Neoepitope in Systemic Lupus Erythematosus
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DOI：
10.1002/art.41768
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发表时间：
2021-09-28
影响因子：
13.3
通讯作者：
Pinho, Salome S.
中科院分区：
文献类型：
--
作者：
Alves, Ines;Santos-Pereira, Beatriz;Pinho, Salome S.
目的蛋白质糖基化改变是免疫介导疾病的标志。聚糖是炎症反应的主要调节剂，是自我-非自我辨别的重要分子。本研究旨在探讨狼疮性肾炎（LN）是否表现出改变的细胞糖基化，以确定一个独特的糖标志，其特征在于LN的发病机制。方法对系统性红斑狼疮（SLE）患者的肾脏组织进行糖组学分析。进行先进的组织质谱、原位糖表征和离体糖表型分析的组合以在结构上映射LN组织样品中的N-聚糖库。结果LN显示出独特的聚糖特征，其特征在于通常在低等微生物中发现的不寻常的富含甘露糖的聚糖的丰度和空间分布增加。这种糖标记对LN是特异性的，因为在其他肾脏疾病中没有观察到。LN中甘露糖基化聚糖的暴露显示发生在肾细胞的细胞表面，促进免疫细胞表达的特异性聚糖识别受体的识别增加。LN的这种异常糖基化特征被证明是由于缺乏复杂的N-糖基化途径和熟练的O-甘露糖基化途径。此外，在诊断时从LN患者的肾活检样本中检测到的甘露糖基化水平被证明可以预测慢性肾脏疾病（CKD）的发展，特异性为93%。结论细胞甘露糖基化是LN的一个标志物，可预测CKD的发展，因此代表了一个潜在的糖生物标志物，可用于LN的诊断和预后评估。
Objective Changes in protein glycosylation are a hallmark of immune-mediated diseases. Glycans are master regulators of the inflammatory response and are important molecules in self-nonself discrimination. This study was undertaken to investigate whether lupus nephritis (LN) exhibits altered cellular glycosylation to identify a unique glycosignature that characterizes LN pathogenesis. Methods A comprehensive tissue glycomics characterization was performed in kidney specimens from patients with systemic lupus erythematosus and biopsy-proven LN. A combination of advanced tissue mass spectrometry, in situ glyco-characterization, and ex vivo glycophenotyping was performed to structurally map the repertoire of N-glycans in LN tissue samples. Results LN exhibited a unique glycan signature characterized by increased abundance and spatial distribution of unusual mannose-enriched glycans that are typically found in lower microorganisms. This glycosignature was specific for LN, as it was not observed in other kidney diseases. Exposure of mannosylated glycans in LN was shown to occur at the cell surface of kidney cells, promoting increased recognition by specific glycan-recognizing receptors expressed by immune cells. This abnormal glycosignature of LN was shown to be due to a deficient complex N-glycosylation pathway and a proficient O-mannosylation pathway. Moreover, mannosylation levels detected in kidney biopsy samples from patients with LN at the time of diagnosis were demonstrated to predict the development of chronic kidney disease (CKD) with 93% specificity. Conclusion Cellular mannosylation is a marker of LN, predicting the development of CKD, and thus representing a potential glycobiomarker to be included in the diagnostic and prognostic algorithm of LN.