IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN.

To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls.

Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA.

Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.

IgA 肾病 (IgAN) 是全世界最常见的原发性肾小球疾病，是导致肾衰竭的主要原因。疾病机制尚不完全清楚，但较高丰度的半乳糖缺陷型 IgA 被认为在 IgAN 发病机制中起着至关重要的作用。尽管两种类型的人类 IgA（IgA1 和 IgA2）都有几个N-聚糖作为翻译后修饰，但只有 IgA1 具有广泛的铰链区O-糖基化。O-聚糖上的 IgA1 半乳糖缺乏通常通过基于凝集素的方法检测。迄今为止，关于 IgAN 中 IgA O-和N-糖基化的详细信息有限。

为了深入了解IgAN 中血清 IgA1 和 IgA2的复杂O-和N-糖基化，我们使用液相色谱-质谱法 (LC-MS) 分析了 83 名 IgAN 患者和 244 名年龄-和性别匹配的健康对照。

在我们的横断面研究中，IgA1 和 IgA2 N-糖基化的多种结构特征与 IgAN 和肾小球功能相关。这些特征包括半乳糖基化、唾液酸化、二等分、岩藻糖基化和N-聚糖复杂性的差异。此外，IgA1 O-聚糖唾液酸化与疾病和肾小球功能相关。最后，与基于凝集素的 ELISA 测量的缺乏半乳糖的 IgA1 水平相比，糖肽是 IgAN 和肾小球功能的更好预测因子。

我们的高分辨率数据表明，IgA O - 和N-糖肽是未来 IgAN 病理生理学研究的有前途的目标，也是疾病预测和肾功能恶化的潜在非侵入性生物标志物。