Serum IgA1 shows increased levels of α 2,6-linked sialic acid in breast cancer

The lectin Helix pomatia agglutinin (HPA) recognizes altered glycosylation in solid cancers and the identification of HPA binding partners in tumour tissue and serum is an important aim. Among the many HPA binding proteins, IgA1 has been reported to be the most abundant in liver metastases. In this study, the glycosylation of IgA1 was evaluated using serum samples from patients with breast cancer (BCa) and the utility of IgA1 glycosylation as a biomarker was assessed. Detailed mass spectrometric structural analysis showed an increase in disialo-biantennary N- linked glycans on IgA1 from BCa patients ( p < 0.0001: non-core fucosylated; p = 0.0345: core fucosylated) and increased asialo-Thomsen–Friedenreich antigen (TF) and disialo-TF antigens in the O- linked glycan preparations from IgA1 of cancer patients compared with healthy control individuals. An increase in Sambucus nigra binding was observed, suggestive of increased α 2,6-linked sialic acid on IgA1 in BCa. Logistic regression analysis showed HPA binding to IgA1 and tumour size to be significant independent predictors of distant metastases ( χ 2 13.359; n = 114; p = 0.020) with positive and negative predictive values of 65.7% and 64.6%, respectively. Immunohistochemical analysis of tumour tissue samples showed IgA1 to be detectable in BCa tissue. This report provides a detailed analysis of serum IgA1 glycosylation in BCa and illustrates the potential utility of IgA1 glycosylation as a biomarker for BCa prognostication.

Loss of the Golgi Matrix Protein 130 Cause Aberrant IgA1 Glycosylation in IgA Nephropathy

Background: Aberrant O-glycosylation IgA1 production is a major factor in the pathogenesis of IgA nephropathy, but the underlying mechanism is still unclear. IgA1 glycosylation modification is in Golgi, and downregulation of the Golgi peripheral membrane protein Golgi matrix protein 130 (GM130) could lead to glycosylation deficiency. In this study, we aimed to explore the role of GM130 in glycosylate deficiency IgA1 (Gd-IgA1) production. Methods: We enrolled 27 IgA nephropathy patients, 12 patients with chronic tonsillitis, 15 non-IgAN chronic kidney disease patients, and 15 healthy volunteers as healthy control. We explored GM130 expression in Tonsillar tissue by immunofluorescence staining and Western blotting and expression in peripheral blood mononuclear cells (PBMCs) by flow cytometry. The concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia Villosa lectin-binding assay. Real-time PCR and Western blot were used to analyze the levels of β1,3-Gal transferase (C1GALT1) and ST6GalNAC2, respectively. To explore the contribution of GM130 in IgA1 O-glycosylation modification, cells were subjected to experiments for evaluation of GM130 silencing by GM130-siRNA transfection. Results: GM130 expression was significantly decreased in tonsil tissues and PBMC of IgAN patients; the expression of C1GALT1 decreased and Gd-IgA1 level increased significantly in patients with IgAN patients. The expression of GM130 was negatively related to Gd-IgA1 production. By siRNA transfection, our results clearly indicated that the downregulation of GM130 can increase IgA1 O-glycosylation deficiency, which is thought to reduce C1GALT1 expression but not affect the expression of ST6GalNAC2. Conclusion: We identified and demonstrated that GM130 plays an important role in IgA1 O-glycans deficiency in IgAN patients, by negatively regulating C1GALT1 expression. We believe that this finding will provide theoretical foundations for a new mechanism of Gd-IgA1 production in IgAN patients.

Elevated Plasmaα-Defensins (HNP1–3) Levels Correlated with IgA1 Glycosylation and Susceptibility to IgA Nephropathy

Aim. IgA nephropathy (IgAN) is the most common form of glomerulonephritis. Recent genome-wide association study (GWAS) suggested that DEFA locus (which encodesα-defensins) may play a key role in IgAN.Methods. The levels ofα-defensins in 169 IgAN patients and 83 healthy controls were tested by ELISA.Results. We observed thatα-defensins human neutrophil peptides 1–3 (HNP1–3) in IgAN patients were elevated compared with healthy controls. The mean levels ofα-defensins of 83 healthy controls and 169 IgAN patients were 50 ng/mL and 78.42 ng/mL. When the results were adjusted to the mean levels ofα-defensins of IgAN patients, the percentage of individuals with high levels ofα-defensins increased in IgAN patients (22.5%) compared to healthy controls (9.6%) (p=0.013). The elevation ofα-defensins in IgAN patients was independent of renal function or neutrophil count, which were major sources ofα-defensins in circulation. More importantly, negative correlation was observed between galactose-deficient IgA1andα-defensins.Conclusion. Asα-defensin is a lectin-like peptide, we speculated that it might be involved in IgA galactose deficiency. The data implied that patients with IgAN had higher plasmaα-defensins levels and highα-defensins correlated with IgA galactose deficiency, further suggesting a pathogenic role ofα-defensins in IgAN.

Treatment of IgA nephropathy

IgA nephropathy is the most common primary glomerulonephritis worldwide. The clinical spectrum covers a wide range of features from minor urinary abnormalities (asymptomatic hematuria and mild proteinuria with normal renal function) to acute and chronic renal insufficiency. Ideally, the goal of treatment would be to correct any defects in IgA1 glycosylation and to modify mesangial deposition or removal of IgA1 deposits. There are only a few randomized controlled trials in IgA nephropathy; for this reason most treatment options are largely based on expert opinion. Authors discuss therapeutic options of different clinical pictures and the optimized renoprotective treatment of all IgA nephropathy patients. Orv. Hetil., 2011, 152, 2039–2046.