Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels

Abstract

Immunoglobulin A (IgA) nephropathy is the most prevalent form of glomerulonephritis worldwide. A renal biopsy is required for an accurate diagnosis, as no convenient biomarker is currently available. We developed a serological test based upon the observation that this nephropathy is characterized by undergalactosylated IgA1 in the circulation and in mesangial immune deposits. In the absence of galactose, the terminal saccharide of O-linked chains in the hinge region of IgA1 is terminal or sialylated N-acetylgalactosamine. A lectin from Helix aspersa, recognizing N-acetylgalactosamine, was used to develop an enzyme-linked immunosorbent assay that measures galactose-deficient IgA1 in serum. The median serum lectin-binding IgA1 level was significantly higher for 153 Caucasian adult patients with IgA nephropathy without progression to end-stage renal disease as compared with that for 150 healthy Caucasian adult controls. As the lectin-binding IgA1 levels for the controls were not normally distributed, the 90th percentile was used for determination of significant elevation. Using a value of 1076 U/ml as the upper limit of normal, 117 of the 153 patients with IgA nephropathy had an elevated serum lectin-binding IgA1 level. The sensitivity as a diagnostic test was 76.5%, with specificity 94%; the positive predictive value was 88.6% and the negative predictive value was 78.9%. We conclude that this lectin-binding assay may have potential as a noninvasive diagnostic test for IgA nephropathy.

Identification of Distinct Glycoforms of IgA1 in Plasma from Patients with Immunoglobulin A (IgA) Nephropathy and Healthy Individuals

“…IgA1 Isolated from IgAN Patients and From Healthy Controls Exhibit Similar PNA and HPA Reactivity-The above results appear to conflict with many studies on IgA1 O-glycosylation suggesting that the presence of Tn and/or STn antigens on IgA1 is a characteristic change in IgA nephropathy (42,47,48). To further test our results indicating that Tn and/or STn antigens are found in IgA1 from IgAN patients and controls, we analyzed affinity purified IgA from plasma samples of all IgAN patients and controls by lectin blots with HPA and with peanut agglutinin (PNA) after treatment with neuraminidase.…”

“…tures-A common feature reported in IgAN patients is an increase of plasma IgA as compared with healthy controls (42). We determined the concentration of plasma IgA by ELISA, and found that, consistent with earlier studies, IgA was present at an average of 4.77 mg/ml (Ϯ 1.09 mg/ml) from 14 IgAN patients, whereas in control plasma from 14 healthy donors we found 2.97 mg/ml (Ϯ 0.70 mg/ml) IgA, thus representing a low, but significant ϳ1.6 fold elevation of IgA in patients with IgAN ( Fig.…”

Clustered O-Glycans of IgA1

“…Carbohydratespecific lectin analysis of O-glycoproteins can provide information on glycan composition and comparative differences between samples, such as those from healthy controls and patients with various disease states. We have successfully demonstrated this in the analysis of IgA1 O-glycans from patients with IgAN versus healthy controls and disease controls (13)(14)(15). This included proximal assessment of sites with galactose (Gal)-deficient O-glycans after digests with IgAspecific proteases (8).…”

“…1). Aberrantly glycosylated IgA1, deficient in Gal in some of the O-glycans in the HR, in serum is rare in healthy individuals but is present at elevated levels in IgAN patients (13,15). This distinctive IgA1 is in circulating immune complexes (8,10,15) and in the glomerular deposits of IgAN patients (16,29).…”

Relationship between rs1047763 polymorphism of the C1GALT1 gene and susceptibility to immunoglobulin A nephropathy in Xinjiang Uyghur people

“…Researchers in Italy, Japan, the USA, and China studied IgAN patients of different races and ethnic backgrounds using enzyme-linked immunosorbent assay (ELISA), fluorophore-assisted carbohydrate electrophoresis (FACE), and mass spectrometry to provide the data for this study. The results suggest that there were some defects in O-glycan galactosylation in the hinge region of serum IgA1 molecules in IgAN patients (Moldoveanu et al, 2007;Gharavi et al, 2008;Shimozato et al, 2008;Lin et al, 2009). Xia and McEver (2006) found that C1GALT1 (core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase), which is an enzyme encoded by the C1GALT1 gene, is a critical regulatory site in the protein glycosylation process.…”