Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy

Abstract

Mesangial and circulating IgA1 with aberrantly glycosylated hinge region O-glycans characterize IgA nephropathy (IgAN). Unlike healthy individuals, some IgA1 is galactose deficient in patients with IgAN, leaving terminal N-acetylgalactosamine residues in the hinge region exposed. Circulating autoantibodies that recognize such galactose-deficient IgA1 as an autoantigen, or the levels of the autoantigen itself, may allow prediction of disease progression. Here, we analyzed serum samples obtained at diagnosis for autoantigen and autoantibodies from 97 patients with IgAN selected from our prospective cohort according to their absolute renal risk for progression to dialysis or death (0, very low; 1, low; 2, high; 3, very high). We also analyzed samples from controls comprising 30 healthy volunteers and 30 patients with non-IgAN disease. The mean follow-up was 13.8 years. We found that mean serum levels of total autoantigen, normalized IgG autoantibody, and total IgA autoantibody were significantly higher in patients than in the combined controls (all P#0.01). Furthermore, increasing levels correlated with worse clinical outcomes. In Cox regression and Kaplan-Meier analyses, IgG autoantibody levels $1.33 predicted dialysis or death (both P#0.01). In conclusion, these data suggest that serum levels of IgG and IgA autoantibodies strongly associate with the progression of IgAN nephropathy.

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

“…Several studies have also reported minimal or even no differences between galactosylation of IgA1 from IgAN patients and IgA1 from control donors, showing in their data similar reactivity with lectins (HAA, HPA or VVA) specific to galactose-deficient O-glycans (48,60,61). Yet, the conclusions of many of these reports identify galactose-deficient IgA1 as a hallmark of IgAN and as a marker to discriminate between IgAN patients and healthy individuals.…”

Henoch–Schönlein purpura nephritis

“…Polymeric IgA1 molecules with a reduced content of galactose-carrying GalNac residues (Gd-IgA1) are found in Henoch-Schönlein purpura nephritis and IgA-nephritis patients [35]. The finding of IgA antibodies directed against Gd-IgA1 could explain the lack of IgG deposition, but in a different study although the serum levels of IgA and IgG antibodies against Gd-IgA1 correlated with the clinical progression of IgAN, not all patients had increased levels compared to controls and none showed renal IgG deposition [36]. Therefore, it remains to be proven whether serum antibodies against GdIgA1 are a specific requirement for the formation of the renal IgA1-containing immune complexes found in IgAN.…”

Association of C4d Deposition with Clinical Outcomes in IgA Nephropathy

“…The following processes are involved in the pathogenesis (7) of IgAN: aberrant glycosylation of IgA1 (8), synthesis of antibodies directed against galactosedeficient IgA1, binding of the galactose-deficient IgA1 by antibodies to form immune complexes, and deposition of these complexes in the glomerular mesangium, inducing activation of mesangial cells and glomerular damage (9)(10)(11)(12).…”