Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy.

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.

[1]  R. Camilla,et al.  Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating factor that mediates nephrin loss in cultured podocytes. , 2010, Kidney international.

[2]  J. Barratt,et al.  Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients. , 2001, Kidney international.

[3]  B. Julian,et al.  Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG. , 1997, Kidney international.

[4]  Yusuke Suzuki,et al.  Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. , 2009, The Journal of clinical investigation.

[5]  Y. Hiki,et al.  Underglycosylation of IgA1 hinge plays a certain role for its glomerular deposition in IgA nephropathy. , 1999, Journal of the American Society of Nephrology : JASN.

[6]  J. Berger.  IgA glomerular deposits in renal disease. , 1969, Transplantation proceedings.

[7]  B. Julian,et al.  IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. , 2005, Kidney international.

[8]  B. Julian,et al.  Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[9]  S. Harper,et al.  Galactosylation of N‐ and O‐linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy , 1995, Clinical and experimental immunology.

[10]  Y. Hiki,et al.  Evaluation of the specific structures of IgA1 hinge glycopeptide in 30 IgA nephropathy patients by mass spectrometry. , 2010, Journal of nephrology.

[11]  B. Julian,et al.  Oxidative stress and galactose-deficient IgA1 as markers of progression in IgA nephropathy. , 2011, Clinical journal of the American Society of Nephrology : CJASN.

[12]  H. Cooper,et al.  Determination of Aberrant O-Glycosylation in the IgA1 Hinge Region by Electron Capture Dissociation Fourier Transform-Ion Cyclotron Resonance Mass Spectrometry* , 2005, Journal of Biological Chemistry.

[13]  B. Julian,et al.  Recognition of galactose-deficient O-glycans in the hinge region of IgA1 by N-acetylgalactosamine-specific snail lectins: a comparative binding study. , 2010, Biochemistry.

[14]  A. Michael,et al.  Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus. , 1980, The Journal of clinical investigation.

[15]  J. Berger,et al.  Intercapillary deposits of IgA-IgC. , 2000, Journal of the American Society of Nephrology : JASN.

[16]  S. Bellur,et al.  Immunostaining findings in IgA nephropathy: correlation with histology and clinical outcome in the Oxford classification patient cohort. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[17]  J. Barratt,et al.  Analysis of IgA1 O-glycans in IgA nephropathy by fluorophore-assisted carbohydrate electrophoresis. , 1999, Journal of the American Society of Nephrology : JASN.

[18]  J. Berger,et al.  [Intercapillary deposits of IgA-IgG]. , 1968, Journal d'urologie et de nephrologie.

[19]  R. Lifton,et al.  Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. , 2008, Journal of the American Society of Nephrology : JASN.

[20]  Y. Hiki,et al.  Analyses of IgA1 hinge glycopeptides in IgA nephropathy by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. , 1998, Journal of the American Society of Nephrology : JASN.

[21]  Jonathan Barratt,et al.  An update on the pathogenesis and treatment of IgA nephropathy. , 2012, Kidney international.

[22]  Michael J Pencina,et al.  Equivalence of improvement in area under ROC curve and linear discriminant analysis coefficient under assumption of normality , 2011, Statistics in medicine.

[23]  L. Thibaudin,et al.  Predicting the risk for dialysis or death in IgA nephropathy. , 2011, Journal of the American Society of Nephrology : JASN.

[24]  Y. Hiki,et al.  Serum under-galactosylated IgA1 is increased in Japanese patients with IgA nephropathy. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[25]  F. Berthoux,et al.  Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses. , 1991, American Journal of Kidney Diseases.

[26]  B. Julian,et al.  Reactivities of N-acetylgalactosamine-specific lectins with human IgA1 proteins. , 2007, Molecular immunology.

[27]  B. Julian,et al.  The pathophysiology of IgA nephropathy. , 2011, Journal of the American Society of Nephrology : JASN.

[28]  Michael J Pencina,et al.  Novel metrics for evaluating improvement in discrimination: net reclassification and integrated discrimination improvement for normal variables and nested models , 2012, Statistics in medicine.

[29]  B. Julian,et al.  Aberrant glycosylation of IgA1 is inherited in both pediatric IgA nephropathy and Henoch-Schönlein purpura nephritis. , 2011, Kidney international.

[30]  G. Alarcón,et al.  IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. , 2008, The Journal of clinical investigation.

[31]  F. Berthoux,et al.  Natural history of primary IgA nephropathy. , 2008, Seminars in nephrology.

[32]  B. Julian,et al.  Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. , 1999, The Journal of clinical investigation.

[33]  Y. Hiki,et al.  Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy. , 2001, Kidney international.

[34]  B. Julian,et al.  Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. , 2007, Kidney international.

[35]  Hong Zhang,et al.  Aberrant galactosylation of IgA1 is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[36]  B. Julian,et al.  IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[37]  B. Julian,et al.  IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy. , 2008, Seminars in nephrology.