Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy

Abstract

IgA nephropathy is an autoimmune disease characterized by IgA1-containing glomerular immune deposits. We previously proposed a multi-hit pathogenesis model in which patients with IgA nephropathy have elevated levels of circulatory IgA1 with some O-glycans deficient in galactose (Gd-IgA1, autoantigen). Gd-IgA1 is recognized by anti-glycan IgG and/or IgA autoantibodies, resulting in formation of pathogenic immune complexes. Some of these immune complexes deposit in the kidney, activate mesangial cells, and incite glomerular injury leading to clinical presentation of IgA nephropathy. Several studies have demonstrated that elevated circulatory levels of either Gd-IgA1 or the corresponding autoantibodies predict progressive loss of renal clearance function. In this study we assessed a possible association between serum levels of Gd-IgA1 and IgG or IgA autoantibodies specific for Gd-IgA1 in serum samples from 135 patients with biopsy-proven IgA nephropathy, 76 patients with other renal diseases, and 106 healthy controls. Our analyses revealed a correlation between the concentrations of the autoantigen and the corresponding IgG autoantibodies in sera of patients with IgA nephropathy, but not of disease or healthy controls. Moreover, our data suggest that IgG is the predominant isotype of Gd-IgA1-specific autoantibodies in IgA nephropathy. This work highlights the importance of both initial hits in the pathogenesis of IgA nephropathy.

Fig 1. Analysis of total Gd-IgA1, Gd-IgA1-specific IgG, and Gd-IgA1-specific IgA in serum samples from patients with IgAN (IgAN), chronic-kidney disease controls (CKD), and healthy controls (HC).

Box and Whisker plots of 10-90^th percentiles with additional points shown as circles (IgAN), squares (CKD), and triangles (HC). Group statistics, including the mean and standard deviation (SD) as well as the result of the D’Agostino & Pearson normality tests, are shown in the tables. Log transformation of each measurement is plotted in the corresponding units, as outlined in Methods.

Fig 2. Serum levels of Gd-IgA1-specific IgG autoantibodies correlate with serum levels of Gd-IgA1 only in patients with IgAN.

Plots of Gd-IgA1 versus Gd-IgA1-specific IgG (A-D) or Gd-IgA1-specific IgA (E-H) in serum samples of patients with IgAN (blue circles; A, E, D, H), CKD controls (red squares; B, F, D, H), or healthy controls (purple triangles; C, G, D, H). Overlays of A-C and E-G are presented in D and H, respectively. Correlation is observed only for Gd-IgA1-specific IgG in IgAN patients (blue circles, r = 0.491) which is depicted by the blue line in panels A and D. No such correlation was observed in either CKD (red) or healthy controls (purple). No correlation was observed for Gd-IgA1-specific IgA autoantibodies. Pearson correlation (r) values and significance (P) are shown for panels A-C and E-G.

Fig 3. IgAN patients predominantly display increased Gd-IgA1-specific IgG.

Plot of the Gd-IgA1-specific IgG versus IgA autoantibodies for the healthy controls (red, H) and IgAN patients (blue, I). Cutoffs were set at 2-standard deviations from the mean values for the healthy controls (1.536 and 0.763 units for IgG and IgA, respectively). Percent occupancy in each quadrant is depicted where occupancy was observed.