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Somatic Mutations Modulate Autoantibodies against Galactose-Deficient IgA1 in IgA Nephropathy.

ABSTRACT: Autoantibodies against galactose-deficient IgA1 drive formation of pathogenic immune complexes in IgA nephropathy. IgG autoantibodies against galactose-deficient IgA1 in patients with IgA nephropathy have a specific amino-acid sequence, Y1CS3, in the complementarity-determining region 3 of the heavy chain variable region compared with a Y1CA3 sequence in similar isotype-matched IgG from healthy controls. We previously found that the S3 residue is critical for binding galactose-deficient IgA1. To determine whether this difference is due to a rare germline sequence, we amplified and sequenced the corresponding germline variable region genes from peripheral blood mononuclear cells of seven patients with IgA nephropathy and six healthy controls from whom we had cloned single-cell lines secreting monoclonal IgG specific for galactose-deficient IgA1. Sanger DNA sequencing revealed that complementarity-determining region 3 in the variable region of the germline genes encoded the Y1C(A/V)3 amino-acid sequence. Thus, the A/V>S substitution in the complementarity-determining region 3 of anti-galactose-deficient-IgA1 autoantibodies of the patients with IgA nephropathy is not a rare germline gene variant. Modeling analyses indicated that the S3 hydroxyl group spans the complementarity-determining region 3 loop stem, stabilizing the adjacent ?-sheet and stem structure, important features for effective binding to galactose-deficient IgA1. Understanding processes leading to production of the autoantibodies may offer new approaches to treat IgA nephropathy.

SUBMITTER: Huang ZQ

PROVIDER: S-EPMC5084875 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Somatic Mutations Modulate Autoantibodies against Galactose-Deficient IgA1 in IgA Nephropathy.

Huang Zhi Qiang ZQ Raska Milan M Stewart Tyler J TJ Reily Colin C King R Glenn RG Crossman David K DK Crowley Michael R MR Hargett Audra A Zhang Zhixin Z Suzuki Hitoshi H Hall Stacy S Wyatt Robert J RJ Julian Bruce A BA Renfrow Matthew B MB Gharavi Ali G AG Novak Jan J

Journal of the American Society of Nephrology : JASN 20160310 11

Autoantibodies against galactose-deficient IgA1 drive formation of pathogenic immune complexes in IgA nephropathy. IgG autoantibodies against galactose-deficient IgA1 in patients with IgA nephropathy have a specific amino-acid sequence, Y1CS3, in the complementarity-determining region 3 of the heavy chain variable region compared with a Y1CA3 sequence in similar isotype-matched IgG from healthy controls. We previously found that the S3 resid ...[more]

PMID: 26966014

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Project description:IntroductionPatients with IgA nephropathy (IgAN) have elevated serum levels of galactose-deficient IgA1 (Gd-IgA1) that are bound by Gd-IgA1-specific autoantibodies in pathogenic immune complexes. Renal biopsy histopathologic features of IgA vasculitis (IgAV) with nephritis (IgAV-N) are similar to those of IgAN. Mucosal infections often are associated with clinical onset and exacerbation in both diseases. We investigated whether patients with IgAV-N share pathogenic characteristics of IgAN.MethodsWe generated IgA1- and IgG-secreting cell lines from Epstein-Barr virus (EBV)-immortalized cells of patients with IgAV without nephritis (IgAV-woN), IgAV-N, and IgAN and from healthy individuals. Sera and cell-culture supernatants were used for analysis of Gd-IgA1 and Gd-IgA1-specific IgG autoantibodies.ResultsIgA1-producing cells from patients with IgAV-N, like cells from patients with IgAN, secreted more Gd-IgA1 than did cells from patients with IgAV-woN or healthy control subjects, in agreement with elevated serum Gd-IgA1 levels in patients with IgAV-N and IgAN. IgA1-producing cells from patients with IgAV-N had altered expression of genes involved in O-glycan biosynthesis: decreased for core 1 synthase (glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1; C1GALT1) and C1GALT1 Specific Chaperone 1 (C1GALTC1; COSMC) and elevated for N-acetylgalactosaminide α-2,6-sialyltransferase 2 (ST6GALNAC2). Levels of Gd-IgA1-specific IgG in sera and supernatants of IgG-producing cells were similar for patients with IgAV-N and IgAN and higher than those for IgAV-woN patients or healthy control subjects. Moreover, patients with IgAV-N who had active disease, manifested by hematuria and substantial proteinuria, had higher serum levels of Gd-IgA1-specific IgG autoantibodies than did patients with IgAV-N who had inactive disease.ConclusionSerum levels and cellular production of Gd-IgA1 and Gd-IgA1-specific IgG autoantibodies were elevated in patients with IgAV-N, supporting the hypothesis that IgAV-N and IgAN share pathogenic features.

Project description:Background and objectivesIncreased circulating galactose-deficient IgA1 and subsequently complement activation both play important roles in the pathophysiology of IgA nephropathy. However, their relationship to disease severity and progression remains unclear.Design, setting, participants, & measurementsWe assessed 1210 participants in a cohort study of biopsy-proven IgA nephropathy at Peking University First Hospital. Plasma concentrations of galactose-deficient IgA1 and complement component C3 were measured at the time of biopsy. We tested associations of galactose-deficient IgA1 and galactose-deficient IgA1/C3 ratio with CKD progression event, defined as ESKD or 50% decline in eGFR, using Cox proportional hazards models and restricted cubic splines.ResultsAfter a median follow-up of 43 months (interquartile range, 24-76 months), 172 (14%) participants reached the CKD progression event. The association of galactose-deficient IgA1 levels and CKD progression event showed a nonlinear relationship. The risk of CKD progression events was greater with higher plasma galactose-deficient IgA1 levels but reached a plateau when galactose-deficient IgA1>325 U/ml, whereas the risk of CKD progression events monotonically increased with higher galactose-deficient IgA1/C3 ratio. After adjustment for traditional risk factors (demographics, eGFR, proteinuria, hypertension, Oxford pathologic score, and corticosteroids/immunosuppressive therapy), higher levels of galactose-deficient IgA1/C3 ratio were independently associated with CKD progression event (per natural log-transformed [galactose-deficient IgA1/C3], hazard ratio, 2.03; 95% confidence interval [95% CI], 1.25 to 3.29; P=0.004). In reference to the first quartile of the galactose-deficient IgA1/C3 ratio, hazard ratios were 1.71 (95% CI, 1.01 to 2.89) for the second quartile, 1.55 (95% CI, 0.91 to 2.63) for the third quartile, and 2.17 (95% CI, 1.33 to 3.56) for the fourth quartile.ConclusionsIn IgA nephropathy, plasma galactose-deficient IgA1/C3 ratio was associated with CKD progression event independent of clinical and biopsy characteristics.

Dataset Information

Somatic Mutations Modulate Autoantibodies against Galactose-Deficient IgA1 in IgA Nephropathy.

Publications

Somatic Mutations Modulate Autoantibodies against Galactose-Deficient IgA1 in IgA Nephropathy.

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