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J Am Soc Nephrol. 2016 Nov;27(11):3278-3284. Epub 2016 Mar 10.

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

Author information

1
University of Alabama at Birmingham, Birmingham, Alabama.
2
Palacky University and University Hospital Olomouc, Olomouc, Czech Republic.
3
University of Nebraska Medical Center, Omaha, Nebraska.
4
West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
5
Juntendo University Faculty of Medicine, Tokyo, Japan.
6
University of Tennessee Health Science Center, Memphis, Tennessee; and.
7
Columbia University, New York, New York.
8
University of Alabama at Birmingham, Birmingham, Alabama; jannovak@uab.edu.

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 β-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.

KEYWORDS:

IgA nephropathy; immune complexes; immunology

PMID:
26966014
PMCID:
PMC5084875
[Available on 2017-11-01]
DOI:
10.1681/ASN.2014101044
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