title: 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 Y1CA3sequence in similar isotype-matched IgG from healthy controls. We previously found that the S3residue 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)3amino-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 S3hydroxyl 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.
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Zhi Qiang
authors.initials: ZQ
authors.lastname: Huang
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.|Palacky University and University Hospital Olomouc, Olomouc, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Raska
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Stewart
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Colin
authors.initials: C
authors.lastname: Reily
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: R Glenn
authors.initials: RG
authors.lastname: King
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: David K
authors.initials: DK
authors.lastname: Crossman
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Crowley
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Audra
authors.initials: A
authors.lastname: Hargett
authors.affiliation: University of Nebraska Medical Center, Omaha, Nebraska.|West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.|Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Stacy
authors.initials: S
authors.lastname: Hall
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wyatt
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Julian
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Renfrow
authors.affiliation: Columbia University, New York, New York.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama; jannovak@uab.edu.
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
mesh_terms: D001323:Autoantibodies / Q000235:genetics*; D005690:Galactose / Q000172:deficiency*; D005922:Glomerulonephritis, IGA / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A; D009154:Mutation
chemical_list: D001323:Autoantibodies; D007070:Immunoglobulin A; D005690:Galactose
keywords: IgA nephropathy; immune complexes; immunology