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Analysis of O‐glycosylation of IgA1: Implications for IgA Nephropathy (IgAN)
Author(s) -
Novak Jan,
Suzuki Hitoshi,
Wall Stephanie B.,
Lyas Claretha N.,
Gomes Michelle M.,
Moldoveanu Zina,
Julian Bruce A.,
Hall Stacy,
Brown Rhubell,
Kilian Mogens,
Poulsen Knud,
Mestecky Jiri,
Herr Adrew B.,
Renfrow Matthew B.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.469
Subject(s) - glycan , glycosylation , chemistry , antibody , epitope , immunoglobulin a , blot , microbiology and biotechnology , immunoglobulin g , biochemistry , immunology , biology , glycoprotein , gene
IgA1 in the circulation and glomerular deposits of IgAN patients is aberrantly glycosylated; hinge‐region O ‐glycans are galactose (Gal)‐deficient (Gd‐IgA1). Gd‐IgA1 produced in polymeric form by IgA1‐secreting cells is recognized by anti‐glycan antibodies, resulting in formation of immune complexes (IC). IgA1 contains several clustered O ‐glycosylation sites per heavy chain. To address the question whether the glycosylation defects occur randomly or preferentially at specific sites and what epitopes are recognized by the antibodies, we analyzed several IgA1 myeloma proteins. We included two Gd‐IgA1 myeloma proteins with distinct characteristics; only one of them bound anti‐glycan IgG and formed IC. O ‐glycans were analyzed after digestion with bacterial IgA proteases by lectin‐western blotting and high‐resolution mass spectrometry. Both proteins had Gal‐deficient glycans at residues T228/S230, but differed in the distribution of Gal‐containing sites. Only the IgA1 protein that bound IgG had no Gal‐containing site in the distal hinge region. Furthermore, patients with IgAN had circulatory Gd‐IgA1 with similarly localized defects. In conclusion, Gal‐deficient O ‐glycans are localized at specific sites of IgA1 and their recognition by anti‐glycan IgG and thus IC formation may also be affected by adjacent glycans. Supported by NIH grants DK078244, DK071802, and DK080301.