Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies

Circulating immune complexes (CICs) isolated from sera of patients with IgA nephropathy (IgAN) consist of undergalactosylated, mostly polymeric, and J chain-containing IgA1 and IgG antibodies specific for N-acetylgalactosamin e (GalNAc) residues in O-linked glycans of the hinge region of IgA1 heavy c hains. Antibodies with such specificity occur in sera of IgAN patients, and in smaller quantities in patients with non-IgA proliferative glomeruloneph ritis and in healthy controls; they are present mainly in the IgG (predomin antly IgG2 subclass), and less frequently in the IgA1 isotype. Their specif icity for GalNAc was determined by reactivity with IgA1 myeloma proteins wi th enzymatically removed N-acetylneuraminic acid (NeuNAc) and gallactose (G al); removal of the O-linked glycans of IgA1 resulted in significantly decr eased reactivity. Furthermore, IgA2 proteins that lack the hinge region wit h O-linked glycans but are otherwise structurally similar to IgA1 did not r eact with IgG or IgA1 antibodies. The re-formation of isolated and acid-dis sociated CICs was inhibited more effectively by IgA1 lacking NeuNAc and Gal than by intact IgA1. Immobilized GalNAc and asialo-ovine submaxillary muci n (rich in O-linked glycans) were also effective inhibitors. Our results su ggest that the deficiency of Gal in the hinge region of IgA1 molecules resu lts in the generation of antigenic determinants containing GalNAc residues that are recognized by naturally occurring IgG and IgA1 antibodies.