Pathogenic potential of galactose-deficient IgA1 in IgA nephropathy

Recent studies have demonstrated that immune complexes (IC) in the circulation and mesangial deposits in IgA nephropathy (IgAN) patients contain IgA1 molecules deficient in galactose (Gal) in their O -linked hinge-region-associated glycans. Due to this Gal deficiency, terminal n -acetylgalactosamine (GalNAc) in these side chains is recognized by naturally occurring IgG and IgA1 antibodies as an antigenic determinant responsible for the formation of IC. Thus, IgAN can be classified as one of several human autoimmune diseases in which glycan aberrancies play a pathogenic role. In a rare disease, Tn syndrome, terminal GalNAc on cell surface glycoproteins of erythrocytes, platelets, lymphocytes, and/or monocytes is recognized by GalNAc-specific antibodies, resulting in their in vitro agglutination and in vivo manifestations (anaemia and thrombocytopenia). However, the antigenic determinants and corresponding antibodies in Tn syndrome differ from those of IgAN. The Tn antigen is composed of three adjacent GalNAc residues, a configuration not present in the IgA1 hinge region. The anti-Tn antibodies are of the IgM isotype while GalNAc-specific antibodies in IgAN patients are of the IgG and IgA1 isotypes. Furthermore, monoclonal antibodies to the Tn antigen and sialylated Tn antigens (NeuAcalpha2,6GalNAc) do not react with intact or glycan-modified IgA1 myeloma proteins. Antibodies to GalNAc are present in cord blood (devoid of IgM and IgA1) and in purified serum IgG. The true antigen (Gal-deficient IgA1)-antibody (IgG or IgA1) interaction, rather than non-specific aggregation, was demonstrated by the dissociation of circulating IC from IgAN patients at acid pH but not in high-salt concentrations, and the in vitro reassociation at neutral pH (and its inhibition by de-galactosylated IgA1). The binding of anti-GalNAc antibodies to Gal-deficient IgA1 profoundly influences the catabolism and tissue distribution of the IgA1. The masking of GalNAc residues by corresponding antibodies diminishes binding to the hepatic asialoglycoprotein receptor (ASGP-R) specific for terminal Gal and GalNAc residues of glycoproteins, and results in the deposition of IgA1-containing IC deposit in the renal mesangium.