Notes: SUMMARY: 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 (GaINAc) 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 GaINAc on cell surface glycoproteins of erythrocytes, platelets, lymphocytes, and/or monocytes is recognized by GaINAc-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 GaINAc residues, a configuration not present in the IgA1 hinge region. the anti-Tn antibodies are of the IgM isotype while GaINAc-specific antibodies in IgAN patients are of the IgG and IgA1 isotypes. Furthermore, monoclonal antibodies to the Tn antigen and sialylated Tn antigens (NeuAcα2,6GaINAc) do not react with intact or glycan-modified IgA1 myeloma proteins. Antibodies to GaINAc 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 nonspecific 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-GaINAc antibodies to Gal-deficient IgA1 profoundly influences the catabolism and tissue distribution of the IgA1. the masking of GaINAc residues by corresponding antibodies diminishes binding to the hepatic asialoglycoprotein receptor (ASGP-R) specific for terminal Gal and GaINAc residues of glycoproteins, and results in the deposition of IgA1-containing IC deposit in the renal mesangium.

Notes: Summary: IgA nephropathy (Berger's disease), the most common primary glomerulonephritis worldwide, leads to end-stage renal failure in 20–40% of patients after 20 years of clinical disease. No consensus has emerged about treatment to slow or prevent the loss of renal function, and in large part this has been due to a critical lack of understanding of the pathogenetic mechanisms. Several approaches that reduce glomerular scarring and inflammation in other renal diseases, including fish oil supplements, anti-inflammatory agents and angiotensin-converting enzyme inhibitors, have been used, with variable results. For patients reaching end-stage, transplantation has shown excellent long-term outcomes.

Notes: Summary: IgA nephropathy (IgAN) is characterized by the deposition of IgA1 in kidney mesangia and the presence of IgA1-containing immune complexes in the circulation. Structural studies of IgA1 isolated from sera of IgAN patients indicated a statistically significant decrease in the content of galactose (Gal). Using a combination of lectins specific for glycans in O- or N-linked glycan side chains, this Gal deficiency was restricted to O-linked glycans present in the hinge region of IgA1 molecules. Gal-deficient IgA1 displayed a significantly higher binding to mesangial cells through a putative non-internalizing receptor specific for N-acetyl galactosamine (GalNAc) in O-linked glycans. These data suggest that Gal deficiency results in diversion of IgA1 molecules from the usual degradative pathway and deposition of altered IgA1 in the mesangium.