IgA nephropathy (IgA-N) is characterized by the deposition of lgA1 in kidney mesangia and elevated levels of serum lgA1, lgA1-containing immune complexes (lgA1-IC), and lgA1 rheumatoid factor ((gA1-RF). Although elevated levels of lgA1, lgA1-IC, and lgA1-RF are detected in a number of other diseases (e.g., AIDS), lgA1 mesangial deposits are either absent or infrequent. Furthermore, reoccurrences of lgA1 mesangial deposits in IgA-N patients after kidney transplantation suggest an aberrant behavior of lgA1 molecules. Structural studies of lgA1 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 side-chains, we have demonstrated that this Gal deficiency is restricted to O-linked glycans present in the unique hinge region of lgA1 molecules. To determine the impact of Gal deficiency on its biological propertie, lgA1 isolated from patients' sera and myeloma proteins of this subclass structurally modified with relevant glycosidases were tested in vivo and in vitro. Deficiency of Gal in Olinked side chains resulted in an extended half-life in the circulation of mice, decreased deposition in the liver, and increased deposition in the kidney. In vitro, Gal-deficient lgA1 displayed significantly higher binding to human and murine glomeruli, cultured human mesangial cells, and the human monomyelocytic cell line U937 (which expresses Feet-receptor), but decreased binding to hepatocytes. These data suggest that Gal deficiency results in diversion of lgA1 from the usual degradation pathway and deposition of such lgA1 in the mesangium. Supported by DK 28537 and DK 49358.