Structural heterogeneity of glycans in IgA molecules: Implications for IgA nephropathy

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Abstract
Summary: The carbohydrate moieties on glycoproteins, including immunoglobulins (Ig), are involved in a broad spectrum of biological functions. As revealed by enzymatic or chemical removal of carbohydrate moieties, inhibition of glycosylation, or site‐directed mutagenesis of asparagine residues to prevent N‐linked glycosylation, carbohydrates on Ig have been shown to participate in binding, internalization and catabolism by hepatocytes or other cells, binding to Fc receptors on phagocytic cells, activation of complement, and opsonization. the structure of human IgA1 is unique among all Ig. the heavy chain contains a hinge region with a characteristic primary structure not seen in any other Ig, and which contains five short O‐linked oligosaccharide side‐chains composed of serine‐linked N‐acetylgalactosamine (GalNAc) and βl‐3‐linked galactose (Gal). Both of these monosaccharides may be sialylated. In contrast to ubiquitous N‐linked side‐chains, O‐linked carbohydrate moieties are found rarely among human serum glycoproteins. We have demonstrated that IgA1 proteins from the sera of patients with IgA nephropathy (IgAN) are galactosylated to a lesser extent than those from healthy controls. Decreased content of Gal and decreased reactivity of IgA from IgAN patients with lectins specific for GalNAc indicate that these structural changes occur on glycans located in the hinge region of IgA1. Thus, in addition to rheumatoid arthritis, systemic lupus erythmatosus, inflammatory bowel disease and other disorders, IgA nephropathy may represent another example of a chronic disease in which aberrancies of carbohydrates are observed and may participate in aetiopathogenesis.