Role of aberrant glycosylation of IgA1 molecules in the pathogenesis of IgA nephropathy

Abstract

Studies of the properties of immune complexes (IC) in the circulation, urine, and mesangium of IgA nephropathy (IgAN) patients have provided data relevant to the pathogenesis of this disease. IC contain predominantly polymeric IgA1 molecules which are deficient in galactose (Gal) residues on O-linked glycan chains in the hinge region (HR) of their heavy (H) chains. As a result of this aberrancy, a novel antigenic determinant(s) involving N-acetylgalactosamine (GalNAc) and perhaps sialic acid (SA) of O-linked glycans is generated and recognized by naturally occurring GalNAc-specific antibodies. Thus, IC in IgAN consist of Gal-deficient IgA1 molecules as an antigen, and GalNAc-specific IgG and/or IgA1 as an antibody. IgG antibodies to Gal-deficient IgA1 are probably induced by cross-reactive microbial antigens; they are present at variable levels not only in humans with or without IgAN but also in many phylogenetically diverse vertebrate species. Incubation of human mesangial cells with IC from sera of IgAN patients indicated that stimulation of cellular proliferative activity was restricted to the large (>800 kDa) complexes. These findings suggest that experimental approaches that prevent the formation of large Gal-deficient IgA1-IgG IC may be applied ultimately in an immunologically mediated therapy.

Fig. 1.

The HR of human IgA1 and IgA2 including the potential structures of O-linked glycan chains. Glycosyltransferases involved in the biosynthesis and glycosidases involved in the enzymatic removal of sugars are listed on the left and right, respectively. Reactivities of particular O-linked glycans of various structures with lectins specific for GalNAc-β1,3Gal (jacalin) and terminal GalNAc (HAA), ASGP-R expressed on hepatocytes and specific for terminal Gal or GalNAc are specified.

Fig. 2.

Biosynthesis and variants of O-glycans in the HR of human IgA1. Variant 1 reacts with GalNAc-specific lectins, such as HAA; variant 2 reacts with this lectin only after neuraminidase treatment to remove sialic acid (SA); and variants 3 and 4 do not react with HAA. Variants 1 and 2 on serum IgA1 are more common in patients with IgAN than in healthy controls [12, 13, 37, 70]; variants 3 and 4 on the serum IgA1 are more common in healthy controls than in patients with IgAN [71].

Fig. 3.

A model of pathogenesis of IgAN. A portion of IgA1 molecules produced by plasma cells in patients with IgAN is Gal-deficient and is recognized by anti-glycan IgG (or IgA1) antibodies [12, 13, 38, 72] . The formed IC due to their size cannot enter the space of Disse to reach the asialoglycoprotein receptor (ASGP-R) on hepatocytes, but are able to pass through the larger fenestrae in glomerular capillaries overlying the mesangium. These deposited complexes induce glomerular injury and alter the urinary proteome.