Aberrant glycosylation of IgA from patients with IgA nephropathy

Abstract

Despite the prominent role of IgA, particularly IgA1, in the pathogenesis of IgA nephropathy (IgAN), the precise role of this molecule in the process remains unclear. Four biotin-conjugated lectins in sandwich-type enzyme-linked immunosorbent assays were devised to determine the glycosylation profiles of total IgA and its subclasses. We took advantage of differential binding properties of these lectins to sugar residues to dissect the oligosaccharide chains O-linked to the hinge and those N-linked to the Fc region of total IgA and IgA subclasses in 47 patients with IgAN and an equal number of controls. The proportion of sialylated IgA1 was higher in patients compared with controls (p < 0.02), whereas IgA2 in patients appeared less well sialylated. A reduction of galactose in pathological IgA as detected by RCA-I became significant after treatment of the molecule with neuraminidase (p < 0.01). Defective galactosylation was also observed for patient IgA1 when it was probed with ECL, a lectin that has a specificity for Gal 1,4 N-acetylglucosamine groupings on N-linked oligosaccharides. The RCA and ECL results, therefore, suggest that increased sialylation on the IgA1 is on O-linked oligosaccharides in the hinge region. This was partly confirmed by a small increase in the binding of PNA to IgA1 from the patient group. This lectin binds preferentially to Gal 1,3 N-acetylgalactosamine groups that are found on O-linked oligosaccharides.

Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies

“…Several recent studies have shown that a portion of IgA1 molecules in sera of IgAN patients display alterations in O-linked (9)(10)(11)(12)(13)(14)(15)(16)(17), and perhaps N-linked (10), glycans. The most frequently encountered changes were restricted to Gal (9)(10)(11)(12)(13)(14)(15)(16)(17) and NeuNAc (14) in O-linked IgA1 hinge region glycans, as determined by reactivities with NeuNAc-, Gal-, and GalNAc-specific lectins and direct carbohydrate analyses. Studies of lectin reactivities of serum fractions from IgAN patients and from healthy individuals obtained by size-exclusion chromatography revealed Gal-deficient IgA1 molecules in high-molecular-mass fractions containing IgA1 and IgG (9).…”

Genetic remodeling of protein glycosylation in vivo induces autoimmune disease

“…Immunoglobulins with affinity for the Fc region of IgG molecules are found in rheumatoid arthritis, and the severity of the disease is associated with the extent of galactose-deficient N-glycans on Fc (8). Human IgA nephropathy has been associated with altered O-glycosylation of the IgA1 hinge region and Ig deposition in the kidney (9,10). Another possible role for aberrant glycan production in autoimmune disease includes Tn syndrome, in which reduced transcription of the core 1 O-glycan ␤1-3 GalT enzyme occurs among hematopoietic compartments.…”

Development of Immunoglobulin A Nephropathy- Like Disease in β-1,4-Galactosyltransferase-I-Deficient Mice

“…Although many studies have focused on the aberrant O-glycosylation of IgA in human IgAN, there are several reports suggesting that the N-glycosylation on serum IgA from IgAN patients is also defective. 50,51 This study, therefore, suggests that truncation of not only the O-glycans but also the N-glycans of IgA might participate in the development of IgAN in humans and argues that the N-glycans on IgA in the sera from IgAN patients should be analyzed in further detail. An infant patient with a mutation in the ␤4GalT-I gene, designated as a CDG-IId mutation, was reported to suffer from severe psychomotor retardation and muscle weakness.…”