Aberrantly glycosylated IgA1 as a factor in the pathogenesis of IgA nephropathy

Abstract

Predominant or codominant immunoglobulin (Ig) A deposition in the glomerular mesangium characterizes IgA nephropathy (IgAN). Accumulated glomerular IgA is limited to the IgA1 subclass and usually galactose-deficient. This underglycosylated IgA may play an important role in the pathogenesis of IgAN. Recently, antibodies against galactose-deficient IgA1 were found to be well associated with the development of IgAN. Several therapeutic strategies based on corticosteroids or other immunosuppressive agents have been shown to at least partially suppress the progression of IgAN. On the other hand, several case reports of kidney transplantation or acquired IgA deficiency uncovered a remarkable ability of human kidney to remove mesangial IgA deposition, resulting in the long-term stabilization of kidney function. Continuous exposure to circulating immune complexes containing aberrantly glycosylated IgA1 and sequential immune response seems to be essential in the disease progression of IgAN. Removal of mesangial IgA deposition may be a challenging, but fundamental approach in the treatment of IgAN.

Figure 1

The galactose-deficient IgA1 molecule and the immune complexes formation in the pathogenesis of IgAN. IgA1 has characteristic hinge regions between the CH₁ and CH₂ domains (CH, the constant regions of the heavy chain), which contain at least six serine (Ser) or threonine (Thr) residues as O-linked glycosylation sites. In the first step, the enzyme polypeptide N-acetylgalactosaminyltransferase (pp-GalNAc-T2) facilitates the attachment of N-acetylgalactosamine (GalNAc) to these residues. In the second step, the IgA1 glycosylation is extended in two ways. One is the binding of N-acetylneuraminic acid (NeuNAc) to GalNAc through the action of the enzyme N-acetylgalactosamine-specific α2,6-sialyltransferas (ST6GalNAc2) [17]. The other is galactose (Gal) connection to GalNAc through the enzyme core 1 β1,3 galactosyltransferase (C1GalT1) and core-1-β3-Gal-T specific molecular chaperone (Cosmc) [18]. The imbalance between those activities may promote galactose-deficient IgA1 production [10, 18]. Galactose-deficient IgA1 is aggregated with antiglycan IgG or IgA1 antibodies, resulting in formation of immune complexes [13], which may escape the normal catabolism in liver and also accumulate with high affinity in glomerular mesangium.

Figure 2

Repeated kidney biopsies in an HSPN patient with acquired IgA deficiency. (a, b) The first kidney biopsy (performed at 7 years old) showing necrotizing crescentic glomerulonephritis with advanced glomerulosclerosis and severe tubulointerstitial nephritis, which was compatible with HSPN grade 5b. (c, d) The fourth kidney biopsy (performed at 21 years old) showing minor glomerular abnormalities. Kidney biopsy samples were stained with periodic acid methenamine silver (a, b, and c), and periodic acid Schiff (d), respectively. Original magnifications were ×10 (a, c) and ×40 (b, d), respectively.