The pathophysiology of IgA nephropathy

Abstract

Here we discuss recent advances in understanding the biochemical, immunologic, and genetic pathogenesis of IgA nephropathy, the most common primary glomerulonephritis. Current data indicate that at least four processes contribute to development of IgA nephropathy. Patients with IgA nephropathy often have a genetically determined increase in circulating levels of IgA1 with galactose-deficient O-glycans in the hinge-region (Hit 1). This glycosylation aberrancy is, however, not sufficient to induce renal injury. Synthesis and binding of antibodies directed against galactose-deficient IgA1 are required for formation of immune complexes that accumulate in the glomerular mesangium (Hits 2 and 3). These immune complexes activate mesangial cells, inducing proliferation and secretion of extracellular matrix, cytokines, and chemokines, which result in renal injury (Hit 4). Recent genome-wide association studies identify five distinct susceptibility loci--in the MHC on chromosome 6p21, the complement factor H locus on chromosome 1q32, and in a cluster of genes on chromosome 22q22--that potentially influence these processes and contain candidate mediators of disease. The significant variation in prevalence of risk alleles among different populations may also explain some of the sizable geographic variation in disease prevalence. Elucidation of the pathogenesis of IgA nephropathy provides an opportunity to develop disease-specific therapies.

Figure 1.

Human IgA1: hinge-region amino acid sequence (A) and possible glycan variants (B). (A) IgA1 contains up to six O-glycans per hinge region: five major sites are shown (in orange or magenta) and the sixth site is Thr233. Novel approaches using IgA-specific bacterial proteases and lectin binding, and, more recently, high-resolution mass spectrometry with electron capture and electron transfer dissociation, have been used to determine O-glycan heterogeneity, the sites of glycosylation, and the microheterogeneity at the individual sites.^,,,, The model of intact IgA1 was generated from published crystal and solution structures of IgA1.^, N- and O-glycans were modeled using the GlyProt server and related databases (http://www.glycosciences.de), based on observed IgA1 glycoforms.^, For clarity, the O-glycans are shown with transparent spheres for each atom, and are colored orange for GalNAc-galactose residues and magenta for GalNAc; the illustrated O-glycan distribution was taken from a study by Takahashi et al. (B) The variants of O-glycans on circulatory IgA1. Galactose-deficient glycans present in elevated amounts in patients with IgAN are represented by structures I and II in magenta.^, Galactosylated variants are in orange as structures III to VI. The largest O-glycan on circulatory IgA1 is a GalNAc-galactose with two sialic acids, i.e., tetrasaccharide, structure VI. IgA1 with GalNAc and sialylated GalNAc (structures I and II in magenta) is present at elevated serum levels in patients with IgAN due to the changes in expression and activity of specific glycosyltransferases, ST6GalNAcII, and C1GalT1. The stability of C1GalT1 during translation is controlled by Cosmc, a foldase. Structure I is generated by a GalNAc-transferase; structure II, by ST6GalNAcII; structure III, from structure I by C1GalT1; and structures IV to VI, by sialyltransferases. Symbols: rectangle, GalNAc; circle, galactose; diamond, sialic acid.

Figure 2.

Proposed pathways involved in the pathogenesis of IgAN: multi-hit mechanism. Hit 1: Production of galactose-deficient IgA1 by a subpopulation of IgA1-secreting cells. IgA1 production may be affected by the IgAN-associated locus on chromosome 22q12.2. Hit 2: Formation of anti-glycan antibodies with specific characteristics of the variable region of the heavy chain that recognize galactose-deficient IgA1. Hit 3: Formation of immune complexes from autoantigen (galactose-deficient IgA1) and O-glycan-specific antibodies. Hits 2 and 3 may be regulated by the three MHC loci on chromosome 6p21 associated with risk of IgAN. Hit 4: Deposition of pathogenic immune complexes in the mesangium, activation of mesangial cells, and induction of glomerular injury. Hits 3 and 4 may be affected by genotype at the complement factor H locus on chromosome 1q32 that regulates the alternative complement cascade. The first pathway assumes formation of immune complexes in the circulation and their subsequent mesangial deposition (solid lines).^,,, An alternative theory proposes that some of the aberrantly glycosylated IgA1 molecules are in the mesangium as lanthanic deposits (left broken line) and are later bound by newly generated anti-glycan antibodies to form immune complexes in situ (right broken line) that activate mesangial cells. ECM, extracellular matrix.