New insights into the pathogenesis of IgA nephropathy

Abstract

IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic "hits". An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O-galactosylated IgA1 and the inciting factors for the production of O-glycan-specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression.

Keywords: IgA nephropathy; IgA1; Immune complexes; O-galactosylation; Pathogenesis.

Fig. 1

Structure of human IgA1 and its O-glycans. a IgA1 has an extended hinge region that contains between 3 and 6 O-glycans attached to serine or threonine residue between position 225 to 236 (IgA1 with five O-glycans per hinge region is shown). b Glycosylation of IgA1 is mediated by stepwise co−/post-translational modifications. First, N-acetylgalactosamine (GalNAc) is added to serine/threonine residue by activity of N-acetylgalactosaminyl-transferase (GalNAcT2) (step 1). Next, a galactose moiety is added to GalNAc by core 1 beta 1, 3-galactosyltransferase (C1GalT1) and core 1 β3GalT-specific molecular chaperone (Cosmc) (step 2). Sialic acid may then be added to the galactose moiety by α2,3 sialytransferase (ST2,3) (step 3) or to the GalNAc moiety by α2,6 sialytransferase (ST2,6) (step 4). Alternatively, sialic acid may be added to GalNAc by ST2,6 before the addition of galactose (step 2a). Notably, sialylated GalNAc (step 2a) cannot be subsequently galactosylated, whereas galactosylated GalNAc may be sialylated at either the GalNAc or galactose moiety, or both (step 3 and/or 4). c These steps produce a combination of different O-glycoforms of varying degree of galactosylation and sialylation. The relative proportion of poorly galactosylated IgA1 is increased in IgAN

Fig. 2

A proposed pathogenic model for IgAN with a focus on potential therapeutic targets. In this model, a dysregulated mucosal immune system results in excessive mucosal IgA-committed B cell proliferation in response to mucosal antigen exposure, mediated in part through excessive BAFF and APRIL signaling. As a result of mis-homing of a proportion of these mucosal B cells to systemic sites mucosal IgA is secreted directly into the circulation resulting in elevated serum levels of polymeric, poorly galactosylated IgA1. In susceptible individuals, O-glycan-specific antibodies are formed with the consequent generation of circulating IgA immune complexes, which have a propensity for mesangial deposition. Glomerular accumulation of these IgA immune complexes results in mesangial cell activation, and release of pro-inflammatory and pro-fibrotic mediators, and complement activation. Within this model, there are a number of potential targets (denoted by *) for novel therapeutic agents, many of which are currently under evaluation in clinical trials in IgAN

Fig. 3

Formation of circulating IgA-immune complexes in IgA nephropathy. Polymeric poorly galactosylated IgA1 molecules form the substrate for immune complex formation. O-glycan-specific antibodies: either IgG and IgA1 autoantibodies, or cross-reacting anti-microbial antibodies, bind to the exposed neo-epitopes within the poorly galactosylated IgA1 hinge region. An alternative hypothesis for the formation of circulating IgA immune complexes is that soluble CD89 (sCD89) is shed from myeloid cells in response to polymeric IgA1, and form large circulating IgA1-sCD89 immune complexes

Fig. 4

Pathological consequences of IgA immune complex deposition in IgAN. IgA1 immune complexes deposit in the mesangium and trigger mesangial cell activation, resulting in release of pro-inflammatory, chemotactic, and pro-fibrotic mediators. Released soluble mediators result in mesangial cell proliferation, extracellular matrix (ECM) synthesis, recruitment of inflammatory cells, and in severe cases, glomerular crescent formation. Filtered mesangial cell-derived mediators cause podocyte damage (glomerulopodocytic crosstalk) and with damage to the permselective glomerular basement membrane filtered IgA immune complexes compound podocyte injury. Filtered mesangial cell-derived mediators and IgA immune complexes are also capable of injuring proximal tubule epithelial cells (PTECs), promoting tubulointerstitial inflammation and scarring (glomerulotubular crosstalk). These pathogenic processes result in mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescent formation (C), pathological features that define the Oxford classification and have been shown to be independent predictors of outcome in IgAN