New Insights into the Pathogenesis of IgA Nephropathy

Abstract

Background: IgA nephropathy, a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli and induce renal injury. Multiple genetic loci associated with disease risk have been identified. The prevalence of risk alleles varies geographically, highest in eastern Asia and northern Europe, fewer in other parts of Europe and North America, and the least in Africa. IgA nephropathy is diagnosed from pathological assessment of a renal biopsy specimen. Currently, therapy is not disease-targeted but rather is focused on maintaining control of blood pressure and proteinuria, ideally with suppression of angiotensin II. Possible additional approaches differ between countries. Disease-specific therapy as well as new tools for diagnosis, prognosis, and assessment of responses to therapy are needed.

Summary: Glycosylation pathways associated with aberrant O-glycosylation of IgA1 and, thus, production of autoantigen, have been identified. Furthermore, unique characteristics of the autoantibodies in IgA nephropathy have been uncovered. Many of these biochemical features are shared by patients with IgA nephropathy and Henoch-Schönlein purpura nephritis, suggesting that the two diseases may represent opposite ends of a spectrum of a disease process. Understanding the molecular mechanisms involved in formation of pathogenic IgA1-containing immune complexes will enable development of disease-specific therapies as well as diagnostic and prognostic biomarkers.

Key messages: IgA nephropathy is an autoimmune disease caused by glomerular deposition of nephritogenic circulating immune complexes consisting of galactose-deficient IgA1 (autoantigen) bound by anti-glycan autoantibodies. A better understanding of the multi-step process of pathogenesis of IgA nephropathy and the genetic and environmental contributing factors will lead to development of biomarkers to identify patients with progressive disease who would benefit from a future disease-specific therapy.

Keywords: Autoantibodies; IgA nephropathy; O-glycans; galactose deficiency; immune complexes.

Fig. 1

Hypothesis on the pathogenesis of IgA nephropathy. Synthesis of IgA1 with some O-glycans deficient in galactose (autoantigen) is elevated. Gd-IgA1 is present in the circulation at increased levels (hit 1). This immunoglobulin is recognized by unique circulating anti-glycan autoantibodies (hit 2) [13,14,20]. This process results in the formation of pathogenic IgA1-containing circulating immune complexes (hit 3), some of which deposit in the glomeruli and induce renal injury (hit 4) [20]. Upstream factors are likely involved in abnormal mucosal immune responses characteristic for patients with IgA nephropathy [3]. An alternative hypothesis has been proposed to suggest that aberrantly glycosylated IgA1 accumulates in the mesangium as lanthanic deposits that are later bound by newly appearing autoantibodies, resulting in the in situ formation of immune complexes [92]. All hits and additional factors may be genetically regulated; 15 distinct genetic loci have been identified by genome-wide association studies to be associated with the risk of IgA nephropathy [7,38]. It is certainly possible that other loci may influence the mechanisms of disease or the clinical expression of IgA nephropathy. ECM = Extracellular matrix.

Fig. 2

Structure and O-glycosylation of human circulatory IgA1: monomeric IgA1 and hinge-region amino acid sequence with the sites of O-glycan attachment (top and middle panels). There are nine threonine and serine amino acids in the hinge region of monomeric IgA1 that can serve as the site for O-glycosylation (in red). Of these, usually up to six have an attached O-linked glycan (underlined and numbered in the amino acid sequence in the middle panel) in serum IgA1 [30]. The most common core 1 glycan consists of a disaccharide of GalNAc and galactose, with or without sialic acid. Serum levels of IgA1 with galactose-deficient glycans (red arrows in the bottom panel) are elevated in patients with IgA nephropathy. The sites most commonly found to have galactose-deficient glycans are shown in italics (S230, T233, T236 in the middle panel) [30]. See table 1 for details on glycoforms of normal serum IgA1.