The genetics and immunobiology of IgA nephropathy

Abstract

IgA nephropathy (IgAN) represents the leading cause of kidney failure among East Asian populations and the most frequent form of primary glomerulonephritis among Europeans. Patients with IgAN develop characteristic IgA1-containing immune complexes that deposit in the glomerular mesangium, producing progressive kidney injury. Recent studies define IgAN as an autoimmune trait of complex architecture with a strong genetic determination. This Review summarizes new insights into the role of the O-glycosylation pathway, anti-glycan immune response, mucosal immunity, antigen processing and presentation, and the alternative complement pathway in the pathogenesis of IgAN.

Figure 1. IgA1 structure and O-glycosylation pathway.

(A) Structure of monomeric IgA1 and its hinge region in comparison with IgA2 (A2m(l) allotype) (36). The IgA1 hinge region consists of a short amino acid sequence between CH1 and CH2 of the α1 heavy chain. In contrast to IgA2, the IgA1 hinge region contains two octapeptide repeats composed of Ser, Thr, and proline (Pro) residues (arrows). Of the nine potential Ser and Thr O-glycosylation sites, three to six are usually occupied (numbered Ser/Thr residues) (–29). (B) Biosynthesis of hinge-region O-glycans of human circulatory IgA1. The possible structures of O-glycans in the hinge region of IgA1 include GalNAc with galactose that may contain up to two N-acetylneuraminic acid residues. Galactose-deficient glycans include terminal or sialylated GalNAc. Enzymes catalyzing the specific steps in this pathway are shown.

Figure 2. Intestinal network of IgA production.

IgA is the most abundant antibody isotype in the body, with the majority of IgA found in mucosal secretions. Mucosal IgA production is induced by T cell–dependent or T cell–independent mechanisms. T cell–independent production of IgA is primarily stimulated by IL-6, IL-10, TGF-β, BAFF, and APRIL produced by intestinal epithelial, dendritic, and stromal cells. In this environment, intestinal B cells undergo class switching from IgM to IgA1. IgA1 to IgA2 class switching can also occur and is promoted by APRIL and the mucosal milieu. IgA-secreting plasma cells migrate to lamina propria, where they release dimeric IgA. The dimers are formed through an interaction of two IgA molecules with a joining chain, which is synthesized by plasma cells. IgA dimers can bind to the polymeric Ig receptor (pIgR) on the basolateral surface of the mucosal epithelium and undergo transcytosis to the apical surface, where they dissociate from pIgR and are secreted into the lumen, carrying the secretory component of the receptor. The secretory component protects IgA molecules from proteolytic enzymes in the gut lumen. The bacteriostatic effects of secretory IgA are accompanied by antimicrobial peptides, such as defensins, secreted into the gut lumen by Paneth cells. The key molecules involved in the intestinal network of IgA production are indicated in orange; molecules implicated by GWAS are indicated in red.