Glycosylation and Size of IgA1 Are Essential for Interaction with Mesangial Transferrin Receptor in IgA Nephropathy

Abstract

Transferrin receptor (TfR) has been identified as a candidate IgA1 receptor expressed on human mesangial cells (HMC). TfR binds IgA1 but not IgA2, co-localizes with mesangial IgA1 deposits, and is overexpressed in patients with IgA nephropathy (IgAN). Here, structural requirements of IgA1 for its interaction with mesangial TfR were analyzed. Polymeric but not monomeric IgA1 interacted with TfR on cultured HMC and mediates internalization. IgA1 binding was significantly inhibited (>50%) by soluble forms of both TfR1 and TfR2, confirming that TfR serves as mesangial IgA1 receptor. Hypogalactosylated serum IgA1 from patients with IgAN bound TfR more efficiently than IgA1 from healthy individuals. Serum IgA immune complexes from patients with IgAN containing aberrantly glycosylated IgA1 bound more avidly to TfR than those from normal individuals. This binding was significantly inhibited by soluble TfR, highlighting the role of TfR in mesangial IgA1 deposition. For addressing the potential role of glycosylation sites in IgA1-TfR interaction, a variety of recombinant dimeric IgA1 molecules were used in binding studies on TfR with Daudi cells that express only TfR as IgA receptor. Deletion of either N- or O-linked glycosylation sites abrogated IgA1 binding to TfR, suggesting that sugars are essential for IgA1 binding. However, sialidase and beta-galactosidase treatment of IgA1 significantly enhanced IgA1/TfR interaction. These results indicate that aberrant glycosylation of IgA1 as well as immune complex formation constitute essential factors favoring mesangial TfR-IgA1 interaction as initial steps in IgAN pathogenesis.

Oxidative Stress and Galactose-Deficient IgA1 as Markers of Progression in IgA Nephropathy

“…These complexes stimulate cultured human mesangial cells (3)(4)(5), resulting in activation of oxidative stress pathways (6 -8). Evidence of increased oxidative stress has been noted in renal tissue of patients with IgAN (9) as well as in their sera and/or erythrocytes (i.e., increased levels of lipoperoxide or malondialdehyde and reduced activity of superoxide dismutase, catalase, and glutathione peroxidase) (10,11).…”

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

“…60 IgA size seems to play a significant role in the pathogenicity of the IgA IC. Indeed, polymeric but not monomeric IgA1 induces TfR hyperexpression on human mesangial cells, 61 leading to increased production of cytokines (IL-6, transforming growth factor-b and tumor necrosis factor-a), mesangial expansion and pIgA1 mesangial deposition. 62,63 Studies employing lectins, which bind to glycosidic residues, revealed that circulating and mesangial IgA1 molecules from IgAN patients possess truncated O-glycans.…”

“…Our group has also shown that aberrant glycosylation of IgA1 and IC formation constitute essential factors favoring mesangial IgA1-TfR interactions as initial steps in IgAN pathogenesis. 61 The formation of the circulating IC may involve at least three distinct mechanisms: the self-aggregation of aberrantly glycosylated IgA1; the formation of complexes with soluble FcaRI; and the induced aggregation by interaction of IgA1 with other circulating proteins. As discussed above, the first mechanism is directly linked to the abnormal structure of IgA1.…”

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

“…IgAN injury [86] . Finally, as an alternative hypothesis, has been proposed that the soluble form of the Fcα receptor (sCD89) might "per se" generate complexes with GdIgA1 [87] .…”

“…Indeed, the mesangial cells binding to IgA-IC containing poorly galactosylated IgA1 triggers the proliferation and the programmed death of the mesangial cells. In addition a reduced synthesis of vascular endothelial growth factor (VEGF), an abnormal integrin production and an abnormal production of extracellular matrix increase the renal damage [86,[90][91][92] . The role of complement in the activation of the mesangial cells in IgAN has been recently reviewed by Maillard et al [93] .…”