Engagement of Transferrin Receptor by Polymeric IgA1

Abstract

IgA nephropathy (IgAN), the most common primary glomerulonephritis in the world, is characterized by IgA immune complex-mediated mesangial cell proliferation. The transferrin receptor (TfR) was identified previously as an IgA1 receptor, and it was found that, in biopsies of patients with IgAN, TfR is overexpressed and co-localizes with IgA1 mesangial deposits. Here, it is shown that purified polymeric IgA1 (pIgA1) is a major inducer of TfR expression (three- to four-fold increase) in quiescent human mesangial cells (HMC). IgA-induced but not cytokine-induced HMC proliferation is dependent on TfR engagement as it is inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. It is dependent on the continued presence of IgA1 rather than on soluble factors released during IgA1-mediated activation. In addition, pIgA1-induced IL-6 and TGF-beta production from HMC was specifically inhibited by mAb A24, confirming that pIgA1 triggers a TfR-dependent HMC activation. Finally, upregulation of TfR expression induced by sera from patients with IgAN but not from healthy individuals was dependent on IgA. It is proposed that deposited pIgA1 or IgA1 immune complexes could initiate a process of auto-amplification involving hyperexpression of TfR, allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation and activation, features that are commonly implicated in the chronicity of mesangial injuries observed in IgAN and that could explain the recurrence of IgA1 deposits in the mesangium after renal transplantation.

Angiotensin II-Induced Regulation of the Expression and Localization of Iron Metabolism-Related Genes in the Rat Kidney

“…Recent studies have suggested that, in addition to reabsorbing the iron compounds filtered from the glomerulus, TfR might act as an immunoglobulin (Ig)A1 receptor and might be involved in the pathogenesis of IgA nephropathy (21,22). It remains of interest whether or not the modulation of TfR expression underlies the renoprotective effects of angiotensin II converting enzyme inhibitor and the AT1 receptor blocker in IgA nephropathy.…”

The Pathophysiology of IgA Nephropathy

“…34 Moreover, CD71 on human mesangial cells effectively binds immune complexes containing galactose-deficient IgA1, leading to enhanced expression of CD71. 35,36 This binding creates a positive feedback loop, causing overexpression of CD71 on proliferating mesangial cells. However, it is not known whether CD71 is the only receptor that binds IgA1-containing immune complexes or whether it has a direct pathogenic role in IgAN.…”

Aberrantly Glycosylated IgA1 in Glomerular Immune Deposits of IgA Nephropathy

“…Recent evidence also exists that mesangial cells are activated by aberrantly glycosylated IgA1 via binding transferrin receptor, with induction of proliferation and release of IL-6 and TGF-␤. 31 Taken together, these data suggest an important role for the spatial organization of IgA and C3c within the immune deposits in influencing the glomerular inflammatory response in IgAN. It is tempting to speculate that the presence of variable , there is prevalence of exposed IgA, whereas in B (case 9), there is marked increase of exposed C3c, with several deposits lacking surface IgA.…”