Transferrin Receptor Engagement by Polymeric IgAI Induces Receptor Expression and Mesangial Cell Proliferation: Role in IgA Nephropathy

摘要

IgA nephropathy (IgAN) is characterized by IgA immune complex-mediated mesangial cell proliferation. We have previously identified the transferrin receptor (TfR) as an IgAI receptor and found that, in kidney biopsies of patients with IgAN, TfR is overexpressed and co-localized with IgAI mesangial deposits. We also showed that IgAI binding to TfR was strikingly increased when IgAI was hypogalactosylated and of high molecular weight, both features found in IgA from IgAN patients. More recently, we showed that purified polymeric IgAI (plgAl) is a major inducer of TfR expression (3-fold increase) in quiescent human mesangial cells (HMC). In addition, sera from IgAN patients upregulate TfR expression in cultured HMC in an IgA-dependent manner. IgAl-induced HMC proliferation is dependent on TfR engagement and can be inhibited by both TfRl and TfR2 ectodomains as well as by the anti-TfR mAb A24. Finally, activation of mesangial cells through plgAl binding to TfR induced secretion of IL-6 and TGF-beta from the cells, that could be involved, respectively, in the inflammatory and pro-fibrogenic events observed in IgAN. We propose that deposited plgAl or IgA immune complexes could initiate an auto-amplification process involving hyper-expression of TfR allowing increased IgAI mesangial deposition. Altogether, these data unveil a functional cooperation between plgAl and TfR for IgAI deposition and HMC proliferation, features which are commonly implicated in the chronic mesangial injuries observed in IgAN.