Transferrin receptor engagement by polymeric IgA1 induces receptor expression and mesangial cell proliferation: role in IgA nephropathy.
IgA nephropathy (IgAN) is characterized by IgA immune complex-mediated mesangial cell proliferation. We have previously identified the transferrin receptor (TfR) as an IgA1 receptor and found that, in kidney biopsies of patients with IgAN, TfR is overexpressed and co-localized with IgA1 mesangial deposits. We also showed that IgA1 binding to TfR was strikingly increased when IgA1 was hypogalactosylated and of high molecular weight, both features found in IgA from IgAN patients. More recently, we showed that purified polymeric IgA1 (pIgA1) 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. IgA1-induced HMC proliferation is dependent on TfR engagement and can be inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. Finally, activation of mesangial cells through pIgA1 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 pIgA1 or IgA immune complexes could initiate an auto-amplification process involving hyper-expression of TfR allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation, features which are commonly implicated in the chronic mesangial injuries observed in IgAN.
Tamouza
Houda
H
INSERM U699, Paris, France.
Vende
Florence
F
Tiwari
Meetu
M
Arcos-Fajardo
Michelle
M
Vrtovsnik
François
F
Benhamou
Marc
M
Monteiro
Renato C
RC
Moura
Ivan C
IC
D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology / Q000378:metabolism*; D050527:Mesangial Cells / Q000276:immunology* / Q000473:pathology; D011990:Receptors, Transferrin / Q000276:immunology* / Q000378:metabolism*
D007070:Immunoglobulin A; D011990:Receptors, Transferrin