Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy.
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.
INSERM U699, Bichat Medical School, 75870 Paris, Cedex 18, France.
Ivan C
IC
Moura
Michelle
M
Arcos-Fajardo
Abdelaziz
A
Gdoura
Valérie
V
Leroy
Charlotte
C
Sadaka
Nizar
N
Mahlaoui
Yves
Y
Lepelletier
François
F
Vrtovsnik
Elie
E
Haddad
Marc
M
Benhamou
Renato C
RC
Monteiro
D000936:Antigen-Antibody Complex / Q000378:metabolism; D001483:Base Sequence; D001704:Biopolymers / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D005246:Feedback; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D000936:Antigen-Antibody Complex; D001704:Biopolymers; D016207:Cytokines; D007070:Immunoglobulin A; D011990:Receptors, Transferrin; D016212:Transforming Growth Factor beta; C034639:polymeric IgA; D004247:DNA