Novel functions of Transferrin receptor: A multi-ligand receptor implicated in health and disease – TFRIGA

IgA, the most abundant immunoglobulin in human is divided in two subclasses: IgA1 and IgA2 that exist also in different multimerization states. In serum, IgA1 is predominant and 90% are found in a monomeric (m) form, whereas 10% are dimeric or polymeric (p). IgA is rarely involved in antibody responses and mIgA plays an anti-inflammatory role. By contrast, the role of pIgA remains unknown. We demonstrated that the transferrin receptor 1 (TfR1) binds pIgA1 and IgA1-containing immune complexes (IgA1-IC). We postulated that the role of pIgA1 is linked to its interaction with TfR1.
The project will address the consequences of the interaction between pIgA1 or IgA1-IC and TfR1 in health and disease. We will use two models where TfR1 is known to play a crucial role: erythropoiesis and IgA nephropathy (IgAN), the first cause of primary glomerulonephritis that results from IgA1-IC deposition in renal mesangium evolving toward renal failure. Our unpublished data (in collaboration with Pr O. Hermine’s group, Necker hospital, Paris) show that serum pIgA1 potentiates erythroblast proliferation induced by erythropoietin (Epo) and Stem cell factor (SCF). On the other hand, in IgAN, mesangial cell proliferation induced by patients’ IgA1-IC potentiates the signaling of platelet-derived growth factor (PDGF) receptor. Therefore, pIgA1/TfR1 interaction appears as a previously unsuspected factor that modulates responses to growth factors implicated in cell proliferation.
The first axis is centered on erythropoiesis. Our unpublished data demonstrate that pIgA1 interaction with TfR1 lowers the signal intensity threshold required for stimulation of erythroblasts by Epo and SCF. As a consequence lower concentrations of growth factors are needed to induce optimal proliferative responses. This mechanism is observed with physiologic concentrations of pIgA1 and of growth factors found in the bone marrow. The molecular basis for this control of cell sensitivity to growth factors by pIgA1 will be analyzed first (task 1). A consequence of our data is that pIgA1 production may be of particular importance in the physiologic response to anemia. Analysis of the regulation of pIgA1 production in normal conditions and under hypoxic stress will be developed (task 2). Task 3 will evaluate the therapeutic potential of treatment based on pIgA1 infusion for patients having impaired Epo production due to chronic kidney disease. Patients hypo-responsive to recombinant Epo treatment may particularly benefit from this new therapeutic strategy.
For the second axis, we developed a passive transfer model in which the injection of IgA complexes induce features of IgAN. Similar to erythropoiesis, IgA1-IC increased sensitivity of cells to a growth factor (PDGF). The PI3K/Akt pathway is involved in this model. Task 4 will dissect the molecular basis of TfR1 signaling allowing this increased sensitivity. Comparison between data obtained in tasks 1 and 4 will help identify precisely the critical signaling steps involved in pIgA1/TfR1-mediated amplification mechanism. The combined activation of mesangial cells by IgA1-IC and PDGF may have important consequences in terms of gene expression and thus in mesangial cell proliferation and local inflammation that is responsible for progression of IgAN toward kidney failure. Thus, gene expression profiles induced by IgA1-IC and PDGF, separately or in combination, will be compared (task 5). Finally, targeting activation of mesangial cells by IgA1-IC by inhibiting the critical pathways mobilized by IgA1-IC/TfR1 interaction could have therapeutic potential in IgAN. This will be evaluated in task 6.
We believe this project will allow to understand the functions of IgA1/TfR1 signaling in the modulation of cell sensitivity to growth factors-induced proliferation in both physiological and pathological situations. It will dissect how this amplifying mechanism takes place and will investigate its clinical and therapeutic potential.