Evidence for downregulation of erythropoietin receptor in bone marrow erythroid cells of patients with chronic idiopathic neutropenia

Objective

The aim of this study is to probe the mechanisms underlying anemia in patients with chronic idiopathic neutropenia (CIN) by evaluating parameters of bone marrow (BM) erythropoiesis.

Patients and Methods

Ten CIN patients fulfilling the criteria of anemia of chronic disease, 27 nonanemic CIN patients, and 30 healthy volunteers were enrolled in the study. Reserves and survival characteristics of BM erythroid cells were evaluated using flow cytometry and clonogenic assays. Serum erythropoietin (EPO) was measured with ELISA. Expression of EPO receptors (EPORs) on BM erythroid cells was evaluated by flow cytometry and reverse-transcription polymerase chain reaction.

Results

CIN patients display defective erythropoiesis in addition to previously reported impaired granulopoiesis. Patients have low number of CD34⁺/CD71⁺ progenitor and CD36⁻/ Glycophorin A⁺ (GlycoA⁺) precursor BM cells, and increased proportion of apoptotic cells within the CD34⁺/CD71⁺ and CD36⁺/GlycoA⁺ compartments. Burst-forming units erythroid (BFU-Es) in BM mononuclear or purified CD34⁺ cells were significantly reduced in the patients. Patient BFU-Es increased significantly following in vitro treatment with tumor necrosis factor-α (TNF-α) and/or interferon γ (IFN-γ)-neutralizing antibodies. Local TNF-α and IFN-γ production was higher in anemic than in nonanemic patients. EPO production was appropriate in the patients, but EPOR expression was significantly reduced in patient GlycoA⁺ cells, especially in anemic patients.

Conclusion

Impaired BM erythropoiesis in CIN patients is probably the result of increased local production of TNF-α and IFN-γ that induce apoptosis, cell growth inhibition, and downregulation of EPOR expression on erythroid cells. We suggest that anemia in CIN patients displays overlapping pathophysiologic features with anemia of chronic disease.