Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells

Papadaki, Helen Α.; Eliopoulos, Aristides G.; Kosteas, Theodoros; Gemetzi, Claudia; Damianaki, Athina; Koutala, Helen; Bux, Juergen; Eliopoulos, George D.

doi:10.1182/blood-2002-09-2898

Cited by 79 publications

(120 citation statements)

References 44 publications

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“…16 In brief, macrophage layers from MDS patients (n=6) or healthy subjects (n=6) in six-well plates were irradiated (10 Gy) and then recharged with 2x10 4 allogeneic normal CD34 + BM cells in the + cells was assessed in a week's time by means of a previously described clonogenic assay and the total colonies were scored and characterized as total colony-forming cells (CFC). 16 Finally, we evaluated the CFC numbers in the non-adherent cell fraction of normal macrophage cultures recharged with allogeneic normal CD34 + BM cells in the presence or absence of rhHMGB1 at a concentration 300 ng/mL, corresponding to the mean cytokine levels measured in the BM plasma of MDS patients.…”

Section: Reverse Transcription and Quantitative Polymerase Chain Reacmentioning

confidence: 99%

Impaired clearance of apoptotic cells leads to HMGB1 release in the bone marrow of patients with myelodysplastic syndromes and induces TLR4-mediated cytokine production

et al. 2013

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Excessive pro-inflammatory cytokine production in the bone marrow has been associated with the pathogenesis of myelodysplastic syndromes. We herein investigated the involvement of toll-like receptors and their endogenous ligands in the induction/maintenance of the inflammatory process in the marrow of patients with myelodysplastic syndromes. We evaluated the expression of toll-like receptors in marrow monocytes of patients (n=27) and healthy controls (n=25) by flow-cytometry and also assessed the activation of the respective signaling using a realtime polymerase chain reaction-based array. We measured the high mobility group box-1 protein, a toll-like receptor-4 ligand, in marrow plasma and long-term bone marrow culture supernatants by an enzyme-linked immunosorbent assay and we performed cross-over experiments using marrow plasma from patients and controls in the presence/absence of a toll-like receptor-4 inhibitor to evaluate the pro-inflammatory cytokine production by chemiluminescence. We assessed the apoptotic cell clearance capacity of patients' macrophages using a fluorescence microscopy-based assay. We found over-expression of toll-like receptor-4 in patients' marrow monocytes compared to that in controls; this over-expression was associated with up-modulation of 53 genes related to the respective signaling. Incubation of patients' monocytes with autologous, but not with normal, marrow plasma resulted in over-production of pro-inflammatory cytokines, an effect that was abrogated by the toll-like receptor-4 inhibitor suggesting that the pro-inflammatory cytokine production in myelodysplastic syndromes is largely mediated through toll-like receptor-4. The levels of high mobility group box-1 protein were increased in patients' marrow plasma and culture supernatants compared to the levels in controls. Patients' macrophages displayed an impaired capacity to engulf apoptotic cells and this defect was associated with excessive release of high mobility group box-1 protein by dying cells. A primary apoptotic cell clearance defect of marrow macrophages in myelodysplastic syndromes may contribute to the induction/maintenance of the inflammatory process through aberrant release of molecules inducing toll-like receptor-4 such as high mobility group box-1 protein.Impaired clearance of apoptotic cells leads to HMGB1 release in the bone marrow of patients with myelodysplastic syndromes and induces TLR4-mediated cytokine production

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Section: Reverse Transcription and Quantitative Polymerase Chain Reacmentioning

confidence: 99%

Impaired clearance of apoptotic cells leads to HMGB1 release in the bone marrow of patients with myelodysplastic syndromes and induces TLR4-mediated cytokine production

et al. 2013

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“…3 In particular, the patients had neutrophil counts less than 1800¥10 6 /L (mean 1209±397¥10 6 /L, range 300-1760¥10 6 /L) for a period of 10-240 months (median duration 84 months), had no clinical, serological or ultrasonic evidence of any underlying disease known to be associated with neutropenia, no history of exposure to irradiation, use of chemical compounds or intake of drugs to which neutropenia might be ascribed, normal BM karyotype, and negative serum leukoagglutination and immunofluorescence tests for antineutrophil antibodies. Cyclic and familial neutropenias were excluded by performing serial neutrophil enumerations in patients and their family members.…”

Section: Patients and Controlsmentioning

confidence: 99%

“…1,2 Defective neutrophil production in CIN has been associated with increased Fas-mediated apoptosis of the granulocytic progenitor cells within an inhibitory bone marrow (BM) microenvironment consisting of pro-inflammatory cytokines, such as tumor necrosis factor-α, interferon-γ, interleukin-1β, interleukin-6, and pro-apoptotic mediators, such as Fas-ligand, CD40-ligand and transforming growth factor-β1 among others. [3][4][5] As far as the cellular origin of these inhibitory molecules is concerned, it has been shown that activated monocytes present in CIN BM play a major role through upregulation of toll-like receptor 4 and activation of the downstream signal transduction pathway leading to pro-inflammatory cytokine production. 6 However, the most important cellular constituent of the inflammatory BM microenvironment in CIN is the T-cell component.…”

Section: Introductionmentioning

confidence: 99%

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Abnormal telomere shortening of peripheral blood mononuclear cells and granulocytes in patients with chronic idiopathic neutropenia

Pavlaki

Kastrinaki²,

Klontzas³

et al. 2011

Haematologica

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BackgroundChronic idiopathic neutropenia is characterized by immune-mediated suppression of neutrophil production. Because patients with immune-mediated bone marrow failure syndromes display age-inappropriate telomere shortening in leukocytes, we investigated telomere lengths in peripheral blood mononuclear cells and granulocytes of patients with chronic idiopathic neutropenia. Design and MethodsWe studied 37 patients with chronic idiopathic neutropenia and 68 age-and sex-matched healthy controls. Relative telomere length and telomerase reverse transcriptase expression were assessed by a quantitative real time polymerase chain reaction. Telomerase activity was determined by a polymerase chain reaction-based immunoassay. ResultsThe mean relative telomere values of peripheral blood mononuclear cells and granulocytes were significantly lower in patients compared to controls, and significantly lower than expected on the basis of the age-adjusted healthy control distribution. The difference in the relative telomere lengths between patients and controls in both peripheral blood mononuclear cells and granulocytes was prominent in those under the age of 50 years. Contrary to the peripheral blood mononuclear cells, in which an inverse correlation was observed between relative telomere values and age, no significant correlation was noted between granulocyte telomere values and patient age. A significant correlation was observed between individual relative telomere values and absolute neutrophil counts. There was no difference in expression of telomerase reverse transcriptase in peripheral blood mononuclear cells between patients and controls but telomerase activity was identified at a significantly higher frequency in controls than in patients. No correlation was found between telomerase activity or telomerase reverse transcriptase expression and relative telomere lengths of peripheral blood mononuclear cells. ConclusionsPatients with chronic idiopathic neutropenia display age-inappropriate telomere shortening of peripheral blood cells and low telomerase activity in peripheral blood mononuclear cells. A compensatory increased proliferation of bone marrow hematopoietic progenitor cells in association with lymphocyte replicative exhaustion probably account for these abnormalities.

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“…TNF-α had been considered for the suppressive effects on hematopoietic progenitor cells by direct cytotoxicity (4)(5)(6)(7)(8)(9), induction of apoptosis (10)(11)(12)(13)(14) and effect on coagulation in bone marrow microenvironment (15,16 i g u r e 1 . Co mp u t e d t o mo g r a p h y o f t h e n e c k s h o wi n g a n n a r r o wi n g o f t h e a i r wa y a n d l e f t n e c k l y mp h n o d e s we l l i n g .…”

Section: Pancytopenia Has a Variety Of Causes Including Aplastic Anemmentioning

confidence: 99%

Transient Severe Pancytopenia due to Elevated Tumor Necrosis Factor-.ALPHA. in Overwhelming Infection

et al. 2009

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Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells

Cited by 79 publications

References 44 publications

Impaired clearance of apoptotic cells leads to HMGB1 release in the bone marrow of patients with myelodysplastic syndromes and induces TLR4-mediated cytokine production

Impaired clearance of apoptotic cells leads to HMGB1 release in the bone marrow of patients with myelodysplastic syndromes and induces TLR4-mediated cytokine production

Abnormal telomere shortening of peripheral blood mononuclear cells and granulocytes in patients with chronic idiopathic neutropenia

Transient Severe Pancytopenia due to Elevated Tumor Necrosis Factor-.ALPHA. in Overwhelming Infection

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