Format

Send to

Choose Destination
J Allergy Clin Immunol. 2016 Jul;138(1):219-228.e9. doi: 10.1016/j.jaci.2015.11.028. Epub 2016 Feb 4.

Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions.

Author information

1
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
2
Junior Research Group "Hematopoietic Stem Cells and Stress," German Cancer Research Center (DKFZ), INF280, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), INF280, Heidelberg, Germany.
3
Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
4
Section of Molecular and Cellular Immunology, UCL Institute of Child Health, London, United Kingdom.
5
Junior Research Group "Hematopoietic Stem Cells and Stress," German Cancer Research Center (DKFZ), INF280, Heidelberg, Germany.
6
Division of Immunology, University Children's Hospital, and Children's Research Centre Zürich, Zurich, Switzerland.
7
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany; Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.
8
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany. Electronic address: grez@gsh.uni-frankfurt.de.

Abstract

BACKGROUND:

Defects in phagocytic nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) function cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by dysfunctional microbicidal activity and chronic inflammation.

OBJECTIVE:

We sought to study the effect of chronic inflammation on the hematopoietic compartment in patients and mice with X-linked chronic granulomatous disease (X-CGD).

METHODS:

We used immunostaining and functional analyses to study the hematopoietic compartment in patients with CGD.

RESULTS:

An analysis of bone marrow cells from patients and mice with X-CGD revealed a dysregulated hematopoiesis characterized by increased numbers of hematopoietic progenitor cells (HPCs) at the expense of repopulating hematopoietic stem cells (HSCs). In patients with X-CGD, there was a clear reduction in the proportion of HSCs in bone marrow and peripheral blood, and they were also more rapidly exhausted after in vitro culture. In mice with X-CGD, increased cycling of HSCs, expansion of HPCs, and impaired long-term engraftment capacity were found to be associated with high concentrations of proinflammatory cytokines, including IL-1β. Treatment of wild-type mice with IL-1β induced enhanced cell-cycle entry of HSCs, expansion of HPCs, and defects in long-term engraftment, mimicking the effects observed in mice with X-CGD. Inhibition of cytokine signaling in mice with X-CGD reduced HPC numbers but had only minor effects on the repopulating ability of HSCs.

CONCLUSIONS:

Persistent chronic inflammation in patients with CGD is associated with hematopoietic proliferative stress, leading to a decrease in the functional activity of HSCs. Our observations have clinical implications for the development of successful autologous cell therapy approaches.

KEYWORDS:

Chronic granulomatous disease; IL-1β; anakinra; cell cycle; competitive repopulation assay; dysfunctional hematopoiesis; engraftment defect; gene therapy; hematopoietic stem cell; hyperinflammation

PMID:
26853280
DOI:
10.1016/j.jaci.2015.11.028
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center