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

Weisser, M; Demel, UM; Stein, S; Chen-Wichmann, L; Touzot, F; Santilli, G; Sujer, S; ... Grez, M; + view all (2016) Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions. Journal of Allergy and Clinical Immunology , 138 (1) pp. 219-228. 10.1016/j.jaci.2015.11.028. Green open access

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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.

Type: Article
Title: Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jaci.2015.11.028
Publisher version: http://dx.doi.org/10.1016/j.jaci.2015.11.028
Language: English
Additional information: Copyright © 2016 American Academy of Allergy, Asthma & Immunology. This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at http://creativecommons.org/ licenses/by/4.0. Access may be initially restricted by the publisher.
Keywords: Science & Technology, Life Sciences & Biomedicine, Allergy, Immunology, Chronic granulomatous disease, hyperinflammation, hematopoietic stem cell, dysfunctional hematopoiesis, competitive repopulation assay, engraftment defect, cell cycle, IL-1 beta, anakinra, gene therapy, GENE-THERAPY, NADPH OXIDASE, INFLAMMATORY MANIFESTATIONS, STERILE INFLAMMATION, NLRP3 INFLAMMASOME, IN-VIVO, CGD, ACTIVATION, MICE, IL-1
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1567962
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