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Cited by 77Immunodeficiency and Autoimmune DisordersHematopoietic Stem Cell TransplantationNeutrophil, Myeloperoxidase and Oxidative Mechanisms

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

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Weisser, Maren, Demel, Uta M., Stein, Stefan, Chen-Wichmann, Linping, Touzot, Fabien, Santilli, Giorgia, Sujer, Stefanie, Brendel, Christian +7 more·2016·Journal of Allergy and Clinical Immunology
DOI 10.1016/j.jaci.2015.11.028
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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.

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Authors
Weisser, M., Demel, U. M., Stein, S., Chen-Wichmann, L., Touzot, F., Santilli, G., Sujer, S., Brendel, C., Siler, U., Cavazzana, M., Thrasher, A. J., Reichenbach, J., Essers, M. A. G., Schwäble, J., & Grez, M.
Affiliations
  • Georg Speyer Haus (DE)
  • German Cancer Research Center (DE)
  • Hôpital Necker-Enfants Malades (FR)
  • University College London (GB)
  • University Children's Hospital Zurich (CH)
  • Goethe University Frankfurt (DE)
Corresponding author
Grez, Manuel
ORCID
Venue
Journal of Allergy and Clinical Immunology
Publisher
Elsevier BV
Published
2016-07
Volume
138
Issue
1
Pages
219-228.e9
ISSN
0091-6749 (ISSN-L)
DOI
10.1016/j.jaci.2015.11.028
OpenAlex
W2256913173
Cited by
77
References
6
Citations by year
2026: 6 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 6 · 2021: 16 · 2020: 11 · 2019: 8 · 2018: 2 · 2017: 9 · 2016: 3
FWCI
4.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Allergy and Clinical Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Deutsche Forschungsgemeinschaft (SFB815)
  • European Union
  • Wellcome Trust
  • LOEWE Center for Cell and Gene Therapy
  • Hessische Ministerium für Wissenschaft und Kunst
  • Zurich Centre for Integrative Human Physiology
  • Ettore e Valeria Rossi Foundation
  • German Federal Ministry of Health
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
chronic granulomatous disease, X-linked CGD, hyperinflammation, hematopoietic stem cells, hematopoietic progenitor cells, NADPH oxidase 2, IL-1β, inflammatory cytokines, HSC exhaustion, long-term engraftment, autologous cell therapy, primary immunodeficiency
MeSH terms
Adolescent, Adult, Animals, Cell Count, Cell Differentiation, Child, Child, Preschool, Colony-Forming Units Assay, Disease Models, Animal, Graft Survival, Granulomatous Disease, Chronic, Hematopoietic Stem Cells, Humans, Mice, Transgenic, Models, Biological, Phenotype, Signal Transduction, Biomarkers, Case-Control Studies, Immunophenotyping, Cytokines, Hematopoietic Stem Cell Transplantation, Inflammation Mediators, Mice, Young Adult

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