Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions.
J Allergy Clin Immunol
; 138(1): 219-228.e9, 2016 07.
Article
en En
| MEDLINE
| ID: mdl-26853280
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-1ß. Treatment of wild-type mice with IL-1ß 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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Células Madre Hematopoyéticas
/
Enfermedad Granulomatosa Crónica
Tipo de estudio:
Etiology_studies
/
Observational_studies
/
Risk_factors_studies
Límite:
Adolescent
/
Adult
/
Animals
/
Child
/
Child, preschool
/
Humans
Idioma:
En
Revista:
J Allergy Clin Immunol
Año:
2016
Tipo del documento:
Article
País de afiliación:
Alemania