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Genetics and immunopathology of chronic granulomatous disease

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Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency syndrome characterized by a greatly increased susceptibility to severe fungal and bacterial infections. CGD results from a failure of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme in the patient’s phagocytes to produce superoxide. It is caused by mutations in any of four genes that encode the components of the NADPH oxidase. Investigation of CGD patients has identified the different subunits and the genes encoding them. Study of rare CGD variants has highlighted sequences involved in the structural stability of affected components or has provided valuable insights into their function in the oxidase activation mechanism. Functional and molecular CGD diagnosis tests are discussed in this review. Long-term antibiotic prophylaxis has been essential in fighting infections associated with CGD, but approaches based on hematopoietic stem cell transplantation and gene therapy offer great hope for the near future.

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Abbreviations

CGD:

chronic granulomatous disease

AR CGD:

autosomal recessive chronic granulomatous disease

X CGD:

X-linked chronic granulomatous disease

NADPH:

reduced nicotinamide adenine dinucleotide phosphate

FAD:

flavin adenine dinucleotide

INT:

iodonitrotetrazolium

ROS:

reactive oxygen species

PHOX:

phagocytic oxidase

TPR:

tetratricopeptide repeat

BMT:

bone marrow transplantation

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Acknowledgements

The US Immunodeficiency Network and the Primary Immunodeficiency Disease Consortium’s National Institutes of Health contract no. N01-AI-30070 supported this work. We thank Françoise Morel for her constant support and belief in our work. We are so grateful to Cécile Martel, Michelle Mollin, Laure Carrichon, Federica Defendi, Sylvain Beaumel, Antoine Picciocchi, and Franck Demeurme for their enthusiasm at work in the CGD diagnosis and research center. Special thanks are extended to Lila Laval for her excellent secretarial work and to Linda Northrup for editing the manuscript.

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Authors and Affiliations

  1. Centre Diagnostic et Recherche sur la Granulomatose Septique Chronique, Laboratoire TIMC/IMAG UMR CNRS 5525, Université J. Fourier, CHU 38043, Grenoble, France

    Marie José Stasia

  2. Department of Pediatrics (Hematology/Oncology), Herman B Wells Center for Pediatric Research Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN, 46202-5225, USA

    Xing Jun Li

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  1. Marie José Stasia
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Correspondence to Marie José Stasia.

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This work was supported by grants from the US Immunodeficiency Network a National Institute of Health consortium, Towson, MD, USA, the Université Joseph Fourier et the Faculté de Médecine, Grenoble, France, the Région Rhône–Alpes, programme Emergence, the Ministère de l’Education et de la Recherche, and the Direction de la Recherche Régionale Clinique.

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Stasia, M.J., Li, X.J. Genetics and immunopathology of chronic granulomatous disease. Semin Immunopathol 30, 209–235 (2008). https://doi.org/10.1007/s00281-008-0121-8

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