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    NBEAL2 is required for neutrophil and NK cell function and pathogen defense

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    Author
    Sowerby, JM; Thomas, DC; Clare, S; Espeli, M; Guerrero, JA; Hoenderdos, K; Harcourt, K; Marsden, M; Abdul-Karim, J; Clement, M; ...
    Date
    2017-09-01
    Source Title
    Journal of Clinical Investigation
    Publisher
    AMER SOC CLINICAL INVESTIGATION INC
    University of Melbourne Author/s
    Dougan, Gordon
    Affiliation
    Microbiology and Immunology
    Metadata
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    Document Type
    Journal Article
    Citations
    Sowerby, J. M., Thomas, D. C., Clare, S., Espeli, M., Guerrero, J. A., Hoenderdos, K., Harcourt, K., Marsden, M., Abdul-Karim, J., Clement, M., Antrobus, R., Umrania, Y., Barton, P. R., Flint, S. M., Juss, J. K., Condliffe, A. M., Lyons, P. A., Humphreys, I. R., Chilvers, E. R. ,... Smith, K. G. C. (2017). NBEAL2 is required for neutrophil and NK cell function and pathogen defense. JOURNAL OF CLINICAL INVESTIGATION, 127 (9), pp.3259-3264. https://doi.org/10.1172/JCI91684.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/256628
    DOI
    10.1172/JCI91684
    Abstract
    Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterized by a lack of α granules in platelets. The functions of the NBEAL2 protein have not been explored outside platelet biology, but there are reports of increased frequency of infection and abnormal neutrophil morphology in patients with GPS. We therefore investigated the role of NBEAL2 in immunity by analyzing the phenotype of Nbeal2-deficient mice. We found profound abnormalities in the Nbeal2-deficient immune system, particularly in the function of neutrophils and NK cells. Phenotyping of Nbeal2-deficient neutrophils showed a severe reduction in granule contents across all granule subsets. Despite this, Nbeal2-deficient neutrophils had an enhanced phagocyte respiratory burst relative to Nbeal2-expressing neutrophils. This respiratory burst was associated with increased expression of cytosolic components of the NADPH oxidase complex. Nbeal2-deficient NK cells were also dysfunctional and showed reduced degranulation. These abnormalities were associated with increased susceptibility to both bacterial (Staphylococcus aureus) and viral (murine CMV) infection in vivo. These results define an essential role for NBEAL2 in mammalian immunity.

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