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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency
Journal of Allergy and Clinical Immunology, Volume 131, No. 3, Year 2013
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Description
Background: Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse. DOCK8 activates cell division cycle 42, which, together with Wiskott-Aldrich syndrome protein, coordinates F-actin reorganization. Although abnormalities in T- and B-cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. Objectives: We sought to understand the role of DOCK8 in NK cell function to determine whether NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. Methods: A cohort of DOCK8-deficient patients was assembled, and patients' NK cells, as well as NK cell lines with stably reduced DOCK8 expression, were studied. NK cell cytotoxicity, F-actin content, and lytic immunologic synapse formation were measured. Results: DOCK8-deficient patients' NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunologic synapse without affecting overall NK cell F-actin content. Conclusions: DOCK8 deficiency results in severely impaired NK cell function because of an inability to form a mature lytic immunologic synapse through targeted synaptic F-actin accumulation. This defect might underlie and explain important attributes of the DOCK8 deficiency clinical syndrome, including the unusual susceptibility to viral infection and malignancy. © 2012 American Academy of Allergy, Asthma & Immunology.
Authors & Co-Authors
Mizesko, Melissa C.
United States, Houston
Baylor College of Medicine
Banerjee, Pinaki P.
United States, Houston
Baylor College of Medicine
Monaco-Shawver, Linda
United States, Philadelphia
The Children's Hospital of Philadelphia
Mace, Emily M.
United States, Houston
Baylor College of Medicine
Bernal, William E.
United States, Philadelphia
The Children's Hospital of Philadelphia
Sawalle-Belohradsky, Julie
Germany, Munich
Klinikum Der Universität München
Belohradsky, Bernd H.
Germany, Munich
Klinikum Der Universität München
Heinz, Valerie
Germany, Munich
Klinikum Der Universität München
Freeman, Alexandra F.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Sullivan, Kathleen E.
United States, Philadelphia
The Children's Hospital of Philadelphia
Holland, Steven M.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Torgerson, Troy Robert
United States, Seattle
University of Washington
Al-Herz, Waleed
Kuwait, Kuwait City
Kuwait University
Chou, Janet S.
United States, Boston
Boston Children's Hospital
Hanson, Imelda Celine Guerra
United States, Houston
Baylor College of Medicine
Albert, Michael Heinrich
Germany, Munich
Klinikum Der Universität München
Geha, Raif S.
United States, Boston
Boston Children's Hospital
Renner, Ellen D.
Germany, Munich
Klinikum Der Universität München
Orange, Jordan S.
United States, Houston
Baylor College of Medicine
Statistics
Citations: 120
Authors: 19
Affiliations: 7
Identifiers
Doi:
10.1016/j.jaci.2012.12.1568
ISSN:
00916749
e-ISSN:
10976825
Research Areas
Cancer
Study Design
Cohort Study