title: Impaired integrin-dependent function in Wiskott-Aldrich syndrome protein-deficient murine and human neutrophils.
abstract: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency that manifests as increased susceptibility to many pathogens. Although the spectrum of infections suffered by WAS patients is consistent with defects in neutrophil (PMN) function, the consequences of WAS protein (WASp) deficiency on this innate immune cell have been unclear. We report that deficiency of WASp in both human and murine PMNs resulted in profound defects in clustering of beta2 integrins, leading to defective adhesion and transendothelial migration under conditions of physiologic shear flow. Wild-type PMNs redistributed clustered beta2 integrins to the uropod of the cell during active migration, whereas WASp-deficient cells remain unpolarized. The WASp-deficient PMNs also showed reduced integrin-dependent activation of degranulation and respiratory burst. PMNs from a WAS patient manifested similar defects in integrin clustering and signaling. These results suggest that impaired beta2 integrin function in WASp-deficient PMNs may contribute substantially to the clinical immunodeficiency suffered by WAS patients.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, California 94143, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Ulrich Y
authors.initials: UY
authors.lastname: Schaff
authors.forename: Chad E
authors.initials: CE
authors.lastname: Green
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Sarantos
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Hu
authors.forename: Diane
authors.initials: D
authors.lastname: Wara
authors.forename: Scott I
authors.initials: SI
authors.lastname: Simon
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D051316:Wiskott-Aldrich Syndrome Protein