期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 127, 期 4, 页码 998-U254出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2011.01.015
关键词
Wiskott-Aldrich syndrome; WASP; WIP; T cells; actin cytoskeleton
资金
- Perkin fund
- National Institutes of Health [5PO1HL059561]
- Dubai Harvard Foundation for Medical Research
Background: The Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by mutations in WAS, which encodes for WAS protein (WASP). The WASP-interacting protein (WIP) stabilizes WASP, as evidenced by severely decreased WASP levels in T cells from WIP-deficient mice. The majority of missense mutations in patients with WAS/XLT are located in the WIP-binding domain of WASP and might result in dissociation of the WASP-WIP complex and WASP degradation. Objective: To restore WASP levels and correct T-cell function in WAS/XLT patients with mutations in the WIP-binding domain of WASP. Methods: WIP, and a WIP-derived 41-amino acid-long peptide, which interacts with WASP and was designated nanoWIP (nWIP), were fused to enhanced green fluorescent protein and introduced by electroporation into EBV-transformed B cells, and by retroviral transduction into purified blood T cells from patients with WAS. WASP levels were measured by intracellular fluorescence-activated cell sorting staining. The actin cytoskeleton was visualized by intracellular phalloidin staining. Results: Introduction of WIP and nWIP restored WASP levels to normal in EBV-transformed B-cell lines from XLT patients with missense mutations in the WIP-binding domain of WASP and residual WASP levels, and corrected the defective spreading and pseudopodia formation of their T cells in response to immobilized anti-CD3. Conclusion: AWASP-binding WIP-derived peptide stabilizes WASP in cells from XLT patients with missense mutations that disrupt WIP binding, and corrects their T-cell actin cytoskeleton defect. This may provide a novel therapeutic strategy for these patients. (J Allergy Clin Immunol 2011;127:998-1005.)
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