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Dendritic cell defects in Wiskott-Aldrich Syndrome

Burns, Siobhan Oisin; (2001) Dendritic cell defects in Wiskott-Aldrich Syndrome. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Migration from peripheral tissues to lymph nodes is a critical process during normal dendritic cell (DC) function and requires dynamic cytoskeletal reorganisation in response to external signals. Despite this, little is known about the intracellular signalling pathways regulating DC actin rearrangement. Over the past decade, Wiskott- Aldrich Syndrome protein (WASp) has emerged as an important regulator of actin polymerisation in haematopoietic cells, transducing signals from surface receptors to the cytoskeleton. Failure to produce WASp results in a potentially fatal X-linked disorder, the Wiskott-Aldrich Syndrome (WAS), characterised by a clinical triad of immunodeficiency, eczema and bleeding. Cytoskeletal defects have been reported for a number of haematopoietic lineages from WAS patients, including DC. The work presented in this thesis examines the role of WASp in regulation of the DC cytoskeleton.Using immunofluorescence techniques, normal immature DC were shown to assemble specialised actin structures called podosomes at their leading edge, which were associated with the recruitment of WASp, the Arp2/3 complex, and p2 integrins. DC from WAS patients lacked podosomes and failed to localise actin-associated proteins or integrins. In time-lapse microscopy experiments, WAS DC formed abnormal lamellipodia and exhibited severely compromised translocation. Expression of WASp in WAS DC restored podosome formation and normal cell morphology. Podosome assembly was shown, using microinjection techniques, to be regulated by the coordinated activation of Cdc42, Rac and Rho. In addition, podosome formation was downregulated by DC maturation, indicating that their function is in early DC migration. Furthermore, podosomes were required for strong adhesion to ICAM-1, but not to fibronectin, suggesting a role in transmigration through endothelium.It is concluded that podosomes function to co-ordinate protrusive and adhesive activity in DC motility, possibly facilitating escape from peripheral tissues to the lymphatic system. In vivo, defective DC motility in WAS patients may contribute significantly to the immunopathology of the disease.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Dendritic cell defects in Wiskott-Aldrich Syndrome
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Wiskott-Aldrich Syndrome
URI: https://discovery.ucl.ac.uk/id/eprint/10105261
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