Article

Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation.

Centre for Immunodeficiency, UCL Institute of Child Health, London, UK.
Immunobiology (Impact Factor: 2.81). 08/2009; 214(9-10):778-90. DOI: 10.1016/j.imbio.2009.06.009
Source: PubMed

ABSTRACT Regulation of the actin cytoskeleton is crucial for many aspects of correct and cooperative functioning of immune cells, such as migration, antigen uptake and cell activation. The Wiskott-Aldrich Syndrome protein (WASp) is an important regulator of actin cytoskeletal rearrangements and lack of this protein results in impaired immune function. This review discusses recent new insights of the role of WASp at molecular and cellular level and evaluates how WASp deficiency affects important immunological features and how defective immune cell function contributes to compromised host defence.

0 Bookmarks
 · 
56 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott-Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency.
    Immunological Reviews 11/2013; 256(1):282-299. · 12.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Collaborative Cross (CC) is an emerging panel of recombinant inbred (RI) mouse strains. Each strain is genetically distinct but all descended from the same eight inbred founders. In 66 strains from incipient lines of the CC (pre-CC), as well as the 8 CC founders and some of their F1 offspring, we examined subsets of lymphocytes and antigen-presenting cells. We found significant variation among the founders, with even greater diversity in the pre-CC. Genome-wide association using inferred haplotypes detected highly significant loci controlling B-to-T cell ratio, CD8 T-cell numbers, CD11c and CD23 expression. Comparison of overall strain effects in the CC founders with strain effects at QTL in the pre-CC revealed sharp contrasts in the genetic architecture of two traits with significant loci: variation in CD23 can be explained largely by additive genetics at one locus, whereas variation in B-to-T ratio has a more complex etiology. For CD23, we found a strong QTL whose confidence interval contained the CD23 structural gene Fcer2a. Our data on the pre-CC demonstrate the utility of the CC for studying immunophenotypes and the value of integrating founder, CC and F1 data. The extreme immunophenotypes observed could have pleiotropic effects in other CC experiments.Genes and Immunity advance online publication, 7 November 2013; doi:10.1038/gene.2013.59.
    Genes and immunity 11/2013; · 4.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.
    Science translational medicine 03/2014; 6(227):227ra33. · 10.76 Impact Factor

Full-text (2 Sources)

View
33 Downloads
Available from
May 31, 2014