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- Keszei, M, et al.
(författare)
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Congenital defects in neutrophil dynamics
- 2014
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Ingår i: Journal of immunology research. - : Hindawi Limited. - 2314-7156 .- 2314-8861. ; 2014, s. 303782-
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil granulocytes are key effector cells of the vertebrate immune system. They represent 50–70% of the leukocytes in the human blood and their loss by disease or drug side effect causes devastating bacterial infections. Their high turnover rate, their fine-tuned killing machinery, and their arsenal of toxic vesicles leave them particularly vulnerable to various genetic deficiencies. The aim of this review is to highlight those congenital immunodeficiencies which impede the dynamics of neutrophils, such as migration, cytoskeletal rearrangements, vesicular trafficking, and secretion.
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- Westerberg, LS, et al.
(författare)
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Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes
- 2010
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 207:6, s. 1145-1152
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Tidskriftsartikel (refereegranskat)abstract
- X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP–expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP–expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP–expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability.
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- Westerberg, LS, et al.
(författare)
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Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function
- 2012
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 119:17, s. 3966-3974
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Tidskriftsartikel (refereegranskat)abstract
- The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homolog of WASP, may serve some redundant functions with WASP in B cells. In the present study, we generated mice lacking WASP and N-WASP in B cells (conditional double knockout [cDKO] B cells) and show that cDKO mice had decreased numbers of follicular and marginal zone B cells in the spleen. Receptor-induced activation of cDKO B cells led to normal proliferation but a marked reduction of spreading compared with wild-type and WKO B cells. Whereas WKO B cells showed decreased migration in vitro and homing in vivo compared with wild-type cells, cDKO B cells showed an even more pronounced decrease in the migratory response in vivo. After injection of 2,4,6-trinitrophenol (TNP)–Ficoll, cDKO B cells had reduced antigen uptake in the splenic marginal zone. Despite high basal serum IgM, cDKO mice mounted a reduced immune response to the T cell–independent antigen TNP-Ficoll and to the T cell–dependent antigen TNP–keyhole limpet hemocyanin. Our results reveal that the combined activity of WASP and N-WASP is required for peripheral B-cell development and function.
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