Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis

Abstract

To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central versus peripheral B-cell development. Whereas WASp is dispensable for early bone marrow B-cell development, WASp deficiency results in a marked reduction in each of the major mature peripheral B-cell subsets, exerting the greatest impact on marginal zone and B1a B cells. Using in vivo bromodeoxyuridine labeling and in vitro functional assays, we show that these deficits reflect altered peripheral homeostasis, partially resulting from an impairment in integrin function, rather than a developmental defect. Consistent with these observations, we also show that: (1) WASp expression levels increase with cell maturity, peaking in those subsets exhibiting the greatest sensitivity to WASp deficiency; (2) WASp+ murine B cells exhibit a marked selective advantage beginning at the late transitional B-cell stage; and (3) a similar in vivo selective advantage is manifest by mature WASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype of WAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease.

Validation of a mutated PRE sequence allowing high and sustained transgene expression while abrogating WHV-X protein synthesis: application to the gene therapy of WAS

“…A selective advantage of WASp-expressing B cells has only been reported very recently and is likely to explain our results. 25 These novel observations consolidate and extend the existing preclinical data to show that ex vivo gene therapy with the WAS LV is expected to correct multiple lineages of immune cells and could provide a therapeutic benefit notably by reducing the pathophysiological signs of autoimmunity. Biosafety studies in normal or tumor-prone mice could potentially assess the potential genotoxicity of the vector and of its components in sensitive models.…”

Cytoskeletal control of B cell responses to antigens

“…For instance, the majority of patients with Wiskott-Aldrich syndrome suffer from antibody-mediated autoimmunity, which is largely caused by B cell hyperactivity [5][6][7][8] . These symptoms suggest that cytoskeleton dynamics are closely interwoven with both positive and negative regulation of B cell activation.…”

Wiskott-Aldrich syndrome protein–mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells

“…Some typical features of these diseases, such as skin lesions, arthritis, renal diseases, and cutaneous vasculitis, are also present in a proportion of WAS patients. Moreover, autoantibodies that are known to convert self-nucleic acid into potent triggers of pDCs are abundant in a murine model of WAS deficiency and are also detected in a proportion of WAS patients (DupuisGirod et al, 2003;Meyer-Bahlburg et al, 2008;Trifari et al, 2010;Becker-Herman et al, 2011;Bosticardo et al, 2011). To investigate a possible contribution of altered pDC homeostasis to the pathophysiology of WAS, we first analyzed spleen sections and peripheral blood of WAS patients.…”

“…WASp is also required on the APC side of the immune synapse for proper transmission of activating signals (Pulecio et al, 2008;Bouma et al, 2011). Defective signaling through antigen receptors affects the function of invariant natural killer T cells (Astrakhan et al, 2009;Locci et al, 2009) and B cells (Meyer-Bahlburg et al, 2008;Westerberg et al, 2008;BeckerHerman et al, 2011). Furthermore, altered actin polymerization and integrin signaling in WASp-deficient immune cells cause defective homing and directional migration of T, B, and DCs (de Noronha et al, 2005;Westerberg et al, 2005;Gallego et al, 2006).…”