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

Abstract

To more precisely identify the B-cell phenotype inWiskott-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. WhereasWASp 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 matureWASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype ofWAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease. © 2008 by The American Society of Hematology.