Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis.
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.
Meyer-Bahlburg
Almut
A
Department of Pediatrics, Seattle Children's Hospital Research Institute, WA, USA.
Becker-Herman
Shirly
S
Humblet-Baron
Stephanie
S
Khim
Socheath
S
Weber
Michele
M
Bouma
Gerben
G
Thrasher
Adrian J
AJ
Batista
Facundo D
FD
Rawlings
David J
DJ
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000276:immunology*
C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein