B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice.
Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell-intrinsic mechanisms critically contribute to WAS-associated autoimmunity.
Children's Hospital, Division of Immunology and Manton Center for Orphan Disease Research, Boston, MA, USA.
Mike
M
Recher
Siobhan O
SO
Burns
Miguel A
MA
de la Fuente
Stefano
S
Volpi
Carin
C
Dahlberg
Jolan E
JE
Walter
Kristin
K
Moffitt
Divij
D
Mathew
Nadine
N
Honke
Philipp A
PA
Lang
Laura
L
Patrizi
Hervé
H
Falet
Marton
M
Keszei
Masayuki
M
Mizui
Eva
E
Csizmadia
Fabio
F
Candotti
Kari
K
Nadeau
Gerben
G
Bouma
Ottavia M
OM
Delmonte
Francesco
F
Frugoni
Angela B Ferraz
AB
Fomin
David
D
Buchbinder
Emma Maria
EM
Lundequist
Michel J
MJ
Massaad
George C
GC
Tsokos
John
J
Hartwig
John
J
Manis
Cox
C
Terhorst
Raif S
RS
Geha
Scott
S
Snapper
Karl S
KS
Lang
Richard
R
Malley
Lisa
L
Westerberg
Adrian J
AJ
Thrasher
Luigi D
LD
Notarangelo
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002452:Cell Count; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein