A dual role for Src homology 2 domain–containing inositol-5-phosphatase (SHIP) in immunity: aberrant development and enhanced function of B lymphocytes in SHIP …

CD Helgason, CP Kalberer, JE Damen… - The Journal of …, 2000 - rupress.org
CD Helgason, CP Kalberer, JE Damen, SM Chappel, N Pineault, G Krystal, RK Humphries
The Journal of experimental medicine, 2000rupress.org
In this report, we demonstrate that the Src homology 2 domain–containing inositol-5-
phosphatase (SHIP) plays a critical role in regulating both B cell development and
responsiveness to antigen stimulation. SHIP−/− mice exhibit a transplantable alteration in B
lymphoid development that results in reduced numbers of precursor B (fraction C) and
immature B cells in the bone marrow. In vitro, purified SHIP−/− B cells exhibit enhanced
proliferation in response to B cell receptor stimulation in both the presence and absence of …
In this report, we demonstrate that the Src homology 2 domain–containing inositol-5-phosphatase (SHIP) plays a critical role in regulating both B cell development and responsiveness to antigen stimulation. SHIP−/− mice exhibit a transplantable alteration in B lymphoid development that results in reduced numbers of precursor B (fraction C) and immature B cells in the bone marrow. In vitro, purified SHIP−/− B cells exhibit enhanced proliferation in response to B cell receptor stimulation in both the presence and absence of Fcγ receptor IIB coligation. This enhancement is associated with increased phosphorylation of both mitogen-activated protein kinase and Akt, as well as with increased survival and cell cycling. SHIP−/− mice manifest elevated serum immunoglobulin (Ig) levels and an exaggerated IgG response to the T cell–independent type 2 antigen trinitrophenyl Ficoll. However, only altered B cell development was apparent upon transplantation into nonobese diabetic–severe combined immunodeficient (NOD/SCID) mice. The in vitro hyperresponsiveness, together with the in vivo findings, suggests that SHIP regulates B lymphoid development and antigen responsiveness by both intrinsic and extrinsic mechanisms.
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