Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 196K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Helgason, C. D. Articles by Humphries, R. K. Search for Related Content PubMed PubMed Citation Articles by Helgason, C. D. Articles by Humphries, R. K. Social Bookmarking                            What's this?

Original Article

Cheryl D. Helgason^a, Christian P. Kalberer^a, Jacqueline E. Damen^a, Suzanne M. Chappel^a, Nicolas Pineault^a, Gerald Krystal^a,b, and R. Keith Humphries^a,c

^a Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada
^b Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
^c Department of Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
Terry Fox Laboratory, 601 W. 10th Ave., Vancouver, British Columbia V5Z 1L3, Canada.604-877-0712604-877-6070

keith{at}terryfox.ubc.ca

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 Fc 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.

Key Words: signal transduction • B cell receptor • FcRIIB • immunoglobulin • antigen response

Abbreviations used in this paper: BCR, B cell receptor; ERK, extracellular signal–regulated kinase; HF, HBSS containing 2% fetal bovine serum; HSA, heat-stable antigen; MAPK, mitogen-activated protein kinase; NOD, nonobese diabetic; PIP₃, phosphatidylinositol-3,4,5-trisphosphate; pre-B cell, precursor B cell; pro-B cell, progenitor B cell; RAG, recombination activating gene; RFM, RPMI 1640 supplemented with 10% fetal bovine serum, 2 mM glutamine, and 10^–4 β-mercaptoethanol; SH, Src homology; SHIP, SH2 domain–containing inositol-5-phosphatase; TI-2, T cell–independent type 2.

© 2000 The Rockefeller University Press

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS