Activation via the B cell antigen receptor (BCR) by antigen leads to B cell proliferation and immunoglobulin (Ig) secretion. However, engagement of the BCR simultaneously with the Ig receptor on B cells (FcgammaRIIB), delivers a potent inhibitory signal that prevents B cell proliferation and antibody secretion. Such co-ligation, which can be mediated by antigen-antibody complexes that can exist in later stages of the immune response, is thought to act as a """"""""feedback suppression"""""""" to limit excessive antibody production. Absence of this receptor results in enhanced antibody and anaphylactic responses in Fcgamma RIIB knock-out mice. In humans, certain rheumatoid factors, such as an IgM that reacts with the Fc portion of IgG, interfere with FcgammaRIIB-mediated regulation of antibody production. Thus, understanding the molecular mechanisms of this signaling process has important implications for B cell activation and regulation in normal physiology and pathology. FcgammaRIIB crosslinking with the BCR leads to inhibition of BCR-induced calcium entry into cells, diminution of Ras activation and attenuation of specific transcription factor activation, ultimately leading to inhibition of B cell proliferation. Recently, the inositol phosphatase, SHIP, has been identified as essential for mediating the inhibitory signaling via FcgammaRIIB. However, the mechanism(s) by which SHIP regulates these seemingly disparate pathways is completely unknown. This proposal will attempt to define the molecular mechanisms of inhibitory signaling via FcgammaRIIB and SHIP. Using the approaches of reconstitution of a cell line lacking SHIP expression and overexpression of mutant SHIP proteins, Aim I will address the molecular mechanism(s) by which SHIP regulates the calcium entry into cells. The region(s) of SHIP necessary for this regulation will also defined. The role of SHIP in regulating the two phosphoinositide substrates of SHIP, IP4 and IP3, and the implications in vivo will be rigorously tested.
Aim 2 address the role of SHIP in protecting B cells against FcgammaRIIB-induced apoptosis and attempts to identify the specific signaling molecules. The second part of this aim will attempt to """"""""rescue"""""""" the FcgammaRIIB-mediated inhibitory signaling. A detailed molecular understanding of FcgammaRIIB-mediated inhibitory signaling may yield important clues to B cell activation and desensitization, and point to possible future therapeutic interventions in certain autoimmune states.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Organized Research Units
United States
Zip Code
Giles, Amber J; Bender, Timothy P; Ravichandran, Kodi S (2009) The adaptor protein Shc plays a key role during early B cell development. J Immunol 183:5468-76
Thomas, Matthew D; Kremer, Christopher S; Ravichandran, Kodi S et al. (2005) c-Myb is critical for B cell development and maintenance of follicular B cells. Immunity 23:275-86
March, Michael E; Ravichandran, Kodi (2002) Regulation of the immune response by SHIP. Semin Immunol 14:37-47
Aman, M J; Tosello-Trampont, A C; Ravichandran, K (2001) Fc gamma RIIB1/SHIP-mediated inhibitory signaling in B cells involves lipid rafts. J Biol Chem 276:46371-8
Carver, D J; Aman, M J; Ravichandran, K S (2000) SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization. Blood 96:1449-56
Aman, M J; Ravichandran, K S (2000) A requirement for lipid rafts in B cell receptor induced Ca(2+) flux. Curr Biol 10:393-6
March, M E; Lucas, D M; Aman, M J et al. (2000) p135 src homology 2 domain-containing inositol 5'-phosphatase (SHIPbeta ) isoform can substitute for p145 SHIP in fcgamma RIIB1-mediated inhibitory signaling in B cells. J Biol Chem 275:29960-7
Aman, M J; Lamkin, T D; Okada, H et al. (1998) The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells. J Biol Chem 273:33922-8