Abstract

B lymphocytes express antigen specific membrane immunoglobulins [mIg] on their surface. Engagement of mIg and interaction with helper T cells stimulates B cells to undergo an ordered process of signal transduction leading to cell growth and antibody production. Receptor crosslinking by anti-Ig initiates several immediate responses including, the mobilization of calcium, the breakdown of polyphosphoinositides and the activation of protein kinase C. Endocytosis of occupied MIg allows the internalization of antigen and its subsequent processing and NHC restricted presentation to T cells. MIg has only a short cytoplasmic tail suggesting that it is not sufficient to mediate signal transduction. However, MIg associates with at least two other membrane proteins, Ig-alpha and Ig-beta, to form a B cell receptor complex [BCR]. Tyrosine phosphorylation is one of the earliest signaling events, in B cell activation induced by ligation of the mlg receptor. This includes the induction of phosphorylation and enhanced kinase activity as well as association of a novel protein tyrosine kinase, PTK72/syk, and several src- related tyrosine kinases including lyn, blk, fyn and 1ck. We demonstrated that tyrosine kinase inhibitors block the internalization of MIg-ligand complexes following receptor crosslinking. Furthermore, Takagi and co- workers reported the concentration of tyrosine phosphorylated proteins associated with the plasma membrane under MIg receptors modulated by anti- Ig. Based on these observations we propose to test our hypothesis that tyrosine phosphorylation is an important mediator of ligand induced internalization of MIg, possibly by mediating the induced association of the receptor complex with the cytoskeleton. This will entail cloning human and murine syk, establishing localization of MIg, tyrosine kinases and components of the cytoskeleton and a molecular genetic analysis to define the role of the tyrosine kinases in MIg mediated B cell activation and internalization.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025185-07
Application #
2062912
Study Section
Immunobiology Study Section (IMB)
Project Start
1987-09-30
Project End
1998-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Wistar Institute
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Pure, E; Cuff, C A (2001) A crucial role for CD44 in inflammation. Trends Mol Med 7:213-21
Li, H L; Davis, W; Pure, E (1999) Suboptimal cross-linking of antigen receptor induces Syk-dependent activation of p70S6 kinase through protein kinase C and phosphoinositol 3-kinase. J Biol Chem 274:9812-20
Noorchashm, H; Bui, A; Li, H L et al. (1999) Characterization of anergic anti-DNA B cells: B cell anergy is a T cell-independent and potentially reversible process. Int Immunol 11:765-76
Li, H L; Davis, W W; Whiteman, E L et al. (1999) The tyrosine kinases Syk and Lyn exert opposing effects on the activation of protein kinase Akt/PKB in B lymphocytes. Proc Natl Acad Sci U S A 96:6890-5
Li, H L; Forman, M S; Kurosaki, T et al. (1997) Syk is required for BCR-mediated activation of p90Rsk, but not p70S6k, via a mitogen-activated protein kinase-independent pathway in B cells. J Biol Chem 272:18200-8
Scheynius, A; Camp, R L; Pure, E (1996) Unresponsiveness to 2,4-dinitro-1-fluoro-benzene after treatment with monoclonal antibodies to leukocyte function-associated molecule-1 and intercellular adhesion molecule-1 during sensitization. J Immunol 156:1804-9
Scheynius, A; Camp, R L; Pure, E (1993) Reduced contact sensitivity reactions in mice treated with monoclonal antibodies to leukocyte function-associated molecule-1 and intercellular adhesion molecule-1. J Immunol 150:655-63
Camp, R L; Scheynius, A; Johansson, C et al. (1993) CD44 is necessary for optimal contact allergic responses but is not required for normal leukocyte extravasation. J Exp Med 178:497-507
Birkeland, M L; Kraus, T; Tardelli, L et al. (1992) Progressive changes in CD45RB phenotype and lymphokine production by murine CD4+ T cells after alloantigen exposure. Immunology 75:632-8
Pure, E; Tardelli, L (1992) Tyrosine phosphorylation is required for ligand-induced internalization of the antigen receptor on B lymphocytes. Proc Natl Acad Sci U S A 89:114-7

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