The terms """"""""apoptosis"""""""" or """"""""programmed cell death"""""""" are sometimes used as if they are the result of one single pathway. And the 'Pathway' in mind more often than not is the prototype Fas/CD95-receptor pathway. However, there are many distinct ways to initiate cell death, and the downstream effector and regulatory mechanisms of death pathways may be different. This study will explore two aspects of B lymphocyte death: 1) how the pathway of B cell receptor (BCR-induced death compares to the well-defined Fas pathway and 2) how the B cell surface molecule CD22 regulates this BCR pathway. Signaling through the BCR can lead to clonal expansion of specific B cells, clonal inactivation (anergy) or clonal elimination/death. Whether or not BCR ligation leads to proliferation, anergy or death depends on the stage of B cell and the activity of co- receptors such as CD22. The investigators have found that members of the MAP family of protein kinases (MAPK family) including the stress- activated/Jun protein kinases (JNKs) and p38 MAPK regulate B cell death and anergy. They also found that B cells in CD22-deficient mice have a short life span and are more susceptible to BCR-induced cell death. The goal of this project is to define how members of the MAPK family of kinases and CD22 regulate B cell fate. A combination of biochemical and genetic approaches will be taken to test the hypotheses that: 1) CD22 regulates B cell fate through distinct """"""""functional domains"""""""" within its cytoplasmic tail which recruit and activate the Syk protein tyrosine kinase (PTK) and the SHP1 protein tyrosine phosphatase (PTPase); 2) BCR- induced cell death is mediated via a death pathway distinct from the Fas-mediated death pathway and requires new gene transcription of death pathway genes; and 3) a specific subset of short-lived B cells are dysregulated in CD22 -/- mice and that these B cells have a dysregulated BCR death pathway. This work will provide new insights into how the fate of B lymphocytes is regulated, which may be pertinent to understanding origins of leukemias, lymphomas and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI044250-01
Application #
2744355
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Ridge, John P
Project Start
1998-12-01
Project End
2003-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Veterinary Sciences
Type
Other Domestic Higher Education
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Yankee, Thomas M; Draves, Kevin E; Clark, Edward A (2005) Expression and function of the adaptor protein Gads in murine B cells. Eur J Immunol 35:1184-92
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Graves, Jonathan D; Craxton, Andrew; Clark, Edward A (2004) Modulation and function of caspase pathways in B lymphocytes. Immunol Rev 197:129-46
Niiro, Hiroaki; Clark, Edward A (2003) Branches of the B cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1. Immunity 19:637-40
Yankee, Thomas M; Solow, Sasha A; Draves, Kevin D et al. (2003) Expression of the Grb2-related protein of the lymphoid system in B cell subsets enhances B cell antigen receptor signaling through mitogen-activated protein kinase pathways. J Immunol 170:349-55
Lajaunias, Frederic; Ida, Akinori; Kikuchi, Shuichi et al. (2003) Differential control of CD22 ligand expression on B and T lymphocytes, and enhanced expression in murine systemic lupus. Arthritis Rheum 48:1612-21
Jiang, A; Clark, E A (2001) Involvement of Bik, a proapoptotic member of the Bcl-2 family, in surface IgM-mediated B cell apoptosis. J Immunol 166:6025-33
Ura, S; Masuyama, N; Graves, J D et al. (2001) Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation. Proc Natl Acad Sci U S A 98:10148-53
Otipoby, K L; Draves, K E; Clark, E A (2001) CD22 regulates B cell receptor-mediated signals via two domains that independently recruit Grb2 and SHP-1. J Biol Chem 276:44315-22

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