A unique population of B-lymphocytes, termed B-1, is elevated in certain autoimmune states in mice and humans. Unlike the conventional B-cells (B-2 subset), some B-1 cells express a T-cell differentiation marker CD5 and are primarily found in peritoneal and plural cavities. The B-1 cells can self-renew and have a propensity to make poly-reactive antibodies. B-1 cells fail to proliferate in vitro and undergo apoptosis in vivo in response to B-cell receptor (BCR) cross-linking whereas B-2 cells undergo clonal expansion. Similarly, B-2 but not B-1 cells proliferate to stimulation with antibodies to CD72, a B-cell differentiation antigen. Based on our recent studies with CD5-/- mice, the investigator postulates that CD5 acts as a negative regulator of B-1 cells by interfering with BCR induced signal transduction in B-1 cells.
Our specific aims are: 1) The investigator will test the possibility that CD5 inhibits BCR signaling in B-1 cells by recruiting an SH2 domain containing protein tyrosine phosphatase (SHP-1). He will identify the regions of CD5 cytoplasmic domains involved in binding to SHP-1 and test the in vivo relevance of such interaction for B-1 cell responses. 2) The investigator will define the BCR induced biochemical signaling events that are regulated by CD5-SHP-1 interaction in B-1 cells. He will examine the role of Src and non-Src family protein tyrosine kinases, CD19, MAP kinases as well as activation of the transcription factors NF-AT and NF-kappa-B. 3) He will test the hypothesis that receptors other than CD5 will also participate in negative regulation of B-1 cells, especially the B-1 subset that does not express CD5. 4) Since CD72 responses are not restored in CD5-/- mice, the investigator will test the hypothesis that B-1 cells signaling is regulated by a novel mechanism that is independent of CD5. 5) The investigator proposes that CD5 is important for keeping self-reactive B-1 cell in check. This will be tested by examining the effect of CD5 expression on the recruitment of self and foreign antigen specific B-cells in to B-1 compartment of BCR transgenic mice bred to CD5-/-mice. He will determine if absence of CD5 affects B-cell tolerance and enhances autoantibody production in such CD5-/- -transgenic hybrids. These studies should lead to the development of better means of controlling autoimmune diseases and B-cell leukemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI021490-15
Application #
6169926
Study Section
Immunobiology Study Section (IMB)
Program Officer
Deckhut Augustine, Alison M
Project Start
1984-07-01
Project End
2003-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
15
Fiscal Year
2000
Total Cost
$270,715
Indirect Cost
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Dasu, Trivikram; Sindhava, Vishal; Clarke, Stephen H et al. (2009) CD19 signaling is impaired in murine peritoneal and splenic B-1 B lymphocytes. Mol Immunol 46:2655-65
Wu, Hsin-Jung; Bondada, Subbarao (2009) CD72, a coreceptor with both positive and negative effects on B lymphocyte development and function. J Clin Immunol 29:12-21
Dasu, Trivikram; Qualls, Joseph E; Tuna, Halide et al. (2008) CD5 plays an inhibitory role in the suppressive function of murine CD4(+) CD25(+) T(reg) cells. Immunol Lett 119:103-13
Gururajan, Murali; Simmons, Alan; Dasu, Trivikram et al. (2008) Early growth response genes regulate B cell development, proliferation, and immune response. J Immunol 181:4590-602
Gururajan, Murali; Dasu, Trivikram; Shahidain, Seif et al. (2007) Spleen tyrosine kinase (Syk), a novel target of curcumin, is required for B lymphoma growth. J Immunol 178:111-21
Landers, Cheri D; Bondada, Subbarao (2005) CpG oligodeoxynucleotides stimulate cord blood mononuclear cells to produce immunoglobulins. Clin Immunol 116:236-45
Gururajan, Murali; Chui, Roger; Karuppannan, Anbu K et al. (2005) c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells. Blood 106:1382-91
Chelvarajan, R Lakshman; Collins, Sarah M; Van Willigen, Juliana M et al. (2005) The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function. J Leukoc Biol 77:503-12
Chelvarajan, R L; Collins, S M; Doubinskaia, I E et al. (2004) Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens. J Leukoc Biol 75:982-94
Sen, Goutam; Wu, Hsin-Jung; Bikah, Gabriel et al. (2002) Defective CD19-dependent signaling in B-1a and B-1b B lymphocyte subpopulations. Mol Immunol 39:57-68

Showing the most recent 10 out of 54 publications