B lymphocytes are selected early in development for further maturation in peripheral sites. This positive selection step involves the emigration of lymphocytes form the bone marrow to secondary lymphoid organs where they enter lymphoid follicles. Initially generated B lymphocytes are short-lived and after two distinguishable maturation steps these lymphocytes receive a signal that converts them into a long-lived form. Bruton's tyrosine kinase (Btk) is functionally linked to the B-cell receptor and is indispensable for the conversion of short-lived B-cells into long-lived cells. The least mature short-lived cells can be distinguished from all other peripheral B-cells by their inability to proliferate in response to antigen receptor ligation. A major goal of these studies is to molecularly dissect the checkpoint that regulates the conversion of short-lived B-cells into long-lived cells. The order of events in peripheral B-cell maturation will be established by following a cohort in in vivo labeled B-cells and also by experiments involving the transfer of purified B-cell populations. Cell death at presumed checkpoints will be assessed in wild type mice and in selected mutant strains. The least mature peripheral B-cell fraction will be functionally compared with immature bone-marrow B-cells (which are believed to be critical for the generation of tolerance). The mechanisms involved in preventing cells at this stage from proliferating in response to antigen receptor signaling will be investigated. Six putative molecular targets of Btk and three molecular targets of Lyn (a Src-family tyrosine kinase associated with the B-cell receptor), all of which are phosphorylated on tyrosine residues after B-cell activation, will be characterized in detail. A complete analysis of targets of these kinases may yield important clues to the mechanisms involved in generating long-lived B-cells and in antigen receptor mediated B-cell proliferation. Since the majority of human lymphomas develop form activated B-cells, these signaling mechanisms are likely to be of direct relevance for a significant proportion of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033507-07
Application #
6149781
Study Section
Immunobiology Study Section (IMB)
Program Officer
Ridge, John P
Project Start
1994-05-01
Project End
2003-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
7
Fiscal Year
2000
Total Cost
$287,297
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Naikawadi, Ram P; Cheng, Ni; Vogel, Stephen M et al. (2012) A critical role for phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger 1 in endothelial junction disruption and vascular hyperpermeability. Circ Res 111:1517-27
Faraji, Amir H; Wipf, Peter (2009) Nanoparticles in cellular drug delivery. Bioorg Med Chem 17:2950-62
Moran, Stewart T; Cariappa, Annaiah; Liu, Haoyuan et al. (2006) Protein kinase C-associated kinase is not required for the development of peripheral B lymphocyte populations. Mol Immunol 43:1694-9
Cariappa, Annaiah; Shoham, Tsipi; Liu, Haoyuan et al. (2005) The CD9 tetraspanin is not required for the development of peripheral B cells or for humoral immunity. J Immunol 175:2925-30
Pillai, Shiv; Cariappa, Annaiah; Moran, Stewart T (2005) Marginal zone B cells. Annu Rev Immunol 23:161-96
Pillai, Shiv; Cariappa, Annaiah; Moran, Stewart T (2004) Positive selection and lineage commitment during peripheral B-lymphocyte development. Immunol Rev 197:206-18
Cariappa, Annaiah; Chen, Luojing; Haider, Khaleda et al. (2003) A catalytically inactive form of protein kinase C-associated kinase/receptor interacting protein 4, a protein kinase C beta-associated kinase that mediates NF-kappa B activation, interferes with early B cell development. J Immunol 171:1875-80
Moran, Stewart T; Haider, Khaleda; Ow, Yongkai et al. (2003) Protein kinase C-associated kinase can activate NFkappaB in both a kinase-dependent and a kinase-independent manner. J Biol Chem 278:21526-33
Cariappa, Annaiah; Pillai, Shiv (2002) Antigen-dependent B-cell development. Curr Opin Immunol 14:241-9
Kim, Tae Jin; Cariappa, Annaiah; Iacomini, John et al. (2002) Defective proliferative responses in B lymphocytes and thymocytes that lack neurofibromin. Mol Immunol 38:701-8

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