The fundamental goal of this proposal is to investigate how human B cell activation and growth are regulated through cell surface molecules. We will focus on characterizing the ligands and signal transduction pathways induced via three major B cell-associated surface molecules, namely CD20, CD40 and Bgp95. We will make use of a set of agonistic monoclonal antibodies (mAb) to these markers and full length cDNAs in expression vectors encoding CD20 and CD40.
Our specific aims are:
Aim 1) to define the ligands for CD20 and CD40, making use of cell lines transformed with either CD20 or CD40;
Aim 2) to characterize the signal transduction pathways for CD20 and CD40 by measuring inositol phospholipid metabolism, protein kinases and/or anti-CD40;
Aim 3) to isolate cDNAs encoding Bgp95 for use in characterizing the structure and function of this surface molecule involved in the regulation of B cell activation;
and Aim 4) to assess the role that the membrane protein tyrosine phosphatase (PTPase) CD45 plays in regulating competence (CD20, Bgp95) and progression (CD40) signals in human B cells. These studies will help to elucidate not only the basic mechanisms regulating small resting B cells, but will also provide new information on how the transition of G0 to the Gl phase of the cell cycle is controlled.
| Richards, Sabrina M; Clark, Edward A (2009) BCR-induced superoxide negatively regulates B-cell proliferation and T-cell-independent type 2 Ab responses. Eur J Immunol 39:3395-403 |
| Ma, Daphne Y; Clark, Edward A (2009) The role of CD40 and CD154/CD40L in dendritic cells. Semin Immunol 21:265-72 |
| Watanabe, Chie; Shu, Geraldine L; Zheng, Timothy S et al. (2008) Caspase 6 regulates B cell activation and differentiation into plasma cells. J Immunol 181:6810-9 |
| Richards, Sabrina; Watanabe, Chie; Santos, Lorna et al. (2008) Regulation of B-cell entry into the cell cycle. Immunol Rev 224:183-200 |
| Craxton, Andrew; Draves, Kevin E; Clark, Edward A (2007) Bim regulates BCR-induced entry of B cells into the cell cycle. Eur J Immunol 37:2715-22 |
| Acosta-Rodriguez, Eva V; Craxton, Andrew; Hendricks, Deborah W et al. (2007) BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas-mediated cell death. Eur J Immunol 37:990-1000 |
| Paterson, Jennifer C; Tedoldi, Sara; Craxton, Andrew et al. (2006) The differential expression of LCK and BAFF-receptor and their role in apoptosis in human lymphomas. Haematologica 91:772-80 |
| Graves, Jonathan D; Craxton, Andrew; Clark, Edward A (2004) Modulation and function of caspase pathways in B lymphocytes. Immunol Rev 197:129-46 |
| Craxton, Andrew; Magaletti, Dario; Ryan, Elizabeth J et al. (2003) Macrophage- and dendritic cell--dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF. Blood 101:4464-71 |
| Olson, N Eric; Graves, Jonathan D; Shu, Geraldine L et al. (2003) Caspase activity is required for stimulated B lymphocytes to enter the cell cycle. J Immunol 170:6065-72 |
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