The principal goal of this research proposal is to investigate how proliferation and differentiation of human B cells are regulated. A major focus will be on interactions occurring at the cell surface that involve B cell differentiation antigens. Our approach stems from our findings that monoclonal antibodies (mAb) to certain epitopes on certain B cell-associated antigens have agonistic activity: the mAb 1F5 to the 35Kd pan B cell marker Bp35 activates resting B cells to leave G0 and enter the G1 phase of the cell cycle. In contrast, the mAb G28-5 to the 50Kd pan B cell antigen Bp50 does not affect resting B cells, but like certain B cell growth factors (BCGF), stimulates activated B cells to traverse the cell cycle. Our rationale is that agonistic mAb provide an alternative and complementary approach to soluble factors for studying B cell immunoregulation. Our current hypothesis is that Bp35 and Bp50 are surface receptors for either soluble B cell stimulating factors (BSF) or for transmembrane cell-cell interaction signals from accessory cells.
The specific aims of the proposal are: 1) to test whether Bp35 or Bp50 are receptors for known soluble BSF, 2) to assess the effects that anti-Bp35 and anti-Bp50 agonistic mAb have on growth factor regulation, 3) to characterize and contrast the intracellular pathways that are induced in B cells by agonistic mAb, and 4) to clone and isolate the gene which encodes for the Bp35 surface polypeptide. Further information about Bp35 and Bp50 structure and their role in B cell activation will contribute to our understanding of the etiology and possible control of lymphoid malignancies and antibody-mediated autoimmune diseases.
| Ma, Daphne Y; Clark, Edward A (2009) The role of CD40 and CD154/CD40L in dendritic cells. Semin Immunol 21:265-72 |
| 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 |
| 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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