B-1 cells constitute a unique population of B cells, with numerous distinguishing phenotypic, transcriptomic, and functional characteristics. B-1 cells differ from conventional B-2 cells in the rules that govern stimulated cell cycle responses and in the unstimulated, spontaneous secretion of non-immune immunoglobulin. The long term objectives of the proposed work are twofold: 1) to elucidate pdmary characteristics that dictate the unique nature of B-1 cells; 2) to identify key mediators that specify proliferative responses in, and differentiative features of, B-1 cells. The proposed studies build on a longstanding collaboration between the two project leaders that has already produced new insights regarding previously unrecognized restriction points regulating cell cycle progression in B cells. The proposed study will exploit these advances to further probe the nature of cell cycle regulation, and at the same time take advantage of the proven complimentary expertise of the investigators, and recent key findings, to extend this work to elucidate the determinants of immunoglobulin secretion. Several molecular approaches will be utilized to address the function of cyclin D3-cdk4 complexes in B cells (Project 1) and relationship between Bcl-6 and immunoglobulin secretion, and !the role of the peritoneal environment, in B-1 cells (Project 2). These studies will generate new information regarding the underlying nature of B-1 cells, and will identify means to manipulate B cell clonal expansion and spontaneous immunoglobulin secretion to improve resistance to infection and/or intoxication by natural microorganisms or bioterrorism agents, and to forestall and/or treat autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
7P01AI060896-03
Application #
7220650
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$308,336
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Zhong, Xuemei; Rothstein, Thomas L (2011) L2pB1: a new player in autoimmunity. Mol Immunol 48:1292-300
Gumina, Maria R; Xu, Chenjia; Chiles, Thomas C (2010) Cyclin D3 is dispensable for human diffuse large B-cell lymphoma survival and growth: evidence for redundancy with cyclin E. Cell Cycle 9:820-8
Kaku, H; Rothstein, T L (2010) Octamer binding protein 2 (Oct2) regulates PD-L2 gene expression in B-1 cells through lineage-specific activity of a unique, intronic promoter. Genes Immun 11:55-66
Holodick, Nichol E; Tumang, Joseph R; Rothstein, Thomas L (2010) Immunoglobulin secretion by B1 cells: differential intensity and IRF4-dependence of spontaneous IgM secretion by peritoneal and splenic B1 cells. Eur J Immunol 40:3007-16
Holodick, Nichol E; Tumang, Joseph R; Rothstein, Thomas L (2009) Continual signaling is responsible for constitutive ERK phosphorylation in B-1a cells. Mol Immunol 46:3029-36
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Zhong, Xuemei; Lau, Stanley; Bai, Chunyan et al. (2009) A novel subpopulation of B-1 cells is enriched with autoreactivity in normal and lupus-prone mice. Arthritis Rheum 60:3734-43
Holodick, Nichol E; Repetny, Karen; Zhong, Xuemei et al. (2009) Adult BM generates CD5+ B1 cells containing abundant N-region additions. Eur J Immunol 39:2383-94
Dufort, Fay J; Bleiman, Blair F; Gumina, Maria R et al. (2007) Cutting edge: IL-4-mediated protection of primary B lymphocytes from apoptosis via Stat6-dependent regulation of glycolytic metabolism. J Immunol 179:4953-7
Nikolajczyk, Barbara S; Sardi, Sylvia H; Tumang, Joseph R et al. (2007) Immunoglobulin kappa enhancers are differentially regulated at the level of chromatin structure. Mol Immunol 44:3407-15

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