A critical feature of the immune system is its ability to distinguish between self and nonself seemingly ignoring self antigens while responding to and eliminating potential pathogens. Failure of this discrimination can result in autoimmunity. While, auto-reactive antigen receptors are clearly encoded in the genome, cells expressing these receptors are silenced by a variety of mechanisms. In the B cell compartment this occurs by antigen induced editing of receptors to change specificity, deletion by apoptosis, anergy and CD5 dependent hyporesponsiveness In the latter two cases, cells remain viable and competent to bind antigen, but antigen receptor signaling is altered. The long-term objectives of the application are to elucidate the molecular mechanisms underlying the antigen hyporesponsiveness of anergic B cells and peritoneal CD5+ cells.
Specific Aims are to elucidate the biochemical underpinning and biological functions of three specific mechanisms of signal modulation revealed by studies conducted during the last funding period. Two of these mechanisms, active in anergic B cells, involve (1) destabilization of the antigen receptor preventing normal transmission of signals from membrane immunoglobulin to Ig-alpha/Ig-beta dimers which function as the receptor's transmembrane transducer, and (2) activation of a negative feedback regulatory loop involving the inositol 5 phosphatase SHIP and the linker Downstream of kinase, Dok. A third mechanism, apparently operative only in peritoneal CD5+ cells, is an inhibitory loop involving Lck, CD5 and SHP-2 and targets BLNK (SLP-65). The proposed studies will be pursued using multiple lymphoma and animal models, but will rely principally on the newly described Ars/A 1 transgenic model of anergy and the VH 11 VK9 transgenic model of CD5+ B 1 cells. They will involve genetic manipulation and a variety of biochemical and biological assays of signal transduction and cellular responses. These studies may reveal drug discovery targets for autoimmunity and immunodeficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG013983-17
Application #
6395390
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Fuldner, Rebecca A
Project Start
1984-12-01
Project End
2006-05-31
Budget Start
2001-08-15
Budget End
2002-05-31
Support Year
17
Fiscal Year
2001
Total Cost
$380,250
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Hinman, Rochelle M; Smith, Mia J; Cambier, John C (2014) B cells and type 1 diabetes ...in mice and men. Immunol Lett 160:128-32
O'Neill, Shannon K; Getahun, Andrew; Gauld, Stephen B et al. (2011) Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity 35:746-56
Yarkoni, Yuval; Cambier, John C (2011) Differential STIM1 expression in T and B cell subsets suggests a role in determining antigen receptor signal amplitude. Mol Immunol 48:1851-8
Yarkoni, Yuval; Getahun, Andrew; Cambier, John C (2010) Molecular underpinning of B-cell anergy. Immunol Rev 237:249-63
Chan, Marcia A; Gigliotti, Nicole M; Matangkasombut, Ponpan et al. (2010) CD23-mediated cell signaling in human B cells differs from signaling in cells of the monocytic lineage. Clin Immunol 137:330-6
Waterman, Paul M; Cambier, John C (2010) The conundrum of inhibitory signaling by ITAM-containing immunoreceptors: potential molecular mechanisms. FEBS Lett 584:4878-82
Cambier, John C; Getahun, Andy (2010) B cell activation versus anergy; the antigen receptor as a molecular switch. Immunol Lett 128:6-7
Getahun, Andrew; O'Neill, Shannon K; Cambier, John C (2009) Establishing anergy as a bona fide in vivo mechanism of B cell tolerance. J Immunol 183:5439-41
O'Neill, Shannon K; Liu, Edwin; Cambier, John C (2009) Change you can B(cell)eive in: recent progress confirms a critical role for B cells in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 16:293-8
Crowley, Jenni E; Stadanlick, Jason E; Cambier, John C et al. (2009) FcgammaRIIB signals inhibit BLyS signaling and BCR-mediated BLyS receptor up-regulation. Blood 113:1464-73

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