Mast cells have high proinflammatory potential because they contain a large number of bioactive mediators of three classes: preformed, secretory granule-derived mediators such as histamine and proteases; newly generated lipid mediators such as leukotriene C4 (LTC4), prostaglandin D2, and the platelet-activating factor; and a panoply of proinflammatory cytokines including IL-1B, IL-6, and TNF-a. Mast cells, which reside in normal tissues at the interface between self and non-self, must be tightly regulated to prevent the deleterious effects of innate or immunologic activation. Indeed, inappropriate activation of mast cells leads to immediate hypersensitivity reactions and bronchial asthma. The investigator has discovered and characterized the mouse mast cell gp49 gene family, which is part of the Immunoglobulin Superfamily. The cytoplasmic domain of one member of the family, gp49B1, contains two Immunoreceptor Tyrosine-based Inhibition Motifs (ITIMs). He showed that the cross-linking of gp49B1 with the high affinity IgE receptor (FceRI) on mast cells inhibits the exocytosis of histamine and B-hexosaminidase, as well as the generation of LTC4. Thus, gp49B1 is a newly recognized counter-regulator of mast cell activation. However, the mechanism(s) by which gp49B1 inhibits mast cell activation is known, as is the natural ligand for gp49B1 (""""""""gp49B1L""""""""). The broad objective of the proposed research is to understand more about the cellular and molecular biology of gp49B1 in mast cells, with the long range goal of harnessing its ligand-driven inhibitory pathway to control deleterious mast cell activation that causes allergic reactions and contributes to the pathogenesis of bronchial asthma and other forms of inflammation. The application proposes to achieve the first stage of its broad objective by pursuing the following Specific Aims: 1) to define the molecular mechanism(s) by which gp49B1 inhibits the signal transduction pathways leading to mast cell activation; and 2) to clone, characterize, and express gp49B1L so as to define the biologic significance of its interaction with gp49B1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041144-05
Application #
6488981
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Plaut, Marshall
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
5
Fiscal Year
2002
Total Cost
$241,411
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Fanning, Laura B; Buckley, Carolyn C; Xing, Wei et al. (2013) Downregulation of key early events in the mobilization of antigen-bearing dendritic cells by leukocyte immunoglobulin-like Receptor B4 in a mouse model of allergic pulmonary inflammation. PLoS One 8:e57007
Breslow, Rebecca G; Rao, Jayanti J; Xing, Wei et al. (2010) Inhibition of Th2 adaptive immune responses and pulmonary inflammation by leukocyte Ig-like receptor B4 on dendritic cells. J Immunol 184:1003-13
Balestrieri, Barbara; Maekawa, Akiko; Xing, Wei et al. (2009) Group V secretory phospholipase A2 modulates phagosome maturation and regulates the innate immune response against Candida albicans. J Immunol 182:4891-8
Murphy, Thomas R; Legere 3rd, Henry J; Katz, Howard R (2007) Activation of protein kinase D1 in mast cells in response to innate, adaptive, and growth factor signals. J Immunol 179:7876-82
Zhou, Joseph S; Xing, Wei; Friend, Daniel S et al. (2007) Mast cell deficiency in Kit(W-sh) mice does not impair antibody-mediated arthritis. J Exp Med 204:2797-802
Zhou, Joseph S; Friend, Daniel S; Lee, David M et al. (2005) gp49B1 deficiency is associated with increases in cytokine and chemokine production and severity of proliferative synovitis induced by anti-type II collagen mAb. Eur J Immunol 35:1530-8
Feldweg, Anna M; Friend, Daniel S; Zhou, Joseph S et al. (2003) gp49B1 suppresses stem cell factor-induced mast cell activation-secretion and attendant inflammation in vivo. Eur J Immunol 33:2262-8
Zhou, Joseph S; Friend, Daniel S; Feldweg, Anna M et al. (2003) Prevention of lipopolysaccharide-induced microangiopathy by gp49B1: evidence for an important role for gp49B1 expression on neutrophils. J Exp Med 198:1243-51
Castells, M C; Klickstein, L B; Hassani, K et al. (2001) gp49B1-alpha(v)beta3 interaction inhibits antigen-induced mast cell activation. Nat Immunol 2:436-42
Daheshia, M; Friend, D S; Grusby, M J et al. (2001) Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J Exp Med 194:227-34

Showing the most recent 10 out of 13 publications