Mast cells are most recognized for their role in IgE-dependent allergic responses and host defense against parasitic infection. However, several recent studies have led to an expansion of this view to include the role of mast cells in the normal immune response to bacterial infection and most recently, the profound role of mast cells in the pathogenesis of autoimmunity (e.g. arthritis, multiple sclerosis). The overall goal of these studies is to define inhibitory signaling pathways in mast cells that may serve as potential targets for therapeutic intervention in the treatment of autoimmunity and atopic disease. It has become increasingly clear that mast cell activation is subject to negative regulation by members of a growing family of inhibitory receptors. The most characterized member of this family is FcgammaRIIB, the low-affinity receptor for IgG. The importance of FcgammaRIIB-mediated inhibitory signals in regulating immune responses is evident in FcgammaRIIB-deficient mice, which exhibit enhanced anaphylactic responses and autoimmunity. Recent studies have further demonstrated that FcgammaRIIB inhibitory signals are mediated by the inositol 5- phosphatase SHIP. Several studies implicate SHIP inhibitory activity in the prevention of human disease. Specifically, decreased SHIP expression has been observed in lgE+ basophils from allergic individuals and in primary leukemia cells from patients with CML. In addition, a dominant negative mutation of the SHIP gene was identified in primary leukemia cells from a patient with AML. The proposed studies will utilize genetic, biochemical, and cellular approaches to define the molecular mechanisms by which SHIP regulates mast cell activation.
The specific aims of this proposal are to i) dissect the molecular mechanisms by which SHIP regulates Fc receptor-mediated mast cell activation, ii) determine the role of SHIP in transducing inhibitory signals downstream of MAIR-1, a novel inhibitory receptor expressed in mast cells, and iii) define the role of SHIP, FcgammaRIIB, and MAIR-1 in regulating mast cell function in vivo using a mouse model of human rheumatoid arthritis. The successful completion of these aims will provide new insights into the mechanisms by which SHIP regulates mast cell function which may be useful in the development of therapeutic strategies for the treatment of arhtritis and atopic disease.
|Wiemer, Andrew J; Wernimont, Sarah A; Cung, Thai-Duong et al. (2013) The focal adhesion kinase inhibitor PF-562,271 impairs primary CD4+ T cell activation. Biochem Pharmacol 86:770-81|
|Wiemer, Andrew J; Wernimont, Sarah; Huttenlocher, Anna (2012) Live imaging of LFA-1-dependent T-cell motility and stop signals. Methods Mol Biol 757:191-204|
|Wiemer, Andrew J; Hegde, Subramanya; Gumperz, Jenny E et al. (2011) A live imaging cell motility screen identifies prostaglandin E2 as a T cell stop signal antagonist. J Immunol 187:3663-70|
|Wernimont, Sarah A; Wiemer, Andrew J; Bennin, David A et al. (2011) Contact-dependent T cell activation and T cell stopping require talin1. J Immunol 187:6256-67|
|Wernimont, Sarah A; Simonson, William T N; Greer, Peter A et al. (2010) Calpain 4 is not necessary for LFA-1-mediated function in CD4+ T cells. PLoS One 5:e10513|
|Wernimont, Sarah A; Legate, Kyle R; Simonson, William T N et al. (2010) PIPKI gamma 90 negatively regulates LFA-1-mediated adhesion and activation in antigen-induced CD4+ T cells. J Immunol 185:4714-23|
|Wiemer, Andrew J; Lokuta, Mary A; Surfus, Jill C et al. (2010) Calpain inhibition impairs TNF-alpha-mediated neutrophil adhesion, arrest and oxidative burst. Mol Immunol 47:894-902|
|Wang, Xiaohua; Chen, Xiuxu; Rodenkirch, Lance et al. (2008) Natural killer T-cell autoreactivity leads to a specialized activation state. Blood 112:4128-38|
|Lokuta, Mary A; Senetar, Melissa A; Bennin, David A et al. (2007) Type Igamma PIP kinase is a novel uropod component that regulates rear retraction during neutrophil chemotaxis. Mol Biol Cell 18:5069-80|