Mechanisms that restrict the immune response are critical to avoid damaging reactivity that can lead to allergies and inflammatory responses or, in more severe cases, to lethal autoimmune diseases. Our goal is to understand mechanisms that downregulate the immune response, control lymphocyte proliferation and antibody production. With this intention we initiated a study of the negative regulatory pathway mediated by the inositol phosphatase SHIP. Absence of SHIP results in reduced viability of the mice due to a myeloproliferative-like syndrome, with profound splenomegaly and massive myeloid cell accumulation in the lungs. The very pleiotropic phenotype of SHIP-/- mice reflects the fact that SHIP is a general down-modulator of growth factor, cytokine, Fc and antigen receptor activity. To get a more precise idea of the in vivo function of SHIP in specific cells while avoiding pleiotropic interactions, we have begun to characterize tissue-specific or inducible SHIP mutations in mice. We have generated loxP-flanked SHIP mice that can be crossed to several Cre recombinase-expressing mice. In collaboration with Jeff Ravetch we have determined the essential role of SHIP in the formation of the splenic marginal zone utilizing mice with macrophage specific deletion of SHIP. We are now characterizing the functional role of SHIP in T lymphocyte selection, tolerance as well as the effects of mast cell-specific deletion of SHIP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000911-04
Application #
7196698
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Perez de Diego, R; Lopez-Granados, E; Rivera, J et al. (2008) Naturally occurring Bruton's tyrosine kinase mutations have no dominant negative effect in an X-linked agammaglobulinaemia cellular model. Clin Exp Immunol 152:33-8
Tarasenko, Tatyana; Kole, Hemanta K; Chi, Anthony W et al. (2007) T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses. Proc Natl Acad Sci U S A 104:11382-7
Leung, Wai-Hang; Bolland, Silvia (2007) The inositol 5'-phosphatase SHIP-2 negatively regulates IgE-induced mast cell degranulation and cytokine production. J Immunol 179:95-102
Pantelic, Milica; Kim, Young-June; Bolland, Silvia et al. (2005) Neisseria gonorrhoeae kills carcinoembryonic antigen-related cellular adhesion molecule 1 (CD66a)-expressing human B cells and inhibits antibody production. Infect Immun 73:4171-9
Bolland, Silvia (2005) A newly discovered Fc receptor that explains IgG-isotype disparities in effector responses. Immunity 23:2-4
Karlsson, Mikael C I; Guinamard, Rodolphe; Bolland, Silvia et al. (2003) Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone. J Exp Med 198:333-40
Chen, T; Zimmermann, W; Parker, J et al. (2001) Biliary glycoprotein (BGPa, CD66a, CEACAM1) mediates inhibitory signals. J Leukoc Biol 70:335-40
Ravetch, J V; Bolland, S (2001) IgG Fc receptors. Annu Rev Immunol 19:275-90