Binding of allergen to IgE complexed to its high affinity receptors (FceRI) on mast cells and basophils initiates release of histamine and other mediators. These mediators are largely responsible for the various manifestations of atopic disease which affects more than 20% of the human population. Based on recent findings, we hypothesize that FceRI mediated basophil and mast cell degranulation is subject to potent negative regulation by co-ligation with a coexpressed receptor for IgG Fc, FcgRIIB, and, further, that this effect is mediated by FcgRIIB1 tyrosine phosphorylation leading to recruitment and activation of the cytoplasmic phosphotyrosine phosphatase PTP1C and PTP1D. Studies proposed in Aim 1 will determine which FcgRIIB1 isoforms are expressed and operative in inhibitory signaling in human blood basophils. Studies in Aim 2 will assess and map tyrosine phosphorylation in the FcgRIIB and identify potential effectors which bind the phosphorylated receptor.
Aim 3 will define the role of these effectors, most notably PTP1C and PTP1D, in inhibitory signaling, and Aim 4 will identify the molecular site of action of PTP1C and PTP1D (or other implicated effectors) in the FceRI signal transduction pathway. The proposed studies will utilize contemporary cell biological and biochemical approaches, along with mutational analysis to define structure-function relationships, and receptor reconstitution to establish the mechanism of FcgRIIB-mediated inhibitory signaling. Finally, mast cells derived from PTP1C negative mice (motheaten mice) and PTP1D knockout embryonal stem cells and dominant negative mutants of these enzymes will be used to confirm the role of enzymes in the FcgRIIB effect. Studies of the ability of phosphopeptides synthesized based on receptor structure to activate PTP1C and inhibit FceRI function may lead to development of new therapeutic approaches in atopic disease.
| Cady, Carol T; Rice, Jeffrey S; Ott, Vanessa L et al. (2008) Regulation of hematopoietic cell function by inhibitory immunoglobulin G receptors and their inositol lipid phosphatase effectors. Immunol Rev 224:44-57 |
| Ott, Vanessa L; Cambier, John C; Kappler, John et al. (2003) Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat Immunol 4:974-81 |
| Marschner, Susanne; Hunig, Thomas; Cambier, John C et al. (2002) Ligation of human CD4 interferes with antigen-induced activation of primary T cells. Immunol Lett 82:131-9 |
