The aim of this project is to understand how Fc receptors communicate intracellular signals to initiate mast cell activation leading to inflammation. Fc receptors are key players in autoimmune diseases like systemic lupus erythematosus and in allergic disease. We have focused on how receptor activity is regulated for signaling proteins serving as possible links from Fc receptor to gene expression and mast cell degranulation, in order to help identify potential therapeutic targets in autoimmune and allergic disease. Results: The objectives of the past year were met in the following manner. First, studies on how the IgE receptor can distinguish between high- and low-affinity antigens were initiated as well as studies aimed at therapeutic intervention in mast cell function. These studies led us to explore the use for adaptor molecules in mast cells, and showed that the difference in affinity is interpreted into different usage of molecular signaling pathways. In addition, our studies using a parental compound that disrupts lipid raft integrity has demonstrated that such compounds inhibit mast cell degranulation. Additional work explored whether other stimuli that lead to mast cell activation functioned through the use of Lyn or Fyn. This work demonstrates that depending on the stimulus dominance of kinase usage may differ. Conclusions and Significance: In summary, our findings support the view that different stimuli can elicit specific responses through the use of particular molecular signaling modules. These findings provide new avenues for future exploration towards understanding the role of IgE Fc receptors in health and disease.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases
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Falanga, Yves T; Chaimowitz, Natalia S; Charles, Nicolas et al. (2012) Lyn but not Fyn kinase controls IgG-mediated systemic anaphylaxis. J Immunol 188:4360-8
Serra-Pages, Mariona; Olivera, Ana; Torres, Rosa et al. (2012) E-prostanoid 2 receptors dampen mast cell degranulation via cAMP/PKA-mediated suppression of IgE-dependent signaling. J Leukoc Biol 92:1155-65
Furumoto, Yasuko; Charles, Nicolas; Olivera, Ana et al. (2011) PTEN deficiency in mast cells causes a mastocytosis-like proliferative disease that heightens allergic responses and vascular permeability. Blood 118:5466-75
Carmi-Levy, Irit; Motzik, Alex; Ofir-Birin, Yifat et al. (2011) Importin beta plays an essential role in the regulation of the LysRS-Ap(4)A pathway in immunologically activated mast cells. Mol Cell Biol 31:2111-21
Suzuki, Ryo; Liu, Xibao; Olivera, Ana et al. (2010) Loss of TRPC1-mediated Ca2+ influx contributes to impaired degranulation in Fyn-deficient mouse bone marrow-derived mast cells. J Leukoc Biol :
Alvarez-Errico, Damiana; Yamashita, Yumi; Suzuki, Ryo et al. (2010) Functional analysis of Lyn kinase A and B isoforms reveals redundant and distinct roles in Fc epsilon RI-dependent mast cell activation. J Immunol 184:5000-8
van der Kleij, Hanneke; Charles, Nicolas; Karimi, Khalil et al. (2010) Evidence for neuronal expression of functional Fc (epsilon and gamma) receptors. J Allergy Clin Immunol 125:757-60
Gilfillan, Alasdair M; Rivera, Juan (2009) The tyrosine kinase network regulating mast cell activation. Immunol Rev 228:149-69
Alvarez-Errico, Damiana; Lessmann, Eva; Rivera, Juan (2009) Adapters in the organization of mast cell signaling. Immunol Rev 232:195-217
Rivera, Juan; Fierro, Nora A; Olivera, Ana et al. (2008) New insights on mast cell activation via the high affinity receptor for IgE. Adv Immunol 98:85-120

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