|Molecular and Cellular Allergology|
|HEAD||Dr Marc Daëron / firstname.lastname@example.org|
|MEMBERS||Dr Marc Daëron (MD, PhD), Dr Pierre Bruhns (PhD), Dr Cécile Schiffer-Mannioui (PhD), Dr Michel Elser (PhD), Dr Friedericke Jönsson (PhD)
Dr Vincent Rouget-Quermalet (PhD), Odile Malbec, Bruno Iannascoli, Christine Detchepare, David Mancardi, Paul Loriaux, Ioana Baiu
The activation of hematopoietic cells is positively and negatively controlled by membrane receptors. Among these are receptors for the Fc portion of antibodies (FcRs). Antibodies can both activate and inhibit cell activation when engaging activating and/or inhibitory FcRs. Activating FcRs are constitutively associated with FcR subunits which contain Immunoreceptor Tyrosine-based Activation Motifs(ITAMS). They include high-affinity IgE receptors (FcεRI) and low-affinity IgG receptors (FcγRIIIA) that are both expressed by mast cells. Signals triggered by activating FcRs are integrated in signalosomes that are organized by transmembrane adapters. These include the Linker of Activation of T cells(LAT) and the Non T cell Activation Linker(NTAL). Inhibitory FcRs are a subclass of low-affinity IgG Receptors (FcγRIIB) which contain an Immunoreceptor Tyrosine-based Inhibition Motif(ITIM). When FcγRIIB are co-aggregated with activating receptors on the same cell, their ITIM is phosphorylated and recruits the phosphatidylinositol 5-phosphatase SHIP1. SHIP1 is a major inhibitor of mast cell activation. Our research project lies on the hypothesis that inflammatory diseases, including allergies, but also some tissue-specific IgG-dependent autoimmune diseases, can develop as a consequence of defects of negative regulation that normally controls cell — particularly mast cell — activation. Our works investigate the interplay between positive and negative FcR signaling and their integration by LAT and NTAL in physiology and pathology. Our recent results are as follows.
The specificity of murine and human FcRs revisited. FcγRIV are a novel type of activating high-affinity IgG receptors expressed by mouse macrophages and neutrophils. We found that FcγRIV also bind IgE antibodies with a low-affinity and that, upon aggregation by IgE immune complexes, they trigger activation signals. FcγRIV thus enable inflammatory cells which are recruited at allergic sites to respond to IgE and possibly to contribute to chronic inflammation (D. Mancardi). We have also undertaken a systematic investigation of the subclass specificity of the 4 mouse IgG subclasses for the 4 mouse FcγRs (O. Malbec) and of the 4 human IgG subclasses for the 5 human FcγRs including their allelic forms (P. Bruhns).
A new model of primary mouse mast cells. Bone Marrow-derived Mast Cells (BMMC) have been extensively used as an in vitro model of mouse mast cells. BMMC, however, are immature cells which have no known in vivo equivalent. We showed that one can generate large numbers of mature serosal-type mast cells. These Peritoneal cell-derived Mast Cells (PCMC) markedly differ from BMMC in their biological properties. This novel mast cell model can account for tissue-specific inflammation observed in allergies and in IgG-dependent autoimmune diseases (O. Malbec).
Molecular bases of LAT- and NTAL-dependent negative signaling in mast cells. We found previously that NTAL negatively regulates, whereas LAT positively regulates mast cell activation. We recently found that NTAL positively regulates whereas LAT negatively regulates mast cell survival, and that these effects primarily depend on the recruitment of SHIP1 by LAT in which we identified two SHIP1-binding sites (K. Roget).
Negative regulation of mast cell activation by probiotics. Mast cells can interact with microbial pathogens and, when activated, contribute to innate immunity. We found that some probiotics profoundly inhibit IgE-induced mast cell activation. We are investigating the mechanisms of inhibition and the potential physiopathological significance of this inhibition (C. Schiffer-Mannioui).
In vivo roles of human FcRs in murine models of allergies. Because murine and human FcRs differ in both their structure and their tissue distribution, we have undertaken the construction of mice whose FcRs are being replaced by human FcRs with the same tissue distribution as in humans. Mice thus “humanized” will be injected with human IgE and/or IgG antibodies, and the respective roles of the different human FcRs and of cells on which they are expressed will be examined in experimental models of inflammatory and allergic diseases (P. Bruhns).
Expression and function of FcRs on human basophils. FcRs expressed by effector cells of allergy are not well known. We therefore undertook a study of FcRs on basophils from normal donors and, in collaboration with physicians, at the Medical Center of the Institute, from allergic patients. An unexpected result was that human basophils express the glycosylphosphatidyl-anchored low-affinity IgG receptor FcγRIIIB (CD16B) and that the expression of CD16B by basophils is decreased in atopic dermatitis (N. Meknache).
Keywords: Fc Receptors, Signal transduction, Immunoregulation, Mast cells, allergy, inflammation
O. Malbec, M. Malissen, I. Isnardi, R. Lesourne, A.-M. Mura, W. H. Fridman, B. Malissen and M. Daëron. 2004. Linker for activation of T cells integrates positive and negative signals in mast cells. J. Immunol., 173: 5086-594.
R. Lesourne, W. H. Fridman and M. Daëron. 2005. Dynamic interactions of FcγRIIB with Filamin-bound SHIP1 amplify Filamentous actin-dependent negative regulation of FcεRI signaling. J. Immunol., 174: 1365-1373.
M. Daëron and R. Lesourne. 2006. Negative signaling in Fc Receptor complexes. Adv. Immunol., 89: 39-86
O. Malbec, K. Roget, C. Schiffer, B. Iannascoli, A. Ribadeau Dumas, M. Arock and M. Daëron. 2007. Peritoneal Cell-derived Mast Cells, an in vitro model of mature serosal-type mouse mast cells. J. Immunol., 178: 6465-6475.
O. Malbec and M. Daëron. 2007. The Mast Cell IgG Receptors and their Roles in tissue inflammation. Immunol. Rev., 217: 206-221.
Activity Reports 2007 - Institut Pasteur
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