|Molecular and Cellular Allergology - Inserm U760|
|HEAD||Dr Marc DAËRON / firstname.lastname@example.org|
|MEMBERS||Dr Pierre BRUHNS / Dr Cécile SCHIFFER / Dr Nihad MEKNACHE / Karine ROGET / David MANCARDI / Odile MALBEC
Our research project lies on the hypothesis that inflammatory diseases, including allergies, can develop as a consequence of defects of negative regulation that normally controls cell activation during immune responses. Among the receptors which control cell activation are receptors for the Fc portion of antibodies (FcRs). Activating FcRs include high-affinity IgE Receptors (FcεRI). Signals triggered by activating FcRs are integrated in signaling complexes that are organized by transmembrane adapters such as LAT and NTAL. LAT exerts positive whereas NTAL exerts negative effects on FcεRI signaling. Inhibitory FcRs are low-affinity IgG Receptors (FcγRIIB). We investigate the interplay between positive and negative FcR signaling and their integration by LAT and NTAL.
A new receptor of IgE. FcγRIV are a new type of activating 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 cells which are recruited at allergic sites to respond to IgE and possibly to contribute to chronic inflammation.
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 generated large numbers of mature serosal-type mast cells which 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.
Molecular bases of LAT-dependent negative signaling in mast cells. We found previously that LAT integrates not only positive but also negative signals in mast cells. Using NTAL-deficient mast cells, in which LAT-dependent signals are amplified, we unraveled that LAT recruits a phosphatase that can account for LAT-dependent negative signals.
In vivo roles of human FcRs in murine models of allergies in “humanized” mice. Because murine and human FcRs differ in both their structure and their tissue distribution, we have undertaken the construction of mice the FcRs of which will be replaced by human FcRs with the same tissue distribution as in humans. These “humanized” mice will enable us to evaluate the respective roles of the different human FcRs and of cells on which they are expressed in experimental models of inflammatory and allergic diseases.
Expression and function of FcRs on human basophils. FcRs expressed by effector cells of allergy are not well known. We aim at determining the relative expression of activating and inhibitory FcRs on basophils from normal donors and, in collaboration with clinicians at the Medical Center of the Institute, from allergic patients.
Altogether the above works should enable us to further dissect the mechanisms of negative regulation, to evaluate the contribution of possible defects of this regulation in allergic diseases, and if so, to characterize these defects in order to correct them or, if not so, to utilize negative regulation as a new therapeutic tool.
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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