Unit: Molecular and Cellular Allergology
Director: Marc DAËRON
The activation, proliferation and differentiation of cells involved in the immune response are under the control of membrane receptors that trigger positive and negative signals. These signals are integrated through the sequential interactions of intracellular molecules recruited within signaling complexes that build up underneath co-engaged receptors and whose composition varies with time. As a consequence, the immune response is tightly controlled and, although potentially deleterious, immune effectors are non pathogenic in normal individuals. The research project of the unité lies on the hypothesis according to which allergic diseases can arise as a consequence of defects that might possibly affect any step during the allergic reaction in negative regulation that prevents the outcome of allergic manifestations in normal individuals.
We demonstrated previously that FcγRIIB, a family of receptors for the Fc portion (FcRs) of IgG antibodies expressed by most cells of hematopoietic origin, can inhibit activation and proliferation signals triggered by immunoreceptors and growth factor receptors, respectively. Inhibition depends on an Immunoreceptor Tyrosine-based Inhibition Motif (ITIM) that we first identified in the intracytoplasmic domain of murine and human FcγRIIB and that was subsequently found in a large number of other inhibitory receptors. FcγRIIB-dependent inhibition is triggered when inhibitory receptors are co-aggregated with activating receptors on the same cell by a common extracellular ligand, such as immune complexes. These in vitro results were confirmed in vivo. Mice rendered deficient in FcγRIIB or in another ITIM-containing inhibitory receptor by homologous recombination exhibited enhanced anaphylactic reactions, as well as mice deficient in SHIP1, the phosphatase that was demonstrated to be recruited by FcγRIIB and to account for the inhibitory properties of this receptor. Our research project aims at evaluating the possible contribution of defects in negative regulation by ITIM-containing receptors in allergic diseases, and at characterizing putative defects in order to correct them and/or to utilize negative regulation as a new therapeutic tool.
One mission of the unité being to bring closer basic and clinical research on allergies, three sets of projects will be conducted.
1. A first set of works, mostly fundamental, will continue to explore the molecular and cellular mechanisms of FcγRIIB-dependent negative regulation. Human FcγRIIB will be specially studied as they are closely related but not identical to murine FcγRIIB and as the molecular mechanisms they use are poorly known.
2. A second set of works, mostly clinical, will aim at examining whether negative regulation is or is not operational in cells from patients suffering from various allergic diseases. These works will bear on inhibitory FcγRIIB, but also on activating FcRs that are coexpressed on these cells, and on the reciprocal modulation of antagonistic signals delivered by the two types of receptors.
3. A third set of work will aim at unifying the other two. It lies on the construction of an experimental model that will enable us to investigate the in vivo regulatory roles of human FcRs under conditions close to physiology. This model will consist of "humanized" mice whose FcRs will have been replaced by their human homologues and to which human antibodies against major allergens will be administered.