Molecular and Cellular Allergology - Inserm U.760  

  HEADDr Marc Daëron /
  MEMBERSDr Marc Daëron (MD, PhD), Dr Pierre Bruhns (PhD), Dr Cécile Schiffer (PhD), Dr Nihad Meknache (PharmD), Michel Elser (PhD), Dr Friedericke Jönsson (PhD), Dr Vincent Rouget-Quermalet (PhD), Odile Malbec (IE), Bruno Iannascoli (TS), Christine Detchepare (Secretary), David Mancardi (PhD student), Anne-Laurence Blanc (PhD student), Paul Loriaux (6 months, PhD student), Ioana Baiu (3 months, PhD student)

  Annual Report

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 subunits which contain Immunoreceptor Tyrosine-based Activation Motifs( ITAMs). Signals triggered by activating FcRs are integrated in signalosomes that are organized by transmembrane adapters. Inhibitory FcRs are 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 which inhibits 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. Mast cells are indeed increasingly recognized as being critical for controlling the initiation not only of allergic, but also of autoimmune inflammation. Results obtained in 2008 are as follows.

Molecular bases of LAT- and NTAL-dependent negative signaling in mast cells. The Linker for Activation of T cells (LAT) and the Non-T cell Activation Linker (NTAL) are two transmembrane adapters which organize high-affinity IgE receptor (FcεRI)signaling complexes. We found that NTAL negatively regulates, whereas LAT positively regulates mast cell activation, and that NTAL positively regulates whereas LAT negatively regulates mast cell survival. We identified two binding sites for the SH2 domain of SHIP1 and showed that LAT can recruit SHIP1 in vivo thus providing the molecular bases for LAT-dependent negative signaling in mast cells. Our results thus document how LAT and NTAL can generate both positive and negative signals which differentially regulate mast cell activation and survival (K. Roget et al., J. Immunol. 2008).

A new murine receptor for IgE. FcγRIV is a novel type of activating high-affinity IgG receptor expressed by mouse macrophages and neutrophils. We found that FcγRIV also binds IgE antibodies with a low-affinity, that IgE immune complexes can displace IgG antibodies previously bound to FcγRIV and that, upon engagement by IgE immune complexes, FcRIV triggered activation signals and induced bronchoalveolar and peritoneal macrophages to secrete cytokines. These data suggest that FcγRIV may be an equivalent of human FcεRI which is expressed by macrophages and neutrophils, especially in atopic individuals. Using mice lacking three IgG receptors and two IgE receptors and expressing FcγRIV only, we demonstrated that FcγRIV on macrophages could synergize with FcεRI on mast cells to promote IgE-induced lung inflammation in vivo. These data indicate that IgE-induced lung inflammation in mice represents a much closer model of human allergic asthma than originally thought. (D. Mancardi et al., J. Clin. Invest.2008).

The specificity of human IgG receptor revisited. Distinct genes encode six human receptors for IgG (hFcγRs), three of which have two or three polymorphic variants. The specificity and affinity of individual hFcγRs for the four human IgG subclasses is unknown. This information is critical for antibody-based immunotherapy which has been increasingly used in the clinics. We investigated the binding of polyclonal and monoclonal IgG1, IgG2, IgG3 and IgG4 to FcγRI, FcγRIIA, IIB and IIC, FcγRIIIA and IIIB and all known polymorphic variants. Wt and low-fucosylated IgG1 anti-CD20 and anti-RhD mAbs were also examined. We found: 1) that IgG1 and IgG3 bind to all hFcγRs; 2) that IgG2 bind not only to FcγRIIAH131, but also, with a lower affinity, to FcγRIIAR131 and FcγRIIIAV158; 3) that IgG4 bind to FcγRI, FcγRIIA, IIB and IIC and FcγRIIIAV158; 4) that the inhibitory receptor FcγRIIB has a lower affinity for IgG1, IgG2 and IgG3 than all other hFcγRs. We also identified parameters which determine the specificity and affinity of hFcγRs for IgG subclasses. These results document how hFcγR specificity and affinity may account for the biological activities of antibodies. They therefore highlight the role of specific hFcγRs in the therapeutic and pathogenic effects of antibodies in disease. (P. Bruhns et al., Blood, 2008).

An unexpected IgG receptor on human basophils. Basophils express not only high-affinity IgE receptors, but also low-affinity IgG receptors. Which, among these receptors, are expressed by human basophils is poorly known. We found that, besides FcγRIIB, as previously reported, normal basophils contain FcγRIII transcripts and express FcγRIIIB, but not FcγRIIIA. FcγRIIIB are glycosylphosphatidylinositol-anchored receptor whose function is poorly understood. FcγRIIIB were detected on 24-81% basophils from normal donors and on 12-100% basophils from allergic patients patients. Noticeably, the proportion of FcγRIIIB+basophils was significantly lower in atopic dermatitis patients than in other subjects. Our results challenge the two dogmas 1) that basophils do not express FcγRIII and 2) that FcγRIIIB is exclusively expressed by neutrophils. They suggest that a proportion of basophils may be lost during enrichment procedures in which FcγRIII+cells are discarded by negative sorting using anti-CD16 antibodies. They unravel an unexpected complexity of IgG receptors susceptible to modulate basophil activation. They identify a novel systemic alteration in atopic dermatitis. (N. Meknache, J. Immunol. 2009, in press).

ITIMs: a quest in the past and future. Since we identified the first ITIM, in the intracytoplasmic domain of FcγRIIB, ITIMs have been found in a large number of inhibitory molecules that negatively regulate a large spectrum of biological functions. Because ITIM-dependent negative regulation seems to be a fundamental regulatory mechanism, and because it can be used either as a target or as a powerful tool in various diseases, we undertook 1) a genome-wide search of potential novel ITIM-containing molecules in humans, mice, frogs, birds, and flies, and 2) a comparative analysis of potential ITIMs in major animal phyla, from mammals to protozoa. We found a surprisingly high number of potential ITIM-containing molecules, having a great diversity of extracellular domains, and being expressed by a variety of immune and nonimmune cells. ITIMs could be traced back to the most primitive metazoa. The genes that encode ITIM-containing molecules that belong to the immunoglobulin superfamily or to the C-lectin family seem to derive from a common set of ancestor genes that have dramatically expanded and diverged in Gnathostomata (from fish to mammals). (M. Daëron et al. Immunol. Rev. 2008).

Keywords: Fc Receptors, Signal transduction, Immunoregulation, Mast cells, allergy, inflammation


M. Daëron and R. Lesourne. Negative signaling in Fc Receptor complexes. Adv. Immunol., 2006, 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., 2007, 178: 6465-6475.

FcgammaRIV is a mouse IgE receptor that resembles macrophage FcepsilonRI in humans and promotes IgE-induced lung inflammation. Mancardi DA, Iannascoli B, Hoos S, England P, Daëron M, Bruhns P. J. Clin. Invest. 2008;118:3738-50.

Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, Daëron M. Blood. 2008 Nov 18. [Epub ahead of print]

Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Daëron M, Jaeger S, Du Pasquier L, Vivier E. Immunol. Rev. 2008;224:11-43.

Activity Reports 2009 - Institut Pasteur
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