Mast Cells and Company

Classically, allergy depends on IgE antibodies and on high-affinity IgE receptors expressed by mast cells and basophils. This long accepted IgE/FcεRI/mast cell paradigm, on which the definition of immediate hypersensitivity was based in the Gell and Coomb’s classification, appears too reductionist. Recently accumulated evidence indeed requires that not only IgE but also IgG antibodies, that not only FcεRI but also FcγR of the different types, that not only mast cells and basophils but also neutrophils, monocytes, macrophages, eosinophils, and other myeloid cells be considered as important players in allergy. This view markedly changes our understanding of allergic diseases and, possibly, their treatment

Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation

Mastocytosis is a rare neoplastic disease characterized by a pathologic accumulation of tissue mast cells (MCs). Mastocytosis is often associated with a somatic point mutation in the Kit protooncogene leading to an Asp/Val substitution at position 816 in the kinase domain of this receptor. The contribution of this mutation to mastocytosis development remains unclear. In addition, the clinical heterogeneity presented by mastocytosis patients carrying the same mutation is unexplained. We report that a disease with striking similarities to human mastocytosis develops spontaneously in transgenic mice expressing the human Asp816Val mutant Kit protooncogene specifically in MCs. This disease is characterized by clinical signs ranging from a localized and indolent MC hyperplasia to an invasive MC tumor. In addition, bone marrow–derived MCs from transgenic animals can be maintained in culture for >24 mo and acquire growth factor independency for proliferation. These results demonstrate a causal link in vivo between the Asp816Val Kit mutation and MC neoplasia and suggest a basis for the clinical heterogeneity of human mastocytosis

Mouse and human neutrophils induce anaphylaxis

International audienceAnaphylaxis is a life-threatening hyperacute immediate hypersensitivity reaction. Classically, it depends on IgE, FcεRI, mast cells, and histamine. However, anaphylaxis can also be induced by IgG antibodies, and an IgG1-induced passive type of systemic anaphylaxis has been reported to depend on basophils. In addition, it was found that neither mast cells nor basophils were required in mouse models of active systemic anaphylaxis. Therefore, we investigated what antibodies, receptors, and cells are involved in active systemic anaphylaxis in mice. We found that IgG antibodies, FcγRIIIA and FcγRIV, platelet-activating factor, neutrophils, and, to a lesser extent, basophils were involved. Neutrophil activation could be monitored in vivo during anaphylaxis. Neutrophil depletion inhibited active, and also passive, systemic anaphylaxis. Importantly, mouse and human neutrophils each restored anaphylaxis in anaphylaxis-resistant mice, demonstrating that neutrophils are sufficient to induce anaphylaxis in mice and suggesting that neutrophils can contribute to anaphylaxis in humans. Our results therefore reveal an unexpected role for IgG, IgG receptors, and neutrophils in anaphylaxis in mice. These molecules and cells could be potential new targets for the development of anaphylaxis therapeutics if the same mechanism is responsible for anaphylaxis in humans

Denudation outpaced by crustal thickening in the eastern Tianshan

The modern high topography of the Tianshan resulted from the reactivation of a Paleozoic orogenic belt by the India/Asia collision. Today, the range exhibits tectonically active forelands and intermontane basins. Based on quantitative morphotectonic observations and age constraints derived from cosmogenic 10Be dating, single-grain post-infrared infrared stimulated luminescence (p-IR IRSL) dating and modeling of fault scarp degradation, we quantify the deformation in the Nalati and Bayanbulak intermontane basins in the central Eastern Tianshan. Our results indicate that at least 1.4 mm/yr of horizontal crustal shortening is accommodated within these two basins. This shortening represents over 15% of the 8.5 ± 0.5 mm/yr total shortening rate across the entire range at this longitude. This shortening rate implies that the Eastern Central Tianshan is thickening at a mean rate of ∼1.4 mm/yr, a rate that is significantly higher than the average denudation rate of 0.14 mm/yr derived from our cosmogenic analysis. This discrepancy suggests that the Tianshan range has not yet reached a steady-state topography and remains in a transient state of topographic growth, most likely due to limited denudation rates driven by the arid climate of Central Asia

The immune system as a system of relations

International audienceProgress in neuroimmunology established that the nervous and the immune systems are two functionally related physiological systems. Unique sensory and immune receptors enable them to control interactions of the organism with the inner and the outer worlds. Both systems undergo an experience-driven selection process during their ontogeny. They share the same mediators/ neurotransmitters and use synapses for intercellular communication. They keep a memory of previous experiences. Immune cells can affect nervous cells, nervous cells can affect immune cells, and they regulate each other. I however argue that the two systems differ by three major points: 1) Unlike the nervous system, the immune system has a loose anatomical structure, in which molecular and cellular events mostly occur at random; 2) The immune system can respond to molecules of the living world whereas the nervous system can respond to phenomena of the physical world; 3) Responses of the immune system act both on the organism and on the stimulus that triggered the response, whereas responses of the nervous system act on the organism only. The nervous and the immune systems therefore appear as two complementary systems of relations that closely work together, and whose reactivities are well-suited to deal with physical and biological stimuli, respectively. Its ability both to adapt the organism to the living world and to adapt the living world to the organism endows the immune system with powerful adaptive properties that enable the organism to live in peace with itself and with other living beings, whether pathogens or commensals

Bases moléculaires du recrutement de l'inositol-phosphatase SHIP1 par les RFcgammaIIB, des récepteurs inhibiteurs de l'activation des lymphocytes B

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Rôles pro-inflammatoires des RFcgIV murins, et de leurs deux équivalents fonctionnels humains, les RFcgI et les RFc I(ag)

Un nouveau RFc, nommé RFcgIV, a été récemment cloné. Ce sont des RFc activateurs murins pour les IgG2 exprimés par les macrophages et les neutrophiles. Ils n existent pas chez l homme. Nous avons caractérisé des propriétés biologiques de ces RFc et recherché s ils avaient des équivalents fonctionnels humains. Nous avons mis en évidence une interaction de faible affinité entre les RFcgIV et les IgE. Cette interaction participe à l induction d une inflammation pulmonaire. Dans des modèles d inflammation dépendante des IgG, les RFcgIV sont capables d induire une arthrite auto-immune et des chocs anaphylactiques systémiques. L ensemble de ce travail met en évidence de nouvelles fonctions des RFcgIV, et des cellules qui les expriment, dans des réactions in vivo induites à la fois par des IgE et par des IgG. Deux RFc humains, les RFcgI et les RFc I(ag) pourraient, chez l homme, jouer le rôle que jouent les RFcgIV chez la souris.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Bases moléculaires et cellulaires du recrutement des phosphatases à domaine SH2 par les RFcyIIB, des récepteurs pour la portion Fc des IgG inhibiteurs de l'activation cellulaire

Les RFcyIIB sont des régulateurs négatifs de l'activation cellulaire induite par les récepteurs d'antigène. L'inhibition induite par ces récepteus dépend d'un motif intracytoplasmique, appelé ITIM. Lorsqu'il est phosphorylé, ce motif recrute des phosphatases qui sont les effecteurs de l'inhibition. In vitro, des peptides contenant l'ITIM phosphorylé des RFcyIIB se lient à deux types de phosphatases, les SHP et les SHIP. In vivo, les RFcyIIB phosphorylés recrutent sélectivement les SHIP. Ce travail a consisté à déterminer les bases fondamentales du recrutement sélectif des SHIP par les RFcyIIB. Il démontre, 1) que le degré de phosphorylation des RFcyIIB atteint dans des conditions mimant les situations physiologiques est insuffisant pour leur permettre de recruter les SHP, 2) que le cytosquelette d'actine est nécessaire à l'inbition induite par les RFcyIIB parce qu'il coordonne les interactions entre les SHIP et les RFcyIIB par l'intermédiaire d' une protéine, la filaminePARIS5-BU-Necker : Fermée (751152101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Activating and Inhibitory Receptors on Mast Cells

International audienc