The frequency and morbidity of allergic diseases has been steadily increasing in Western countries afflicting one person in three. This epidemic explosion is the result of an interplay between a genetic predisposition in the population and a growing imbalance between the immune system and the altered environment in a modern hygienic society. Although progress has been made in the understanding of disease development and effector mechanisms, it has become clear recently that associated phenotypes can be complex involving multiple immune and nonimmune associated processes, inflammatory circuits and signaling pathways in effector cells calling for novel approaches to delineate the underlying mechanisms.
Our aim intends to uncover new molecular effectors representing new therapeutic targets to dampen allergic reaction and to understand severe allergic diseases at the genomic and transcriptomic level.
Three major objectives will be pursue:
- ° To identify new effectors in the late signaling steps that critically regulate mast cell (MC) degranulation and cytokine/secretion. By targeting late secretion events, we aim to identify proteins that play a role downstream of different types of receptors activating MC, in addition to FceRI. This appears particularly relevant during chronic allergic diseases fostered by multiple stimuli and inflammatory mediators.
We have recently identified the microtubule motor protein kinesin-1 as a novel effector involved in secretory granule transport processes during degranulation, but not in chemokine/cytokine release (Figure below).
° A genetic dissection by whole exome sequencing (WES) of a precisely defined population of pediatric patients presenting with severe and persistent allergic phenotypes that can be in some cases associated to loss of skin’s barrier or to immunodeficiency, will be performed to identify causative monogenic gene alteration(s).
- °To better stratify allergic patients for improving diagnosis and patient treatment we will perform state-of-art transcriptional analysis at the single cell level.
These studies promise not only to bestow fundamental understanding but also represents a ground-breaking finding towards a more personalized medicine for patients suffering from allergic disorders.
F. Adam, A. Kauskot, M. Kurowska, N. Goudin, I. Munoz, J.C. Bordet, J.D. Huang, A. Fischer, D. Borgel, G. de Saint Basile, O.D. Christophe, G. Ménasché. Kinesin-1, a new actor involved in platelet secretion and thrombus stability by interacting with the granule Slp4/Rab27b effector complex. ATVB 2018, May;38(5):1037-1051
I. Munoz, L. Danelli, J. Claver, N. Goudin, M. Kurowska, J.D. Huang, A. Fischer, C. Gonzales-Espinosa, G. de Saint Basile, U. Blank and G. Ménasché. Kinesin-1 controls mast cell degranulation and anaphylaxis through its PI3K-dependent recruitment to the granular Slp3/Rab27b effector complex. J. Cell Bio. 2016; 215(2) 203-216
Sepulveda FE, Burgess A, Heiligenstein X, Goudin N, Ménager MM, Romao M, Côte M, Mahlaoui N, Fischer A, Raposo G, Ménasché G* and de Saint Basile G* (*equal contribution). LYST controls the biogenesis of the endosomal compartment required for secretory lysosome function. Traffic. 2015 16(2):191-203.
Kurowska M., Goudin N., Nehme N., Court M., Garin J., Fischer A., de Saint Basile G., Ménasché G. Terminal transport of lytic granules to the immune synapse is mediated by the kinesin-1/Slp3/Rab27a complex. Blood. 2012; 119(17):3879-3889.
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