Dendritic cells in the pathophysiology of Multiple Sclerosis
Dates:1 September 2016 - 31 December 2016
Date limite de candidature:1 September 2016
Lab rotation proposal:
~ Sep-Dec 2016 ~ Jan-March 2017 ~ Apr-June 2017
In multiple sclerosis (MS), deregulated T lymphocyte responses are involved in the attack and destruction of myelin in the central nervous system (CNS) leading to neuro-degeneration and irreversible disability. One of the crucial stages in the pathophysiology of MS is the massive CNS infiltration of pathogenic cells that are reactivated in situ by antigen presenting cells (APC), either CNS resident such as perivascular macrophages and microglia or systemic (dendritic cells, macrophages).As part of an international consortium, our team has participated in the identification of 110 genetic polymorphisms involved in MS susceptibility. For each of the polymorphisms site, it was determined the most likely gene involved in MS predisposition and the results confirm the key role of immune dysfunction [1, 2]. Among the 110 genes identified, 55 are involved in the process of differentiation and functions of immune cells and in particular 23 of them have an essential role in the biology of myeloid cells.These results suggest that the genetic susceptibility to MS is due to a global dysfunction of cells of the myeloid lineage.To test this hypothesis, we have stratified a cohort of 3000 MS patients and 800 control subjects according to their genetic load in the 23 polymorphisms associated with myeloid cells functions. From this stratified cohort, the proposed M2 project aims to characterize the phenotype and functional activity of dendritic cells (DCs) differentiated from MS patients blood precursors with a strong genetic load in these polymorphisms, in direct comparison with DCs from MS patients not having this genetic load and with DCs from control subjects. To perform this project the candidate will use cell culture and immunological methods both in vitro and in vivo.
1 Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C. C., Patsopoulos, N. A., Moutsianas, L., Dilthey, A.et al., Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011. 476: 214-219.2 International Multiple Sclerosis Genetics, C., Beecham, A. H., Patsopoulos, N. A., Xifara, D. K., Davis, M. F., Kemppinen, A., Cotsapas, C.et al., Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013. 45: 1353-1360.
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