Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in multiple sclerosis

Vélez de Mendizábal, Nieves; Carneiro, Jorge; Solé Vicente, Ricard, 1962-; Goñi, Joaquín; Bragard, Jean; Martínez Forero, Ivan; Martínez Pasamar, Sara; Sepulcre, Jorge; Torrealdea, Javier; Bagnato, Francesca; García Ojalvo, Jordi; Villoslada, Pablo

Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in multiple sclerosis

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dc.contributor.author Vélez de Mendizábal, Nievesca
dc.contributor.author Carneiro, Jorgeca
dc.contributor.author Solé Vicente, Ricard, 1962-ca
dc.contributor.author Goñi, Joaquínca
dc.contributor.author Bragard, Jeanca
dc.contributor.author Martínez Forero, Ivanca
dc.contributor.author Martínez Pasamar, Saraca
dc.contributor.author Sepulcre, Jorgeca
dc.contributor.author Torrealdea, Javierca
dc.contributor.author Bagnato, Francescaca
dc.contributor.author García Ojalvo, Jordica
dc.contributor.author Villoslada, Pabloca
dc.date.accessioned 2015-03-26T10:52:14Z
dc.date.available 2015-03-26T10:52:14Z
dc.date.issued 2011ca
dc.description.abstract Background: The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS). Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens) that are able to trigger the immune system. Results: The model represents five concepts: central tolerance (T-cell generation by the thymus), T-cell activation, T-cell memory, cross-regulation (negative feedback) between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system. Conclusion: The relapsing dynamic in MS derives from the emergent properties of the immune system operating in a pathological state, a fact that has implications for predicting disease course and developing new therapies for MS.en
dc.description.sponsorship This work was supported by the European Commission (NEST-Pathfinder program: "ComplexDis" grant, contract number: 043241 and ITNMC program: "UEPHA*MS" grant, contract number: 212877) and the Spanish Ministry of Health (PI060117 and RD07/0060/0000-01) to PV and JGO. NV is a fellow of the Programa de Formación de Investigadores del Departamento de Educación, Universidades e Investigación, Gobierno Vasco (BFI05.9 AE). JB acknowledges the support of the MEC through the grant: FIS2005-06912-C02, DINCARD. JG is a fellow of Government of Navarra. Dr Bagnato's contribution to this work was supported by the Intramural Research Program of the NINDS-NIHen
dc.format.mimetype application/pdfca
dc.identifier.citation Vélez de Mendizábal N, Carneiro J, Solé RV, Goñi J, Bragard J, Martinez-Forero I et al. Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in multiple sclerosis. BMC Systems Biology. 2011 July;5:114. DOI: 10.1186/1752-0509-5-114ca
dc.identifier.doi http://dx.doi.org/10.1186/1752-0509-5-114
dc.identifier.issn 1752-0509ca
dc.identifier.uri http://hdl.handle.net/10230/23287
dc.language.iso engca
dc.publisher BioMed Centralca
dc.relation.ispartof BMC Systems Biology. 2011 July;5:114
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP6/743241
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/212877
dc.rights © 2011 Vélez de Mendizábal et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/2.0
dc.subject.other Esclerosi múltipleca
dc.subject.other Models biològicsca
dc.subject.other Limfòcitsca
dc.subject.other Simulació per ordinadorca
dc.title Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in multiple sclerosisen
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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