A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis

Torices et al.

Detalles Bibliográficos
Autores: Torices, Silvia, Varela, Ignacio, Fernández-Luna, J. L.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/164273
Acceso en línea:http://hdl.handle.net/10261/164273
Access Level:acceso abierto
Palabra clave:Infliximab
Rheumatoid arthritis
NFkB
TLR10 variant
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spelling A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritisTorices, SilviaVarela, IgnacioFernández-Luna, J. L.InfliximabRheumatoid arthritisNFkBTLR10 variantTorices et al.[Background]: Toll-like receptor (TLR) family members are key players in inflammation. TLR10 has been poorly studied in chronic inflammatory disorders, and its clinical relevance in rheumatoid arthritis (RA) is as yet unknown. We aimed at identifying TLR10 variants within all coding regions of the gene in patients with RA as well as studying their functional and clinical significance. [Methods]: TLR10 gene variants were studied by performing sequencing of 66 patients with RA and 30 control subjects. A selected variant, I473T, was then analyzed in 1654 patients and 1702 healthy control subjects. The capacity of this TLR10 variant to modify the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) was determined by using a luciferase reporter assay and analyzing the expression of NFkB target genes by quantitative polymerase chain reaction. Differences between groups were analyzed by using the Mann-Whitney U test and the unpaired two-tailed Student's t test. [Results]: We detected ten missense variants in the TLR10 gene and focused on the I473T substitution based on allele frequencies and the predicted functional impact. I473T variant is not associated with susceptibility to RA, but it significantly correlates with erosive disease in patients seropositive for antibodies to citrullinated protein antigens (p = 0.017 in the total cohort and p = 0.0049 in female patients) and with a lower response to infliximab treatment as measured by the change in Disease Activity Score in 28 joints (p = 0.012) and by the European League Against Rheumatism criteria (p = 0.049). Functional studies showed that TLR10 reduced activation of the NFkB inflammatory pathway in hematopoietic cells, whereas the I473T variant lacked this inhibitory capacity. Consistently, after exposure to infliximab, cells expressing the I437T variant showed higher NFkB activity than cells carrying wild-type TLR10. [Conclusions]: A TLR10 allelic variant, I473T, has impaired NFkB inhibitory activity and is highly associated with disease severity and low response to infliximab in patients with RA.This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation grant PI11/02012, Red Temática de Investigación Cooperativa en Cáncer grant RD12/0036/0022, Sociedad Española de Reumatología grant FER13/13, and Instituto de Investigación Valdecilla (IDIVAL) grant APG-03. IV is funded by Programa Ramón y Cajal, Ministerio de Economia y Competitividad, Spain.Peer ReviewedBioMed CentralInstituto de Salud Carlos IIIRed Temática de Investigación Cooperativa en Cáncer (España)Ministerio de Ciencia e Innovación (España)Ministerio de Economía y Competitividad (España)Instituto de Investigación Marqués de ValdecillaSociedad Española de ReumatologíaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2018201820162018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/164273reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1186/s13075-016-1113-zSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1642732026-05-22T06:33:51Z
dc.title.none.fl_str_mv A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis
title A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis
spellingShingle A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis
Torices, Silvia
Infliximab
Rheumatoid arthritis
NFkB
TLR10 variant
title_short A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis
title_full A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis
title_fullStr A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis
title_full_unstemmed A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis
title_sort A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis
dc.creator.none.fl_str_mv Torices, Silvia
Varela, Ignacio
Fernández-Luna, J. L.
author Torices, Silvia
author_facet Torices, Silvia
Varela, Ignacio
Fernández-Luna, J. L.
author_role author
author2 Varela, Ignacio
Fernández-Luna, J. L.
author2_role author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Red Temática de Investigación Cooperativa en Cáncer (España)
Ministerio de Ciencia e Innovación (España)
Ministerio de Economía y Competitividad (España)
Instituto de Investigación Marqués de Valdecilla
Sociedad Española de Reumatología
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Infliximab
Rheumatoid arthritis
NFkB
TLR10 variant
topic Infliximab
Rheumatoid arthritis
NFkB
TLR10 variant
description Torices et al.
publishDate 2016
dc.date.none.fl_str_mv 2016
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/164273
url http://hdl.handle.net/10261/164273
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1186/s13075-016-1113-z
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
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score 15,811543

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