Estamos realizando la búsqueda. Por favor, espere...
Abstract: 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.
Fuente: Arthritis Research & Therapy 2016 18:221
Editorial: BioMed Central
Año de publicación: 2016
Nº de páginas: 9
Tipo de publicación: Artículo de Revista
Consultar en UCrea Leer publicación
SILVIA TORICES DEL VAL
IGNACIO VARELA EGOCHEAGA
FERNÁNDEZ NEBRO, ANTONIO
MARCOS LOPEZ HOYOS
VICTOR MANUEL MARTINEZ TABOADA
JOSE LUIS FERNANDEZ LUNA