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Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis

van Bon, L.; Popa, C.; Huijbens, R.; Vonk, M.; York, M.; Simms, R.; Hesselstrand, Roger LU ; Wuttge, Dirk LU ; Lafyatis, R. and Radstake, T. R. D. J. (2010) In Annals of the Rheumatic Diseases 69(8). p.1539-1547
Abstract
Background Systemic sclerosis (SSc) is an autoimmune disease and accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). Objective To map TLR-mediated cytokine responses of DCs from patients with SSc. Methods 45 patients with SSc were included. Patients were stratified as having diffuse cutaneous SSc (dSSc) or limited cutaneous SSc (lSSc) according to the extent of skin involvement, and further divided into those with late (> 3 years) or early disease (< 2 years). DCs were stimulated with ligands for TLR2, TLR3, TLR4, TLR7/8 or combinations. Plasma samples were collected from patients with SSc (n = 167) and measured for interleukin 6 (IL-6), tumour necrosis factor a (TNF... (More)
Background Systemic sclerosis (SSc) is an autoimmune disease and accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). Objective To map TLR-mediated cytokine responses of DCs from patients with SSc. Methods 45 patients with SSc were included. Patients were stratified as having diffuse cutaneous SSc (dSSc) or limited cutaneous SSc (lSSc) according to the extent of skin involvement, and further divided into those with late (> 3 years) or early disease (< 2 years). DCs were stimulated with ligands for TLR2, TLR3, TLR4, TLR7/8 or combinations. Plasma samples were collected from patients with SSc (n = 167) and measured for interleukin 6 (IL-6), tumour necrosis factor a (TNF alpha), IL-12, IL-10 and interferon gamma. Results Stimulation of DC subsets from patients with early lSSc and dSSc with ligands for TLR2, TLR3 or TLR4 resulted in higher secretion of IL-6 and TNF alpha compared with those having late disease or healthy controls. Remarkably, the production of IL-12 was lower upon stimulation with TLR ligands in most patients with SSc, whereas the secretion of IL-10 was very high in patients with the dSSc phenotype, particularly in those having early dSSc. The combination of various TLR ligands led to reduced cytokine secretion in all patients with SSc. Circulating levels of these cytokines further underscored the presence of differences between various SSc phenotypes. Discussion The altered TLR-mediated activation of DCs may be responsible for Th2 skewed T-cell activation in SSc that may be orchestrated by fibrogenic T-cell cytokines, such as IL-4 and IL-13. DC targeting could thus offer new avenues for therapeutic intervention. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Annals of the Rheumatic Diseases
volume
69
issue
8
pages
1539 - 1547
publisher
British Medical Association
external identifiers
  • wos:000280171700023
  • scopus:77955452418
ISSN
1468-2060
DOI
10.1136/ard.2009.128207
language
English
LU publication?
yes
id
117ce1cc-6961-4d78-9a9c-434c466b9ae0 (old id 1654637)
date added to LUP
2010-08-26 15:26:25
date last changed
2018-05-29 11:30:50
@article{117ce1cc-6961-4d78-9a9c-434c466b9ae0,
  abstract     = {Background Systemic sclerosis (SSc) is an autoimmune disease and accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). Objective To map TLR-mediated cytokine responses of DCs from patients with SSc. Methods 45 patients with SSc were included. Patients were stratified as having diffuse cutaneous SSc (dSSc) or limited cutaneous SSc (lSSc) according to the extent of skin involvement, and further divided into those with late (&gt; 3 years) or early disease (&lt; 2 years). DCs were stimulated with ligands for TLR2, TLR3, TLR4, TLR7/8 or combinations. Plasma samples were collected from patients with SSc (n = 167) and measured for interleukin 6 (IL-6), tumour necrosis factor a (TNF alpha), IL-12, IL-10 and interferon gamma. Results Stimulation of DC subsets from patients with early lSSc and dSSc with ligands for TLR2, TLR3 or TLR4 resulted in higher secretion of IL-6 and TNF alpha compared with those having late disease or healthy controls. Remarkably, the production of IL-12 was lower upon stimulation with TLR ligands in most patients with SSc, whereas the secretion of IL-10 was very high in patients with the dSSc phenotype, particularly in those having early dSSc. The combination of various TLR ligands led to reduced cytokine secretion in all patients with SSc. Circulating levels of these cytokines further underscored the presence of differences between various SSc phenotypes. Discussion The altered TLR-mediated activation of DCs may be responsible for Th2 skewed T-cell activation in SSc that may be orchestrated by fibrogenic T-cell cytokines, such as IL-4 and IL-13. DC targeting could thus offer new avenues for therapeutic intervention.},
  author       = {van Bon, L. and Popa, C. and Huijbens, R. and Vonk, M. and York, M. and Simms, R. and Hesselstrand, Roger and Wuttge, Dirk and Lafyatis, R. and Radstake, T. R. D. J.},
  issn         = {1468-2060},
  language     = {eng},
  number       = {8},
  pages        = {1539--1547},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis},
  url          = {http://dx.doi.org/10.1136/ard.2009.128207},
  volume       = {69},
  year         = {2010},
}