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Ectopic lymphoid neogenesis is strongly associated with activation of the IL-23 pathway in rheumatoid synovitis.

Cañete JD, Celis R, Yeremenko N, Sanmartí R, van Duivenvoorde L, Ramírez J, Blijdorp I, García-Herrero CM, Pablos JL, Baeten DL - Arthritis Res. Ther. (2015)

Bottom Line: IL-23 p19 staining was neither restricted nor enhanced in close proximity of ectopic lymphoid follicles, and neither IL-23 nor IL-17A stimulation induced expression of the ELN-associated CC chemokine ligand, CCL21 and CXC chemokine ligand CXCL13, by FLS.Downstream of IL-23, CD21L expression was significantly associated with IL-17F, IL-21, and IL-22, but not IL-17A in two independent ST sample sets.Synovial ELN in RA is strongly associated with activation of the IL-23 pathway but not with IL-17A.

View Article: PubMed Central - PubMed

Affiliation: Arthritis Unit, Rheumatology Department, Hospital Clinic of Barcelona and IDIBAPS, c/ Villarroel, 170, 08036, Barcelona, Spain. jcanete@clinic.ub.es.

ABSTRACT

Introduction: The functional relevance of synovial ectopic lymphoid neogenesis (ELN) in rheumatoid arthritis (RA) remains unknown. As ELN correlates with the degree of tissue inflammation, we investigated whether ELN was associated with specific cytokine profiles.

Methods: Synovial ELN was determined by immunohistology and long CD21 isoform (CD21L) expression. Cytokine expression was determined by multiplex enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction (PCR) as well as immunohistology in synovial fluid (SF) (n = 44) and tissue (ST) (n = 108), respectively. Production of ELN-associated chemokines by fibroblast-like synoviocytes (FLS) was studied in vitro.

Results: Screening analysis of SF by multiplex ELISA showed higher protein levels of interleukin (IL)-23 (p = 0.018) and IL-17F (p = 0.028) in ELN+ versus ELN- samples. Other cytokines, including IL-17A, IL-6, and tumor necrosis factor (TNF)-α, were not different. The association between IL-23 and ELN was not biased by disease activity or other clinical features and was confirmed by higher IL-23 mRNA expression in ELN+ versus ELN- ST samples (p = 0.030), a correlation between IL-23 and CD21L expression in the same samples (r = 0.70 p < 0.0001), and a similar correlation in two independent ST sample sets (r = 0.778 p < 0.0001 and r = 0.817 p = 0.011). IL-23 p19 staining was neither restricted nor enhanced in close proximity of ectopic lymphoid follicles, and neither IL-23 nor IL-17A stimulation induced expression of the ELN-associated CC chemokine ligand, CCL21 and CXC chemokine ligand CXCL13, by FLS. Downstream of IL-23, CD21L expression was significantly associated with IL-17F, IL-21, and IL-22, but not IL-17A in two independent ST sample sets.

Conclusions: Synovial ELN in RA is strongly associated with activation of the IL-23 pathway but not with IL-17A.

No MeSH data available.


Related in: MedlinePlus

Synovial fluid cytokine levels as determined in RA patients from cohort 1 stratified according to ectopic lymphoid neogenesis (ELN). IL-23 (a), IL-17F (b), IL-6 (c) and TNFa (d). Median and interquartile ranges are represented. RA rheumatoid arthritis. TNF-a: Tumor necrosis factor alpha-
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Fig2: Synovial fluid cytokine levels as determined in RA patients from cohort 1 stratified according to ectopic lymphoid neogenesis (ELN). IL-23 (a), IL-17F (b), IL-6 (c) and TNFa (d). Median and interquartile ranges are represented. RA rheumatoid arthritis. TNF-a: Tumor necrosis factor alpha-

Mentions: To assess whether synovial ELN is associated with a specific proinflammatory cytokine profile, we first assessed SF levels of Th1, Th2, Th17 and proinflammatory cytokines in 25 ELN+ versus 19 ELN- samples. The expression of many cytokines including the Th2 cytokines IL-4, IL-5 and IL-13 were low to undetectable in SF independently of the presence of ELN (data not shown). Strikingly, however, SF levels of IL-23 (p = 0.018) and IL-17F (p = 0.028) were significantly increased in ELN+ versus ELN- samples (Fig. 2a and b). There was also a numerical but not statistically significant increase in IL-22 (p = 0.070), TGF-β1 (p = 0.060), and IFN-γ (p = 0.052) (data not shown). Other proinflammatory cytokines implicated in RA inflammation such as IL-6 and TNF-α (Fig. 2c and d) were not different between both groups, indicating that the increase in IL-23 and IL-17F is not merely reflecting increased local disease activity in ELN+ synovitis.Fig. 2


Ectopic lymphoid neogenesis is strongly associated with activation of the IL-23 pathway in rheumatoid synovitis.

Cañete JD, Celis R, Yeremenko N, Sanmartí R, van Duivenvoorde L, Ramírez J, Blijdorp I, García-Herrero CM, Pablos JL, Baeten DL - Arthritis Res. Ther. (2015)

Synovial fluid cytokine levels as determined in RA patients from cohort 1 stratified according to ectopic lymphoid neogenesis (ELN). IL-23 (a), IL-17F (b), IL-6 (c) and TNFa (d). Median and interquartile ranges are represented. RA rheumatoid arthritis. TNF-a: Tumor necrosis factor alpha-
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4496927&req=5

Fig2: Synovial fluid cytokine levels as determined in RA patients from cohort 1 stratified according to ectopic lymphoid neogenesis (ELN). IL-23 (a), IL-17F (b), IL-6 (c) and TNFa (d). Median and interquartile ranges are represented. RA rheumatoid arthritis. TNF-a: Tumor necrosis factor alpha-
Mentions: To assess whether synovial ELN is associated with a specific proinflammatory cytokine profile, we first assessed SF levels of Th1, Th2, Th17 and proinflammatory cytokines in 25 ELN+ versus 19 ELN- samples. The expression of many cytokines including the Th2 cytokines IL-4, IL-5 and IL-13 were low to undetectable in SF independently of the presence of ELN (data not shown). Strikingly, however, SF levels of IL-23 (p = 0.018) and IL-17F (p = 0.028) were significantly increased in ELN+ versus ELN- samples (Fig. 2a and b). There was also a numerical but not statistically significant increase in IL-22 (p = 0.070), TGF-β1 (p = 0.060), and IFN-γ (p = 0.052) (data not shown). Other proinflammatory cytokines implicated in RA inflammation such as IL-6 and TNF-α (Fig. 2c and d) were not different between both groups, indicating that the increase in IL-23 and IL-17F is not merely reflecting increased local disease activity in ELN+ synovitis.Fig. 2

Bottom Line: IL-23 p19 staining was neither restricted nor enhanced in close proximity of ectopic lymphoid follicles, and neither IL-23 nor IL-17A stimulation induced expression of the ELN-associated CC chemokine ligand, CCL21 and CXC chemokine ligand CXCL13, by FLS.Downstream of IL-23, CD21L expression was significantly associated with IL-17F, IL-21, and IL-22, but not IL-17A in two independent ST sample sets.Synovial ELN in RA is strongly associated with activation of the IL-23 pathway but not with IL-17A.

View Article: PubMed Central - PubMed

Affiliation: Arthritis Unit, Rheumatology Department, Hospital Clinic of Barcelona and IDIBAPS, c/ Villarroel, 170, 08036, Barcelona, Spain. jcanete@clinic.ub.es.

ABSTRACT

Introduction: The functional relevance of synovial ectopic lymphoid neogenesis (ELN) in rheumatoid arthritis (RA) remains unknown. As ELN correlates with the degree of tissue inflammation, we investigated whether ELN was associated with specific cytokine profiles.

Methods: Synovial ELN was determined by immunohistology and long CD21 isoform (CD21L) expression. Cytokine expression was determined by multiplex enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction (PCR) as well as immunohistology in synovial fluid (SF) (n = 44) and tissue (ST) (n = 108), respectively. Production of ELN-associated chemokines by fibroblast-like synoviocytes (FLS) was studied in vitro.

Results: Screening analysis of SF by multiplex ELISA showed higher protein levels of interleukin (IL)-23 (p = 0.018) and IL-17F (p = 0.028) in ELN+ versus ELN- samples. Other cytokines, including IL-17A, IL-6, and tumor necrosis factor (TNF)-α, were not different. The association between IL-23 and ELN was not biased by disease activity or other clinical features and was confirmed by higher IL-23 mRNA expression in ELN+ versus ELN- ST samples (p = 0.030), a correlation between IL-23 and CD21L expression in the same samples (r = 0.70 p < 0.0001), and a similar correlation in two independent ST sample sets (r = 0.778 p < 0.0001 and r = 0.817 p = 0.011). IL-23 p19 staining was neither restricted nor enhanced in close proximity of ectopic lymphoid follicles, and neither IL-23 nor IL-17A stimulation induced expression of the ELN-associated CC chemokine ligand, CCL21 and CXC chemokine ligand CXCL13, by FLS. Downstream of IL-23, CD21L expression was significantly associated with IL-17F, IL-21, and IL-22, but not IL-17A in two independent ST sample sets.

Conclusions: Synovial ELN in RA is strongly associated with activation of the IL-23 pathway but not with IL-17A.

No MeSH data available.


Related in: MedlinePlus