Cytokine Secretion by Pathogen Recognition Receptor-stimulated Dendritic Cells in Rheumatoid Arthritis and Ankylosing Spondylitis

2012 ◽  
Vol 39 (10) ◽  
pp. 1918-1928 ◽  
Author(s):  
CLAUDIA PREVOSTO ◽  
JANE C. GOODALL ◽  
J.S. HILL GASTON
Keyword(s):  
Rheumatoid Arthritis ◽  
Dendritic Cells ◽  
Ankylosing Spondylitis ◽  
Messenger Rna ◽  
Posttranscriptional Regulation ◽  
Th17 Cells ◽  
Cytokine Secretion ◽  
Pathogen Recognition ◽  
Interleukin 23 ◽  
Factor Α

Objective.Interleukin 23 (IL-23) plays a major role in differentiation and survival of IL-17-secreting CD4+ Th17 cells. Having noted a higher frequency of Th17 cells in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) than in healthy donors (HD), we investigated whether IL-23 secretion is increased in these conditions.Methods.Monocyte-derived dendritic cells (moDC) were obtained from peripheral blood of 17 HD, 16 patients with RA, and 30 patients with AS, and stimulated with ligands for several pathogen recognition receptors. Messenger RNA (mRNA) expression and cytokine secretion were analyzed by real-time polymerase chain reaction and ELISA, respectively.Results.The combination of ligands for Toll-like receptors (TLR) 7/8 and TLR3 led to synergistic secretion of both IL-23 and IL-12p70 from all subjects; similar synergy was seen with TLR2 ligands and curdlan. However, for both combinations, moDC from patients with RA produced significantly lower amounts of IL-23 than moDC from patients with AS; in contrast, IL-12p70 secretion did not differ. Similarly, tumor necrosis factor-α, IL-6, and IL-10 were secreted at comparable levels in all subjects, whereas CXCL8 and CCL3 production was actually enhanced in moDC of patients with RA. Equivalent levels of mRNA for both IL-23p19 and IL-12p35 subunits were found in moDC from all donors, suggesting posttranscriptional regulation of IL-23 production in RA.Conclusion.Our observations show that IL-23 production is decreased in RA and maintained in AS. Because increased numbers of CD4+IL-17+ T cells are seen in both diseases, these observations imply that there are different mechanisms underlying chronic inflammation in these 2 forms of inflammatory arthritis.

Reasons for Discontinuation and Adverse Effects of TNFα Inhibitors in a Cohort of Patients With Rheumatoid Arthritis and Ankylosing Spondylitis

2016 ◽  
Vol 51 (5) ◽  
pp. 388-393 ◽  
Author(s):  
María Henar García-Lagunar ◽  
María Rocío Gutiérrez-Cívicos ◽  
María Sergia García-Simón ◽  
Pablo Conesa-Zamora ◽  
Enrique Jimenez-Santos ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ankylosing Spondylitis ◽  
Adverse Effects ◽  
Dosage Regimen ◽  
Survival Rates ◽  
Drug Survival ◽  
Kaplan Meier ◽  
Tnfα Inhibitors ◽  
Treatment Objective ◽  
Factor Α

Background: The introduction of anti–tumor necrosis factor α (anti-TNFα) drugs has improved the clinical outcomes in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, these drugs may cause adverse effects that motivate a change in or discontinuation of the treatment. Objective: To evaluate the causes of discontinuation or changes in the dosage regimen in a cohort of patients with RA and AS treated with infliximab, adalimumab, etanercept, and golimumab under clinical practice conditions. Methods: This was a retrospective observational study that included patients with RA or AS treated with anti-TNFα drugs between 2008 and 2013. Changes in the dosage regimen, reasons for treatment discontinuation, and adverse effects were recorded and analyzed. Time to discontinuation was estimated using Kaplan-Meier survival analysis. Results: A total of 123 patients with RA and 93 patients with AS were treated with anti-TNFα therapy. During the study, 55.3% of RA patients and 41.7% of AS patients had stopped the treatment. The most frequent changes were modifications in the dosing, and the most frequent adverse effects were reactions after the infusion or injection (53.8% and 66.7% in RA and AS, respectively). Drug survival of etanercept in RA (67.9%) is greater than for adalimumab and infliximab, whereas drug survival of infliximab in AS (70.0%) is greater than for etanercept and adalimumab at 5 years, although there were no significant differences ( P = 0.098 in RA and 0.194 in AS). Conclusions: The main cause of discontinuation of anti-TNFα is therapeutic failure in both diseases. Etanercept and infliximab have the best survival rates in RA and AS, respectively.

Designing a new bi-specific tandem single-chain variable fragment antibody against tumor necrosis factor-α and interleukin-23 via in silico studies for the treatment of Rheumatoid arthritis

2020 ◽  
Author(s):  
Asgar Barkhordaria ◽  
Karim Mahnam ◽  
Hamid Mir Mohammad Sadeghi
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Single Chain Variable Fragment ◽  
Single Chain ◽  
Rheumatoid Arthritis Disease ◽  
Interleukin 23 ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background: Rheumatoid arthritis disease is a chronic autoimmune inflammatory disease that mainly causes synovial joint inflammation and cartilage destruction. Tumor necrosis factor-α (TNF-α) is a pivotal cytokine that plays an important role in rheumatoid arthritis. The treatments focusing on a single cytokine' inhibition, are able to clinically produce meaningful responses in only about half of the treated patients due to multiple cytokines involved in this disease. In the present study, a bi-specific tandem single-chain variable fragment was designed in order to suppress both human tumor necrosis factor-α and interleukin-23 (IL23) as a potential therapeutic drug candidate for this disease. To do so, at first, eight bi-specific tandem single-chain variable fragment models were built against tumor necrosis factor-α and interleukin-23 cytokines with different domain orders and then 50 ns molecular dynamics simulation was performed for each one and thereafter structural properties were exploited. Results: MD simulation results indicate that the domains' order strongly affects tandem single-chain variable fragment properties and in overall, the fragment VLIL23+Linker+VHIL23+linker+VLTNF+Linker+VHTNF +His6 (VL is variable light and VH is variable heavy fragments and His6 is six histidine) not only separated antibody domains but also had better stability and solvation energy. Conclusions: Hence, this structure can be considered as a potential drug for rheumatoid arthritis. It is hoped that this research could shed a light for the treatment of Rheumatoid arthritis disease.

scholarly journals Increased Frequencies of Th22 Cells as well as Th17 Cells in the Peripheral Blood of Patients with Ankylosing Spondylitis and Rheumatoid Arthritis

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e31000 ◽  
Author(s):  
Lei Zhang ◽  
Yong-gang Li ◽  
Yu-hua Li ◽  
Lei Qi ◽  
Xin-guang Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ankylosing Spondylitis ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Th22 Cells

scholarly journals Interleukin 34 expression is associated with synovitis severity in rheumatoid arthritis patients

2011 ◽  
Vol 71 (1) ◽  
pp. 150-154 ◽  
Author(s):  
M Chemel ◽  
B Le Goff ◽  
R Brion ◽  
C Cozic ◽  
M Berreur ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Messenger Rna ◽  
Synovial Fibroblasts ◽  
Total Leucocyte Count ◽  
Dependent Manner ◽  
Jnk Pathway ◽  
Dose Time ◽  
Downstream Effector ◽  
Factor Α

ObjectivesInterleukin (IL) 34 is a new cytokine implicated in macrophage differentiation and osteoclastogenesis. This study assessed IL-34 expression in the tissue of patients with rheumatoid arthritis (RA).MethodsImmunohistochemistry was performed in synovial biopsies from patients with RA (n=20), osteoarthritis (n=3) or other inflammatory arthritis (n=4). IL-34 was detected in the synovial fluid by ELISA and its messenger RNA expression was studied by quantitative PCR in rheumatoid synovial fibroblasts after stimulation by tumour necrosis factor α (TNFα) and IL-1β. Wild-type, jnk1−/−–jnk2−/− and nemo−/− murine fibroblasts and pharmacological inhibition were used to determine the involvement of nuclear factor kappa B (NF-κB) and JNK in that effect.ResultsIL-34 was expressed in 24/27 biopsies, with three samples from RA patients being negative. A significant association was found between IL-34 expression and synovitis severity. Levels of IL-34 and the total leucocyte count in synovial fluid were correlated. TNFα and IL-1β stimulated IL-34 expression by synovial fibroblasts in a dose/time-dependent manner through the NF-κB and JNK pathway.ConclusionThis work for the first time identifies IL-34 expression in the synovial tissue of patients with arthritis. This cytokine, as a downstream effector of TNFα and IL-1β, may contribute to inflammation and bone erosions in RA.

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