Regulatory T cells enhance Th17 migration in psoriatic arthritis which is reversed by anti-TNF.
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ABSTRACT:
SUBMITTER: Nguyen DX
PROVIDER: S-EPMC8387926 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAnti-TNF agents have revolutionised rheumatoid arthritis (RA) treatment; however, a third of patients fail to achieve therapeutic responses. Unexpectedly, studies in murine and human arthritis have indicated that anti-TNF treatment can increase circulating T helper 17 (Th17) cells, but the relationship to treatment response is unclear. To identify immune correlates of anti-TNF treatment response, we conducted a longitudinal study using clinical, ultrasound and T cell assessments.MethodsPatients with RA (n = 25) were studied at protocol visits during the initial 12 weeks of anti-TNF treatment. Improvement in the disease activity score of 28 joints (DAS28) >1.2 defined treatment responders (n = 16) and non-responders (n = 9). Changes in synovial thickening and vascularity of 10 metacarpophalangeal joints were quantitatively assessed by grey scale and power Doppler ultrasound. The frequency of circulating Th17 cells was determined by IL17 enzyme-linked immunospot assay (Elispot) and flow cytometry (fluorescence-activated cell sorting (FACS)).ResultsThe frequency of circulating IL17-producing cells increased significantly 12 weeks after anti-TNF initiation (Elispot median (range) specific spot forming cells (spSFC)/106 360 (280-645) vs 632 (367 - 1167), p = 0.003). The increase in CD4 + IL17+ cells at 12 weeks was confirmed by FACS (median (range) %, 0.7 (0.5-0.9) vs 1.05 (0.6-1.3); p = 0.01). The increase in circulating Th17 cells inversely correlated with reduction in synovial vascularity (r = -0.68, p = 0.007) and thickening (r = -0.39; p = 0.04). Higher frequencies of circulating Th17 cells at baseline were associated with poorer anti-TNF treatment response defined by ultrasonographic measures.ConclusionsThese results demonstrate a link between changes in circulating Th17 cells with resolution of ultrasonographic features of synovial inflammation and vascularity during anti-TNF treatment. The findings may reflect redistribution of Th17 cells from inflamed joints or TNF-driven regulation of Th17 cell production.Trial registrationClinicalTrials.gov: NCT01060098 . Registered 29 January 2010.
| S-EPMC5180397 | biostudies-literature
Project description:Tuberculosis (TB) still represents an important issue for public health in underdeveloped countries, but the use of antitumor necrosis factor agents (anti-TNF) for the treatment of inflammatory rheumatic disorders has reopened the problem also in countries with low TB incidence, due to the increased risk of TB reactivation in subjects with latent tuberculosis infection (LTBI). Over the last 5 years, several non-anti-TNF-targeted biologics have been licensed for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. We reviewed the epidemiology of TB, the role of different cytokines and of the immune system cells involved in the immune response against TB infection, the methods to detect LTBI, and the risk of TB reactivation in patients exposed to non-anti-TNF-targeted biologics. Given the limited role exerted by the cytokines different from TNF, as expected, data from controlled trials, national registries of biologics, and postmarketing surveillance show that the risk of TB reactivation in patients receiving non-anti-TNF-targeted biologics is negligible, hence raising the question whether the screening procedures for LTBI would be necessary.
| S-EPMC5474286 | biostudies-other
Project description:The interplay between inflammatory and regulatory pathways orchestrates an effective immune response that provides protection from pathogens while limiting injury to host tissue. Tumor necrosis factor (TNF) is a pivotal inflammatory cytokine, but there is conflicting evidence as to whether it boosts or inhibits regulatory T cells (T reg cells). In this study, we show that the therapeutic anti-TNF antibody adalimumab, but not the soluble TNF receptor etanercept, paradoxically promoted the interaction between monocytes and T reg cells isolated from patients with rheumatoid arthritis (RA). Adalimumab bound to monocyte membrane TNF from RA patients and unexpectedly enhanced its expression and its binding to TNF-RII expressed on T reg cells. As a consequence, adalimumab expanded functional Foxp3(+) T reg cells equipped to suppress Th17 cells through an IL-2/STAT5-dependent mechanism. Our data not only highlight the beneficial effect of membrane TNF on T reg cell numbers during chronic inflammation, but in addition reveal how a therapeutic antibody that is thought to act by simply blocking its target can enhance the regulatory properties of this proinflammatory cytokine.
| S-EPMC4925013 | biostudies-literature
Project description:TNF weakly inducer of apoptosis (TWEAK) is member of the TNF ligand superfamily. Various data support that TWEAK produced by synovial macrophages may contribute to synovitis observed in psoriatic arthritis (PsoA). In PsoA, anti-TNF therapy has been successful in agreement with the key role of TNF in the pathogenesis and the generation by PsoA patients of anti-TNF autoantibodies referred as "beneficial autoimmunity to pro-inflammatory mediators". However, the role of TNF-alpha in the regulation of TWEAK modulation of inflammation during PsoA remains unknown.We have studied level course during anti-TNF therapy of serum soluble TWEAK. In the same cohort, we have investigated the generation of TWEAK-binding autoantibodies by PsoA patients before and after anti-TNF therapy.Patients with PsoA had significantly higher serum levels of TWEAK compared with controls [respective means (±SEM) were 645 pg/ml (64) and 467 pg/ml (23); (p = 0.006)] but serum soluble TWEAK levels were not correlated with BASDAI (Spearman's coefficients <0.003, p > 0.05). Our study showed that soluble TWEAK levels were not modulated by etanercept therapy [respective Means (±SEM) were 605 (95) (week 12) and 744 (97) (week 24) pg/ml; (p > 0.23)]. Anti-TWEAK autoantibodies were detected in 9/13 (69.2 %) PsoA patients at inclusion and only in 3/57 (5.3 %) healthy blood donors (p < 0.0001). These circulating antibodies were persistent in PsoA patients and detected at similar levels during etanercept therapy. Moreover we showed that they had a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro.Our study revealed that during psoriatic arthritis (1) serum TWEAK was up regulated and (2) TWEAK-binding autoantibodies are generated. Both parameters were not influenced by anti-TNF therapy and persisted at high levels during anti-TNF therapy. For the first time we described here TWEAK-binding IgG autoantibodies with a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. Finally, our results suggest that TWEAK may be involved in PsoA pathogeny. Trial registration This clinical trial was approved by the local Ethics Committee "Comité de Protection des Personnes Sud-Méditerranée V" with the registration number: 2011-002954-29, and French health minister registration number AFSSAPS A110784-42 obtained the 08/22/2011. This clinical trial is registered in Clinical trial.gov under the number: NCT02164214.
| S-EPMC4917994 | biostudies-literature
Project description:Objectives TNF-α inhibitors are widely used in rheumatoid arthritis (RA) with varying success. Response to TNF-α inhibition may reflect the evolution of rheumatoid inflammation through fluctuating stages of TNF-α dependence. Our aim was to assess plasma concentrations of Th-17-related cytokines and the presence of circulating effector T-cells to identify predictors of response to TNF-α inhibitors. Methods Ninety-three people with RA were seen prior to and 4–6 months after commencing etanercept or adalimumab. Plasma concentrations of Th17-related cytokines, circulating effector T-cells, their production of relevant transcription factors and intracellular cytokines were measured at baseline. EULAR response criteria were used to define poor (ΔDAS28 ≤ 1.2 and/or DAS28 > 3.2) and good (ΔDAS28 > 1.2 and DAS28 ≤ 3.2) responders. Multivariate logistic regression was used to identify predictors of response. Results Participants with plasma IL-23 present at baseline were more likely to be poor responders [15/20 (75%) of IL-23+ versus 36/73 (49.3%) of IL-23−; p = 0.041]. While frequencies of Th1, Th17, ex-Th17 and Treg cell populations were similar between good and poor responders to anti-TNF therapy, IL-17A+IFNγ+ ex-Th17 cells were more prevalent in good responders (0.83% of ex-TH17 cells) compared to poor responders (0.24% of ex-Th17 cells), p = 0.023. Both plasma IL-23 cytokine status (OR = 0.17 (95% CI 0.04–0.73)) and IL-17A+IFNγ+ ex-Th17 cell frequency (OR = 1.64 (95% CI 1.06 to 2.54)) were independently associated with a good response to anti-TNF therapy. Receiver operator characteristic (ROC) analysis, including both parameters, demonstrated an area under the ROC curve (AUC) of 0.70 (95% CI 0.60–0.82; p = 0.001). Conclusions Plasma IL-23 and circulating IL-17A+IFNγ+ ex-Th17 cells are independently associated with response to anti-TNF therapy. In combination, plasma IL-23 and circulating IL-17A+IFNγ+ ex-Th17 cells provide additive value to the prediction of response to anti-TNF therapy in RA. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02748-3.
| S-EPMC8881822 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint destruction and severe morbidity. Cigarette smoking (CS) can exacerbate the incidence and severity of RA. Although Th17 cells and the Aryl hydrocarbon receptor (AhR) have been implicated, the mechanism by which CS induces RA development remains unclear. Here, using transcriptomic analysis, we show that microRNA-132 is specifically induced in Th17 cells in the presence of either AhR agonist or CS-enriched medium. miRNA-132 thus induced is packaged into extracellular vesicles produced by Th17 and acts as a proinflammatory mediator increasing osteoclastogenesis through the down-regulation of COX2. In vivo, articular knockdown of miR-132 in murine arthritis models reduces the number of osteoclasts in the joints. Clinically, RA patients express higher levels of miR-132 than do healthy individuals. This increase is further elevated by cigarette smoking. Together, these results reveal a hitherto unrecognized mechanism by which CS could exacerbate RA and further advance understanding of the impact of environmental factors on the pathogenesis of chronic inflammatory diseases.
| S-EPMC7817209 | biostudies-literature
Project description:Psoriatic arthritis (PsA) is a heterogeneous chronic musculoskeletal disease, affecting up to 30% of people with psoriasis. Research into PsA pathogenesis has led to the development of targeted therapies, including Tumor Necrosis Factor inhibitors (TNF-i). Good response is only achieved by ~60% of patients leading to 'trial and error' drug management approaches, adverse reactions and increasing healthcare costs. Robust and well-validated biomarker identification, and subsequent development of sensitive and specific assays, would facilitate the implementation of a stratified approach into clinical care. This review will summarise potential genetic biomarkers for TNF-i (adalimumab, etanercept and infliximab) response that have been reported to date. It will also comment upon the importance of managing clinical confounders when understanding drug response prediction. Variants in multiple gene regions including TNF-A, FCGR2A, TNFAIP3, TNFR1/TNFR1A/TNFRSF1A, TRAIL-R1/TNFRSF10A, FCGR3A have been reported to correlate with TNF-i response at various levels of statistical significance in patients with PsA. However, results were often from heterogenous and underpowered cohorts and none are currently implemented into clinical practice. External validation of genetic biomarkers in large, well-documented cohorts is required, and assessment of the predictive value of combining multiple genetic biomarkers with clinical measures is essential to clinically embed pharmacogenomics into PsA drug management.
| S-EPMC9925377 | biostudies-literature
Project description:IntroductionEicosanoids are biological lipids that serve as both activators and suppressors of inflammation. Eicosanoid pathways are implicated in synovitis and joint destruction in inflammatory arthritis, yet they might also have a protective function, underscoring the need for a comprehensive understanding of how eicosanoid pathways might be imbalanced. Until recently, sensitive and scalable methods for detecting and quantifying a high number of eicosanoids have not been available.ObjectiveHere, we intend to describe a detailed eicosanoid profiling in patients with psoriatic arthritis (PsA) and evaluate correlations with parameters of disease activity.MethodsForty-one patients with PsA, all of whom satisfied the CASPAR classification criteria for PsA, were studied. Outcomes reflecting the activity of peripheral arthritis as well as skin psoriasis, Disease Activity Score (DAS)28, Clinical Disease Index (CDAI) and Body Surface Area (BSA) were assessed. Serum eicosanoids were determined by LC-MS, and the correlation between metabolite levels and disease scores was evaluated.ResultsSixty-six eicosanoids were identified by reverse-phase LC/MS. Certain eicosanoids species including several pro-inflammatory eicosanoids such as PGE2, HXB3 or 6,15-dk,dh,PGF1a correlated with joint disease score. Several eicosapentaenoic acid (EPA)-derived eicosanoids, which associate with anti-inflammatory properties, such as 11-HEPE, 12-HEPE and 15-HEPE, correlated with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) as well. Of interest, resolvin D1, a DHA-derived anti-inflammatory eicosanoid, was down-regulated in patients with high disease activity.ConclusionBoth pro- and anti-inflammatory eicosanoids were associated with joint disease score, potentially representing pathways of harm as well as benefit. Further studies are needed to determine whether these eicosanoid species might also play a role in the pathogenesis of joint inflammation in PsA.
| S-EPMC6533065 | biostudies-literature
Project description:In 15 patients with rheumatoid arthritis the baseline expression (t=0) of type I IFN-regulated genes was determined in peripheral blood cells (PAXgene) using cDNA-microarrays and compared to levels one month after (t=1) anti-TNF treatment (infliximab). Therefore, we used 43K cDNA microarrays from the Stanford Functional Genomics Facility (http://microarray.org/sfgf/) printed on aminosilane-coated slides containing ~20.000 unique genes. Only one batch of arrays was used for all experiments. First DNA spots were UV-cross linked to the slide using 150-300 mJoules. Sample preparation and microarray hybridization were performed as described previously (1,2). Data storage and filtering was performed using the Stanford Microarray Database (http://genome-www5.stanford.edu//) as described previously. 1. van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM et al.: Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis 2007, 66: 1008-1014. 2. van der Pouw Kraan TC, van Baarsen LG, Rustenburg F, Baltus B, Fero M, Verweij CL: Gene expression profiling in rheumatology. Methods Mol Med 2007, 136: 305-327. Abbreviations: - Bnrs are the different patients analyzed - PAX or Paxgene indicates the total RNA was isolated from peripheral blood obtained in PAXgene tubes - CRS: common reference sample: We made a common reference that consisted of a mixture of mRNAs isolated from 11 different cell lines (Perou CM, Jeffrey SS, van de RM et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A. 1999; 96:9212-9217) supplemented with RNA from rheumatoid synovial tissue, fibroblasts, and activated peripheral blood mononuclear cells (PBMCs). - PMT: photomultiplier tube: the sensitivity/intensity of the scanner can be adjusted to prevent spot saturation. Compound Based Treatment: anti-TNF (infliximab) reference_design
2010-06-24 | E-GEOD-19821 | biostudies-arrayexpress
Project description:Th17 and TfH cells are thought to promote tissue inflammation and autoantibody production, respectively, in autoimmune diseases including rheumatoid arthritis (RA). TfH cells that co-express Th17 markers (CXCR5+Th17) encompass both of these pathogenic functions, and are increased in some human autoimmune settings including juvenile dermatomyositis. We investigated CXCR5+Th17 cells in RA subjects with stable or active disease and before and after TNF inhibitor therapy. CXCR5+Th17 cell frequency was increased in RA compared to healthy controls, but other helper T cell subsets were not different. CXCR5+Th17 cells correlated with disease activity in subjects with active RA prior to initiation of TNF inhibitor therapy. Baseline CXCR5+Th17 cells also correlated with numbers of swollen joints as late as one year post-therapy. CXCR5+Th17 cell frequencies were unaltered by TNF blockade and in fact remained remarkably stable within individuals. We conclude that CXCR5+Th17 cells are not a direct target of TNF blockade and therefore cannot serve as a biomarker of current disease activity. However, basal CXCR5+Th17 cell frequency may indicate underlying differences in disease phenotype between patients and predict ultimate success of TNF inhibitor therapy.
| S-EPMC5177940 | biostudies-literature