Immune cells involved in the pathogenesis of ankylosing spondylitis

Rezaiemanesh, Alireza; Abdolmaleki, Mohsen; Abdolmohammadi, Kamal; Aghaei, Hamideh; Pakdel, Fatemeh Dadgar; Fatahi, Yousef; Soleimanifar, Narjes; Zavvar, Mahdi; Nicknam, Mohammad Hossein

doi:10.1016/j.biopha.2018.01.108

Cited by 61 publications

(49 citation statements)

References 89 publications

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“…The IL-17 axis represents an established target in AS treatment, and inflammation is associated with an increase in IL-17producing innate immune cells. 12 Two members of the IL-17 cytokine family, IL-17A and IL-17F, share ~50% structural homology and have similar pro-inflammatory function, signalling via the same receptor complex. 13 14 Preclinical evidence from human in vitro assays has shown that IL-17A and IL-17F cooperate with other mediators of inflammation, such as TNF, to amplify inflammatory responses.…”

Section: How Might This Impact On Clinical Practice or Future Developmentioning

confidence: 99%

Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study

Gensler²,

et al. 2020

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ObjectivesBimekizumab selectively neutralises both interleukin (IL)-17A and IL-17F. We report efficacy and safety in a phase IIb dose-ranging study in patients with active ankylosing spondylitis (AS).MethodsAdults with AS (fulfilling modified New York criteria) were randomised 1:1:1:1:1 to bimekizumab 16 mg, 64 mg, 160 mg, 320 mg or placebo every 4 weeks for 12 weeks (double-blind period). At week 12, patients receiving bimekizumab 16 mg, 64 mg or placebo were re-randomised 1:1 to bimekizumab 160 mg or 320 mg every 4 weeks to week 48; other patients continued on their initial dose (dose-blind period). The primary end point was Assessment of SpondyloArthritis international Society (ASAS) 40 response at week 12 (non-responder imputation (NRI) for missing data).Results303 patients were randomised: bimekizumab 16 mg (n=61), 64 mg (n=61), 160 mg (n=60), 320 mg (n=61) or placebo (n=60). At week 12, significantly more bimekizumab-treated patients achieved ASAS40 vs placebo (NRI: 29.5%–46.7% vs 13.3%; p<0.05 all comparisons; OR vs placebo 2.6–5.5 (95% CI 1.0 to 12.9)). A significant dose-response was observed (p<0.001). The primary end point was supported by all secondary efficacy outcomes. At week 48, 58.6% and 62.3% of patients receiving bimekizumab 160 and 320 mg throughout the study achieved ASAS40, respectively (NRI); similar ASAS40 response rates were observed in re-randomised patients. During the double-blind period, treatment-emergent adverse events occurred in 26/60 (43.3%) patients receiving placebo and 92/243 (37.9%) receiving bimekizumab.ConclusionsBimekizumab provided rapid and sustained improvements in key outcome measures in patients with active AS, with no unexpected safety findings versus previous studies.Trial registration numberNCT02963506.

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Section: How Might This Impact On Clinical Practice or Future Developmentioning

confidence: 99%

Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study

Gensler²,

et al. 2020

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“…The pathological process of r-axSpA is characterized by an early inflammatory stage, followed by a phase of pathological new bone formation with syndesmophytes and ankylosis [4], which lead to a decrease in quality of life in these patients. Although an ever-growing list of factors and mechanisms seem to have a role in the pathogenesis of this disease [5][6][7], numerous gaps remain in our understanding of the precise molecular processes associated with the triggering, initiation, development, and regulation of this disease.…”

Section: Introductionmentioning

confidence: 99%

Enhanced NETosis generation in radiographic axial spondyloarthritis: utility as biomarker for disease activity and anti-TNF-α therapy effectiveness

et al. 2020

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Background: Radiographic axial spondyloarthritis (r-axSpA) is a chronic inflammatory form of arthritis in which tumor necrosis factor (TNF)-α, a potent inducer of inflammatory response and a key regulator of innate immunity and of Th1 immune responses, plays a central role. NETosis is a mechanism of innate immune defense that is involved in diverse rheumatology diseases. Nevertheless, spontaneous NETosis generation in r-axSpA, its association to disease pathogenesis, and the NETosis involvement on anti-TNF-α therapy's effects has never been explored.Methods: Thirty r-axSpA patients and 32 healthy donors (HDs) were evaluated. Neutrophil extracellular trap (NET) formation, mediators of signal-transduction cascade required for NETosis induction and cell-free NETosis-derived products were quantified. An additional cohort of 15 r-axSpA patients treated with infliximab (IFX) for six months were further analyzed. In vitro studies were designed to assess the effects of IFX in NETosis generation and the inflammatory profile triggered. (Continued on next page)Results: Compared to HDs, neutrophils from r-axSpA patients displayed augmented spontaneous NET formation, elevated expression of NET-associated signaling components, nuclear peptidylarginine deiminase 4 translocation and increased citrullinated histone H3. Furthermore, patients exhibited altered circulating levels of cell-free NETosisderived products (DNA, nucleosomes and elastase). Additional studies revealed that cell-free NETosis-derived products could be suitable biomarkers for distinguish r-axSpA patients from HDs. Correlation studies showed association between cell-free NETosis-derived products and clinical inflammatory parameters. Besides, nucleosomes displayed potential as a biomarker for discriminate patients according to disease activity. IFX therapy promoted a reduction in both NETosis generation and disease activity in r-axSpA patients. Mechanistic in vitro studies further unveiled the relevance of IFX in reducing NET release and normalizing the augmented inflammatory activities promoted by NETs in mononuclear cells.Conclusions: This study reveals that NETosis is enhanced in r-axSpA patients and identifies the NETosis-derived products as potential disease activity biomarkers. In addition, the data suggests the potential role of NET generation analysis for assessment of therapeutic effectiveness in r-axSpA.

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“…Various immune cells have been reported to play important roles in the initiation, progression and regulation of AS. For example, dendritic cells (DCs) are involved in Th17 immune responses, which are associated with manifestations of AS 3 . Natural killer (NK) cells can recognize HLA class I through the expression of genes named killer immunoglobulin-like receptors (KIRs).…”

Section: Introductionmentioning

confidence: 99%

Gene-regulatory network analysis of ankylosing spondylitis with a single-cell chromatin accessible assay

Zheng

et al. 2020

Sci Rep

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A detailed understanding of the gene-regulatory network in ankylosing spondylitis (AS) is vital for elucidating the mechanisms of AS pathogenesis. Assaying transposase-accessible chromatin in single cell sequencing (scATAC-seq) is a suitable method for revealing such networks. Thus, scATAC-seq was applied to define the landscape of active regulatory DNA in AS. As a result, there was a significant change in the percent of CD8+ T cells in PBMCs, and 37 differentially accessible transcription factor (TF) motifs were identified. T cells, monocytes-1 and dendritic cells were found to be crucial for the IL-17 signaling pathway and TNF signaling pathway, since they had 73 potential target genes regulated by 8 TF motifs with decreased accessibility in AS. Moreover, natural killer cells were involved in AS by increasing the accessibility to TF motifs TEAD1 and JUN to induce cytokine-cytokine receptor interactions. In addition, CD4+ T cells and CD8+ T cells may be vital for altering host immune functions through increasing the accessibility of TF motifs NR1H4 and OLIG (OLIGI and OLIG2), respectively. These results explain clear gene regulatory variation in PBMCs from AS patients, providing a foundational framework for the study of personal regulomes and delivering insights into epigenetic therapy.

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Immune cells involved in the pathogenesis of ankylosing spondylitis

Cited by 61 publications

References 89 publications

Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study

Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study

Enhanced NETosis generation in radiographic axial spondyloarthritis: utility as biomarker for disease activity and anti-TNF-α therapy effectiveness

Gene-regulatory network analysis of ankylosing spondylitis with a single-cell chromatin accessible assay

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