Plasma interleukin-23 and circulating IL-17A+IFNγ+ ex-Th17 cells predict opposing outcomes of anti-TNF therapy in rheumatoid arthritis

Millier, Melanie J; Fanning, Niamh; Frampton, Christopher; Stamp, Lisa K.; Hessian, Paul A.

doi:10.1186/s13075-022-02748-3

Cited by 9 publications

(7 citation statements)

References 51 publications

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“…[112][113][114] However, it has been found that IL-23 does not depend on the inflammatory mechanism of TNF in the pathogenesis of RA. 115 IL-21 secreted by Th17 cells in RA synovium is closely associated with RA. 116 Furthermore, IL-21 induces T cell activation and promotes the secretion of proinflammatory cytokines in RA by suppressing FOXP3+ expression, 117 thereby promoting the differentiation and proliferation of Th17 cells.…”

Section: Ra Pathogenesismentioning

confidence: 99%

Immunomodulatory role of T helper cells in rheumatoid arthritis

Luo

Wang

et al. 2022

Bone & Joint Research

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Rheumatoid arthritis (RA) is an autoimmune disease that involves T and B cells and their reciprocal immune interactions with proinflammatory cytokines. T cells, an essential part of the immune system, play an important role in RA. T helper 1 (Th1) cells induce interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and interleukin (IL)-2, which are proinflammatory cytokines, leading to cartilage destruction and bone erosion. Th2 cells primarily secrete IL-4, IL-5, and IL-13, which exert anti-inflammatory and anti-osteoclastogenic effects in inflammatory arthritis models. IL-22 secreted by Th17 cells promotes the proliferation of synovial fibroblasts through induction of the chemokine C-C chemokine ligand 2 (CCL2). T follicular helper (Tfh) cells produce IL-21, which is key for B cell stimulation by the C-X-C chemokine receptor 5 (CXCR5) and coexpression with programmed cell death-1 (PD-1) and/or inducible T cell costimulator (ICOS). PD-1 inhibits T cell proliferation and cytokine production. In addition, there are many immunomodulatory agents that promote or inhibit the immunomodulatory role of T helper cells in RA to alleviate disease progression. These findings help to elucidate the aetiology and treatment of RA and point us toward the next steps. Cite this article: Bone Joint Res 2022;11(7):426–438.

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Section: Ra Pathogenesismentioning

confidence: 99%

Immunomodulatory role of T helper cells in rheumatoid arthritis

Luo

Wang

et al. 2022

Bone & Joint Research

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“…Our results suggest a role of one-carbon metabolism in the efficacy of anti-TNF-α drugs, and may pave the way for more personalized interventions in the treatment of RA. In perspective, the development of an accurate prediction model based on a wide range of pharmacogenetic, metabolic [ 55 ], clinical [ 56 ], circulating microRNA [ 57 , 58 ], and serological [ 59 ] markers—which may influence the treatment response with an additive score significance—could tailor better personalized anti-TNF-α treatments for RA patients.…”

Section: Discussionmentioning

confidence: 99%

MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis

Ravaei

Pulsatelli

Assirelli

et al. 2023

IJMS

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Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with a prevalence of 1%. Currently, RA treatment aims to achieve low disease activity or remission. Failure to achieve this goal causes disease progression with a poor prognosis. When treatment with first-line drugs fails, treatment with tumor necrosis factor-α (TNF-α) inhibitors may be prescribed to which many patients do not respond adequately, making the identification of response markers urgent. This study investigated the association of two RA-related genetic polymorphisms, c.665C>T (historically referred to as C677T) and c.1298A>C, in the MTHFR gene as response markers to an anti-TNF-α therapy. A total of 81 patients were enrolled, 60% of whom responded to the therapy. Analyses showed that both polymorphisms were associated with a response to therapy in an allele dose-dependent manner. The association for c.665C>T was significant for a rare genotype (p = 0.01). However, the observed opposite trend of association for c.1298A>C was not significant. An analysis revealed that c.1298A>C, unlike c.665C>T, was also significantly associated with the drug type (p = 0.032). Our preliminary results showed that the genetic polymorphisms in the MTHFR gene were associated with a response to anti-TNF-α therapy, with a potential significance for the anti-TNF-α drug type. This evidence suggests a role for one-carbon metabolism in anti-TNF-α drug efficacy and contributes to further personalized RA interventions.

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“…Significant correlations were evident between IL27B/EBI3 (also known as EBV-induced gene 3; also known as IL35B ) expression and the expression of both Δ133TP53 and TP53β mRNAs. In RA synovium, the most obvious presence of IL27B/EBI3 protein is with plasma cells (PC) at the periphery of ELS [ 48 ] and likely acquired during PC differentiation [ 49 ]. Our data show that a subset of synovial PCs expresses the Δ133p53β isoform.…”

Section: Discussionmentioning

confidence: 99%

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis

et al. 2023

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Background The p53 isoform Δ133p53β is known to be associated with cancers driven by inflammation. Many of the features associated with the development of inflammation in rheumatoid arthritis (RA) parallel those evident in cancer progression. However, the role of this isoform in RA has not yet been explored. The aim of this study was to determine whether Δ133p53β is driving aggressive disease in RA. Methods Using RA patient synovia, we carried out RT-qPCR and RNAScope-ISH to determine both protein and mRNA levels of Δ133p53 and p53. We also used IHC to determine the location and type of cells with elevated levels of Δ133p53β. Plasma cytokines were also measured using a BioPlex cytokine panel and data analysed by the Milliplex Analyst software. Results Elevated levels of pro-inflammatory plasma cytokines were associated with synovia from RA patients displaying extensive tissue inflammation, increased immune cell infiltration and the highest levels of Δ133TP53 and TP53β mRNA. Located in perivascular regions of synovial sub-lining and surrounding ectopic lymphoid structures (ELS) were a subset of cells with high levels of CD90, a marker of ‘activated fibroblasts’ together with elevated levels of Δ133p53β. Conclusions Induction of Δ133p53β in CD90+ synovial fibroblasts leads to an increase in cytokine and chemokine expression and the recruitment of proinflammatory cells into the synovial joint, creating a persistently inflamed environment. Our results show that dysregulated expression of Δ133p53β could represent one of the early triggers in the immunopathogenesis of RA and actively perpetuates chronic synovial inflammation. Therefore, Δ133p53β could be used as a biomarker to identify RA patients more likely to develop aggressive disease who might benefit from targeted therapy to cytokines such as IL-6.

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Plasma interleukin-23 and circulating IL-17A+IFNγ+ ex-Th17 cells predict opposing outcomes of anti-TNF therapy in rheumatoid arthritis

Cited by 9 publications

References 51 publications

Immunomodulatory role of T helper cells in rheumatoid arthritis

Immunomodulatory role of T helper cells in rheumatoid arthritis

MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis

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