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Correspondence to ‘Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression’
  1. Li-Tzu Wang1,
  2. Kevin Sheng-Kai Ma2
  1. 1 Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, Republic of China
  2. 2 Department of Life Science, National Taiwan University, Taipei, Taiwan, Republic of China
  1. Correspondence to Dr Kevin Sheng-Kai Ma, National Taiwan University, Taipei, Republic of China;{at}

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We read with great interest the work by Watad et al,1 which the authors demonstrated the characterisation of enthesis-resident T cells and their corresponding cytokine responses upon stimulation. This commendable work mimicked enthesitis-involved inflammatory pathogenesis of spondyloarthritis, for instance, psoriatic arthritis (PsA). Particularly, the authors proposed that entheseal T cells may secrete interleukin (IL)-17 and much more tumour necrosis factor α (TNF-α) in response to anti-CD3 and anti-CD28 (as suggested in figure 3 by Watad et al 1); furthermore, phosphodiesterase 4 (PDE4) inhibitors suppressed the expression of the above mentioned inflammatory cytokines (as suggested in figure 5 by Watad et al 1). As PDE4 inhibitors have been used to treat autoimmune diseases and advanced malignancies,2 we are highly interested in whether infliximab, a neutralised antibody for TNF-α and a widely prescribed biologic disease-modifying antirheumatic drugs for a number of autoimmune diseases, would as well modulate the immunity of entheseal or synovial T cells in patients with PsA in clinical settings.

We compared the RNA-sequencing profiles of synovial biopsies from patients with PsA naive to anti-TNF-α agents before and 10 weeks after infliximab treatment registered in the National Center for Biotechnology Information-Gene Expression Omnibus database. Overall, we identified 39 significantly expressed pathways using p value and Z-score visualisation, with 26 pathways up-regulated at a Z-score of above 1, and 13 pathways down-regulated at a Z-score of less than −1 (figure 1). Among the 26 upregulated pathways after infliximab treatment, well-documented immunomodulatory signalling pathways, including adrenomedullin signalling pathway,3 transforming growth factor-β (TGF-β) signalling and aryl hydrocarbon receptor signalling, were noted; furthermore, B cell-involved pathways, including B cell receptor signalling and systemic lupus erythematosus-associated B cell signalling pathway, were as well activated after TNF-α blockage. Among the 13 downregulated pathways after infliximab treatment, both Tec kinase signalling and signalling by Rho family GTPases were significantly inhibited at a Z-score of less than −2. These findings are consistent with previous studies reporting that Tec kinases regulate signalling pathways downstream of T cell receptor (TCR) activation, followed by T cell development, cytokine production and T-helper cell differentiation.4 On the other hand, these findings are in line with the fact that Rho GTPases initiate signalling following TCR activation, which allow them to modulate pathways responsible for T cell development, differentiation and activation.5 Moreover, as IL-23 signalling, a pathway upstream of Th17 induction,6 was also downregulated after infliximab treatment, it was suggested that reciprocal regulation between TNF-α and IL-17 took place in synovial T cells during anti-TNF-α therapy.7

Figure 1

Canonical pathway analysis on RNA-seq data of synovial biopsy from patients with psoriatic arthritis receiving infliximab treatment after a follow-up of 10 weeks. Upregulated pathways are labelled in red. Downregulated pathways are labelled in blue. FGF, fibroblast growth factor; FLT3, FMS-like tyrosine kinase 3; GNRH, gonadotropin-releasing hormone; IL, interleukin; ILK, integrin-linked kinase; LXR, liver X receptor; NANOG, homeobox transcription factor Nanog; PFKB4, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4; PPARα, peroxisome proliferator-activated receptor α; RXR, retinoid X receptor; TRK, tropomyosin receptor kinase; VEGF, vascular endothelial growth factor.

In conclusion, our data supported that the activity of entheseal and synovial T cells was suppressed in patients with PsA treated with TNF-α inhibitors, potently accompanying with an overall downregulation in pathways underlying the pathogenesis of PsA.

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  • L-TW and KS-KM are joint first authors.

  • Contributors Both authors contributed equally to conceptualization, data analysis and discussion.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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