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Molecular Medicine

, Volume 21, Issue 1, pp 536–543 | Cite as

Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment

  • Karin M. E. Andersson
  • Nicola Filluelo Cavallini
  • Dan Hu
  • Mikael Brisslert
  • Ron Cialic
  • Hadi Valadi
  • Malin C. Erlandsson
  • Sofia Silfverswärd
  • Rille Pullerits
  • Vijay K. Kuchroo
  • Howard L. Weiner
  • Maria I. Bokarewa
Research Article

Abstract

T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6+CXCR3 CD4+ cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6+CXCR3 CD4+ cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.

Notes

Acknowledgments

This work was funded by grants from the Swedish Research Council (521-2011-2414 to M Bokarewa), the Swedish Association against Rheumatism, the King Gustaf Vth 80-year Foundation, Professor Nanna Swartz Foundation, the Torsten Söderberg’s Foundation, Rune and Ulla Amlövs Trust, the Ingabritt and Arne Lundberg’s Foundation, the University of Gothenburg, and the Regional agreement on medical training and clinical research between the Western Götaland county council and the University of Göteborg (ALFGBG-138661). M Bokarewa holds the Medical Society of Gothenburg Chair in Rheumatology (Ingrid Högbergs Fond). The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

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Authors and Affiliations

  • Karin M. E. Andersson
    • 1
  • Nicola Filluelo Cavallini
    • 1
  • Dan Hu
    • 2
  • Mikael Brisslert
    • 1
  • Ron Cialic
    • 2
  • Hadi Valadi
    • 1
  • Malin C. Erlandsson
    • 1
  • Sofia Silfverswärd
    • 1
  • Rille Pullerits
    • 1
  • Vijay K. Kuchroo
    • 2
  • Howard L. Weiner
    • 2
  • Maria I. Bokarewa
    • 1
  1. 1.Department of Rheumatology and Inflammation Research, Sahlgrenska University HospitalGothenburg UniversityGothenburgSweden
  2. 2.Center for Neurologic Diseases, Brigham & Women’s HospitalHarvard Medical SchoolBostonUSA

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