title: Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment.
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.
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
authors.forename: Karin M E
authors.initials: KM
authors.lastname: Andersson
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
authors.forename: Nicola Filluelo
authors.initials: NF
authors.lastname: Cavallini
authors.affiliation: Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Brisslert
authors.affiliation: Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ron
authors.initials: R
authors.lastname: Cialic
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
authors.forename: Hadi
authors.initials: H
authors.lastname: Valadi
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Erlandsson
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Silfverswärd
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
authors.forename: Rille
authors.initials: R
authors.lastname: Pullerits
authors.affiliation: Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D054338:Cell Transdifferentiation / Q000235:genetics*; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism
chemical_list: C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha