Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell

Masaru Takeshita, Katsuya Suzuki, Yasushi Kondo, Rimpei Morita, Yuumi Okuzono, Keiko Koga, Yoshiaki Kassai, Kanae Gamo, Maiko Takiguchi, Rina Kurisu, Hideyuki Mototani, Yukihiko Ebisuno, Akihiko Yoshimura, Tsutomu Takeuchi

Research output: Contribution to journalArticle

Abstract

Objectives: Rheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively. Methods: We enrolled a total of 311 patients with RA and 73 healthy participants, and carefully classified them by disease state, constructed multiple cohorts and analysed clinical samples from them in a stepwise manner. We performed immunophenotyping with multiple evaluation axes, and two independent transcriptome analyses complementary to each other. Results: We identified that 'effector memory-Tfh' subset was specifically expanded in the peripheral blood (PB) of patients with RA in correlation with disease activity, and reverted after treatment. Besides, we revealed distinct features of T cells in synovial fluid (SF) that the expression of Tfh/Tph-related genes and pro-inflammatory cytokines and chemokines, including CXCL13, were significantly enriched, whereas these phenotype were Th1-like. Finally, we identified specific pathways, such as mTORC1, IL-2-stat5, E2F, cell cycle and interferon-related genes, that were significantly enriched in SF, in particular, as well as PB of untreated patients with RA, and notably, these features reverted after treatment. Conclusion: Our multi-dimensional investigation identified disease relevant T-cell subsets and gene signatures deeply involved in pathogenesis of RA. These findings could aid in our understanding of essential roles of T cells in RA and will facilitate to development better diagnostic and therapeutic interventions.

Original languageEnglish
JournalAnnals of the rheumatic diseases
DOIs
Publication statusPublished - 2019 Jan 1

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T-cells
Rheumatoid Arthritis
T-Lymphocytes
Genes
Synovial Fluid
Blood
Computer peripheral equipment
Chemokine CXCL13
Fluids
Lymphocytes
Chemokines
Infiltration
Interferons
Immunophenotyping
Interleukin-2
Synovial Membrane
T-Lymphocyte Subsets
Gene Expression Profiling
Therapeutics
Cells

Keywords

  • rheumatoid arthritis
  • synovial fluid
  • T cell

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell. / Takeshita, Masaru; Suzuki, Katsuya; Kondo, Yasushi; Morita, Rimpei; Okuzono, Yuumi; Koga, Keiko; Kassai, Yoshiaki; Gamo, Kanae; Takiguchi, Maiko; Kurisu, Rina; Mototani, Hideyuki; Ebisuno, Yukihiko; Yoshimura, Akihiko; Takeuchi, Tsutomu.

In: Annals of the rheumatic diseases, 01.01.2019.

Research output: Contribution to journalArticle

Takeshita, Masaru ; Suzuki, Katsuya ; Kondo, Yasushi ; Morita, Rimpei ; Okuzono, Yuumi ; Koga, Keiko ; Kassai, Yoshiaki ; Gamo, Kanae ; Takiguchi, Maiko ; Kurisu, Rina ; Mototani, Hideyuki ; Ebisuno, Yukihiko ; Yoshimura, Akihiko ; Takeuchi, Tsutomu. / Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell. In: Annals of the rheumatic diseases. 2019.
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AU - Takeshita, Masaru

AU - Suzuki, Katsuya

AU - Kondo, Yasushi

AU - Morita, Rimpei

AU - Okuzono, Yuumi

AU - Koga, Keiko

AU - Kassai, Yoshiaki

AU - Gamo, Kanae

AU - Takiguchi, Maiko

AU - Kurisu, Rina

AU - Mototani, Hideyuki

AU - Ebisuno, Yukihiko

AU - Yoshimura, Akihiko

AU - Takeuchi, Tsutomu

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objectives: Rheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively. Methods: We enrolled a total of 311 patients with RA and 73 healthy participants, and carefully classified them by disease state, constructed multiple cohorts and analysed clinical samples from them in a stepwise manner. We performed immunophenotyping with multiple evaluation axes, and two independent transcriptome analyses complementary to each other. Results: We identified that 'effector memory-Tfh' subset was specifically expanded in the peripheral blood (PB) of patients with RA in correlation with disease activity, and reverted after treatment. Besides, we revealed distinct features of T cells in synovial fluid (SF) that the expression of Tfh/Tph-related genes and pro-inflammatory cytokines and chemokines, including CXCL13, were significantly enriched, whereas these phenotype were Th1-like. Finally, we identified specific pathways, such as mTORC1, IL-2-stat5, E2F, cell cycle and interferon-related genes, that were significantly enriched in SF, in particular, as well as PB of untreated patients with RA, and notably, these features reverted after treatment. Conclusion: Our multi-dimensional investigation identified disease relevant T-cell subsets and gene signatures deeply involved in pathogenesis of RA. These findings could aid in our understanding of essential roles of T cells in RA and will facilitate to development better diagnostic and therapeutic interventions.

AB - Objectives: Rheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively. Methods: We enrolled a total of 311 patients with RA and 73 healthy participants, and carefully classified them by disease state, constructed multiple cohorts and analysed clinical samples from them in a stepwise manner. We performed immunophenotyping with multiple evaluation axes, and two independent transcriptome analyses complementary to each other. Results: We identified that 'effector memory-Tfh' subset was specifically expanded in the peripheral blood (PB) of patients with RA in correlation with disease activity, and reverted after treatment. Besides, we revealed distinct features of T cells in synovial fluid (SF) that the expression of Tfh/Tph-related genes and pro-inflammatory cytokines and chemokines, including CXCL13, were significantly enriched, whereas these phenotype were Th1-like. Finally, we identified specific pathways, such as mTORC1, IL-2-stat5, E2F, cell cycle and interferon-related genes, that were significantly enriched in SF, in particular, as well as PB of untreated patients with RA, and notably, these features reverted after treatment. Conclusion: Our multi-dimensional investigation identified disease relevant T-cell subsets and gene signatures deeply involved in pathogenesis of RA. These findings could aid in our understanding of essential roles of T cells in RA and will facilitate to development better diagnostic and therapeutic interventions.

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