HLA-DRB1 Shared Epitope Alleles and Disease Activity Are Correlated with Reduced T Cell Receptor Repertoire Diversity in CD4+ T Cells in Rheumatoid Arthritis

Keiichi Sakurai; Kazuyoshi Ishigaki; Hirofumi Shoda; Yasuo Nagafuchi; Yumi Tsuchida; Shuji Sumitomo; Hiroko Kanda; Akari Suzuki; Yuta Kochi; Kazuhiko Yamamoto; Keishi Fujio

doi:10.3899/jrheum.170909

HLA-DRB1 Shared Epitope Alleles and Disease Activity Are Correlated with Reduced T Cell Receptor Repertoire Diversity in CD4+ T Cells in Rheumatoid Arthritis

J Rheumatol. 2018 Jul;45(7):905-914. doi: 10.3899/jrheum.170909. Epub 2018 Apr 15.

Authors

Keiichi Sakurai^{1

2}, Kazuyoshi Ishigaki^{1

2}, Hirofumi Shoda^{1

2}, Yasuo Nagafuchi^{1

2}, Yumi Tsuchida^{1

2}, Shuji Sumitomo^{1

2}, Hiroko Kanda^{1

2}, Akari Suzuki^{1

2}, Yuta Kochi^{1

2}, Kazuhiko Yamamoto^{1

2}, Keishi Fujio^{3

4}

Affiliations

¹ From the Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
² K. Sakurai, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; K. Ishigaki, MD, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; H. Shoda, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; Y. Nagafuchi, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; Y. Tsuchida, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; S. Sumitomo, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; H. Kanda, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; A. Suzuki, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; Y. Kochi, MD, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; K. Yamamoto, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, and Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; K. Fujio, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo.
³ From the Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan. kfujio-tky@umin.ac.jp.
⁴ K. Sakurai, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; K. Ishigaki, MD, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; H. Shoda, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; Y. Nagafuchi, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; Y. Tsuchida, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; S. Sumitomo, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; H. Kanda, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; A. Suzuki, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; Y. Kochi, MD, PhD, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; K. Yamamoto, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, and Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences; K. Fujio, MD, PhD, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo. kfujio-tky@umin.ac.jp.

PMID: 29657145
DOI: 10.3899/jrheum.170909

Abstract

Objective: Shared epitope (SE) alleles are the most significant genetic susceptibility locus in rheumatoid arthritis (RA); however, their target populations in CD4+ T cells are not well elucidated. We analyzed the association between SE alleles and the T cell receptor (TCR) repertoire diversity of naive and memory CD4+ T cells using next-generation sequencing (NGS).

Methods: The TCR beta chains in naive and memory CD4+ T cells from the peripheral blood of 22 patients with RA and 18 age- and sex-matched healthy donors (HD) were analyzed by NGS. The Renyi entropy was used to evaluate TCR repertoire diversity and its correlations with SE alleles and other variables were examined. Serum cytokine levels were measured by multiplex ELISA.

Results: The TCR repertoire diversity in memory CD4+ T cells was reduced in SE allele-positive patients with RA compared with HD, and showed a significant negative correlation with the SE allele dosage in RA. The TCR repertoire diversity of naive and memory T cells was also negatively correlated with disease activity, and the SE allele dosage and disease activity were independently associated with reduced TCR repertoire diversity. TCR repertoire diversity showed a significant positive correlation with the serum interleukin 2 levels.

Conclusion: SE alleles and disease activity were negatively correlated with the TCR repertoire diversity of CD4+ T cells in RA. Considering the pivotal role of CD4+ T cells in RA, restoring the altered TCR repertoire diversity will provide a potential RA therapeutic target.

Keywords: CYTOKINES; HLA ANTIGENS; NEXT-GENERATION SEQUENCING; RHEUMATOID ARTHRITIS; T LYMPHOCYTES.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Alleles*
Arthritis, Rheumatoid / genetics*
Arthritis, Rheumatoid / immunology
CD4-Positive T-Lymphocytes / immunology*
Cytokines / blood
Epitopes*
Female
Genotype
HLA-DRB1 Chains / genetics*
Humans
Male
Middle Aged
Receptors, Antigen, T-Cell / genetics*

Substances

Cytokines
Epitopes
HLA-DRB1 Chains
Receptors, Antigen, T-Cell