Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis

Takemichi Fukasawa, Ayumi Yoshizaki, Satoshi Ebata, Kouki Nakamura, Ryosuke Saigusa, Syunsuke Miura, Takashi Yamashita, Megumi Hirabayashi, Yohei Ichimura, Takashi Taniguchi, Yoshihide Asano, Hisashi Shimizu, Yutaka Kazoe, Kazuma Mawatari, Takehiko Kitamori, Shinichi Sato

Research output: Contribution to journalArticle

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Abstract

Objective: To determine the function and serum levels of soluble forms of programmed death 1 (sPD-1) and one of its ligands, soluble PD ligand 2 (sPD-L2), in patients with systemic sclerosis (SSc) and in a mouse model of topoisomerase I (topo I)–induced SSc. Methods: Serum levels of sPD-1 and sPD-L2 in 91 patients with SSc were examined by enzyme-linked immunosorbent assay (ELISA). Expression of PD-1 and PD-L2 on T cells, B cells, and macrophages was quantified by flow cytometry. The effects of blockade of PD-1 and PD-L2 were analyzed by microfluidic ELISA (micro-ELISA), a technique that can measure very low amounts of cytokines. In addition, the effects of sPD-1 and sPD-L2 on disease progression were assessed in mice with topo I–induced SSc. Results: Serum levels of sPD-1 and sPD-L2 were elevated in patients with SSc and correlated with the extent of fibrosis and immunologic abnormalities. Expression levels of PD-1 and PD-L2 were significantly elevated on SSc T cells, B cells, and macrophages. Micro-ELISA analysis of serum samples from patients with SSc showed that PD-L2high B cells had higher levels of interleukin-10 (IL-10) production compared with PD-L2low B cells, indicating that PD-L2 acts as a regulator of T cell cytokine production via cognate interactions with T cells and B cells. In mice with topo I–induced SSc, production of IL-10 by topo I–specific B cells in cultures with T cells and topo I protein was significantly higher than that by conventional B cells, and intraperitoneal injection of recombinant chimeric PD-1-Fc and PD-L2-Fc canceled these enhanced effects. Conclusion: These results suggest that sPD-1 and sPD-L2 contribute to disease development in SSc via the regulation of cognate interactions with T cells and B cells.

Original languageEnglish
Pages (from-to)1879-1890
Number of pages12
JournalArthritis and Rheumatology
Volume69
Issue number9
DOIs
Publication statusPublished - 2017 Sep 1

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Systemic Scleroderma
Disease Progression
B-Lymphocytes
Ligands
T-Lymphocytes
Type I DNA Topoisomerase
Enzyme-Linked Immunosorbent Assay
Serum
Interleukin-10
Macrophages
Cytokines
Microfluidics
Intraperitoneal Injections
Flow Cytometry
Fibrosis
Cell Culture Techniques

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis. / Fukasawa, Takemichi; Yoshizaki, Ayumi; Ebata, Satoshi; Nakamura, Kouki; Saigusa, Ryosuke; Miura, Syunsuke; Yamashita, Takashi; Hirabayashi, Megumi; Ichimura, Yohei; Taniguchi, Takashi; Asano, Yoshihide; Shimizu, Hisashi; Kazoe, Yutaka; Mawatari, Kazuma; Kitamori, Takehiko; Sato, Shinichi.

In: Arthritis and Rheumatology, Vol. 69, No. 9, 01.09.2017, p. 1879-1890.

Research output: Contribution to journalArticle

Fukasawa, T, Yoshizaki, A, Ebata, S, Nakamura, K, Saigusa, R, Miura, S, Yamashita, T, Hirabayashi, M, Ichimura, Y, Taniguchi, T, Asano, Y, Shimizu, H, Kazoe, Y, Mawatari, K, Kitamori, T & Sato, S 2017, 'Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis', Arthritis and Rheumatology, vol. 69, no. 9, pp. 1879-1890. https://doi.org/10.1002/art.40164
Fukasawa, Takemichi ; Yoshizaki, Ayumi ; Ebata, Satoshi ; Nakamura, Kouki ; Saigusa, Ryosuke ; Miura, Syunsuke ; Yamashita, Takashi ; Hirabayashi, Megumi ; Ichimura, Yohei ; Taniguchi, Takashi ; Asano, Yoshihide ; Shimizu, Hisashi ; Kazoe, Yutaka ; Mawatari, Kazuma ; Kitamori, Takehiko ; Sato, Shinichi. / Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis. In: Arthritis and Rheumatology. 2017 ; Vol. 69, No. 9. pp. 1879-1890.
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abstract = "Objective: To determine the function and serum levels of soluble forms of programmed death 1 (sPD-1) and one of its ligands, soluble PD ligand 2 (sPD-L2), in patients with systemic sclerosis (SSc) and in a mouse model of topoisomerase I (topo I)–induced SSc. Methods: Serum levels of sPD-1 and sPD-L2 in 91 patients with SSc were examined by enzyme-linked immunosorbent assay (ELISA). Expression of PD-1 and PD-L2 on T cells, B cells, and macrophages was quantified by flow cytometry. The effects of blockade of PD-1 and PD-L2 were analyzed by microfluidic ELISA (micro-ELISA), a technique that can measure very low amounts of cytokines. In addition, the effects of sPD-1 and sPD-L2 on disease progression were assessed in mice with topo I–induced SSc. Results: Serum levels of sPD-1 and sPD-L2 were elevated in patients with SSc and correlated with the extent of fibrosis and immunologic abnormalities. Expression levels of PD-1 and PD-L2 were significantly elevated on SSc T cells, B cells, and macrophages. Micro-ELISA analysis of serum samples from patients with SSc showed that PD-L2high B cells had higher levels of interleukin-10 (IL-10) production compared with PD-L2low B cells, indicating that PD-L2 acts as a regulator of T cell cytokine production via cognate interactions with T cells and B cells. In mice with topo I–induced SSc, production of IL-10 by topo I–specific B cells in cultures with T cells and topo I protein was significantly higher than that by conventional B cells, and intraperitoneal injection of recombinant chimeric PD-1-Fc and PD-L2-Fc canceled these enhanced effects. Conclusion: These results suggest that sPD-1 and sPD-L2 contribute to disease development in SSc via the regulation of cognate interactions with T cells and B cells.",
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AU - Ebata, Satoshi

AU - Nakamura, Kouki

AU - Saigusa, Ryosuke

AU - Miura, Syunsuke

AU - Yamashita, Takashi

AU - Hirabayashi, Megumi

AU - Ichimura, Yohei

AU - Taniguchi, Takashi

AU - Asano, Yoshihide

AU - Shimizu, Hisashi

AU - Kazoe, Yutaka

AU - Mawatari, Kazuma

AU - Kitamori, Takehiko

AU - Sato, Shinichi

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