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- Title
Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis.
- Authors
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
- 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.
- Subjects
ANIMAL experimentation; CYTOKINES; ENZYME-linked immunosorbent assay; FLOW cytometry; GLYCOPROTEINS; INTERLEUKINS; MACROPHAGES; MEMBRANE proteins; MICE; SYSTEMIC scleroderma; T cells; STATISTICAL significance; DISEASE progression; IN vivo studies
- Publication
Arthritis & Rheumatology, 2017, Vol 69, Issue 9, p1879
- ISSN
2326-5191
- Publication type
Article
- DOI
10.1002/art.40164