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

被引：62

作者：

Fukasawa, Takemichi ^{[1
]}

Yoshizaki, Ayumi ^{[1
]}

Ebata, Satoshi ^{[1
]}

Nakamura, Kouki ^{[1
]}

Saigusa, Ryosuke ^{[1
]}

Miura, Syunsuke ^{[1
]}

Yamashita, Takashi ^{[1
]}

Hirabayashi, Megumi ^{[1
]}

Ichimura, Yohei ^{[1
]}

Taniguchi, Takashi ^{[1
]}

Asano, Yoshihide ^{[1
]}

Shimizu, Hisashi ^{[1
]}

Kazoe, Yutaka ^{[1
]}

Mawatari, Kazuma ^{[1
]}

Kitamori, Takehiko ^{[1
]}

Sato, Shinichi ^{[1
]}

机构：

[1] Univ Tokyo, Tokyo, Japan

来源：

ARTHRITIS & RHEUMATOLOGY | 2017年 / 69卷 / 09期

基金：

日本科学技术振兴机构;

关键词：

T-CELL-ACTIVATION; B-CELL; LUNG FIBROSIS; PD-1; ASSOCIATION; AUTOIMMUNITY; EXPRESSION; RECEPTOR; SKIN; SCLERODERMA;

D O I：

10.1002/art.40164

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-L2 high B cells had higher levels of interleukin-10 (IL-10) production compared with PD-L2 low 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.

引用

页码：1879 / 1890

页数：12

共 48 条

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