Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis
Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis
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DOI：
10.1002/art.40164
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发表时间：
2017-09-01
影响因子：
13.3
通讯作者：
Sato, Shinichi
中科院分区：
文献类型：
--
作者：
Fukasawa, Takemichi;Yoshizaki, Ayumi;Sato, Shinichi
Objective.确定系统性硬化症（SSc）患者和拓扑异构酶I（topo I）小鼠模型中可溶性程序性死亡1（sPD-1）及其配体之一可溶性PD配体2（sPD-L2）的功能和血清水平诱导的SSc。方法。采用酶联免疫吸附试验（ELISA）检测91例SSc患者血清sPD-1和sPD-L2水平。通过流式细胞术定量T细胞、B细胞和巨噬细胞上PD-1和PD-L2的表达。通过微流控ELISA（micro-ELISA）分析PD-1和PD-L2阻断的效果，微流控ELISA是一种可以测量非常少量的细胞因子的技术。此外，在topo I诱导的SSc小鼠中评估sPD-1和sPD-L2对疾病进展的影响。SSc患者血清sPD-1和sPD-L2水平升高，并与纤维化程度和免疫异常相关。PD-1和PD-L2的表达水平在SSc T细胞、B细胞和巨噬细胞上显著升高。SSc患者血清样本的微量ELISA分析显示，与PD-L2低B细胞相比，PD-L2高B细胞具有更高水平的白细胞介素-10（IL-10）产生，表明PD-L2通过与T细胞和B细胞的同源相互作用作为T细胞因子产生的调节剂。在Topo I诱导的SSc小鼠中，Topo I特异性B细胞在T细胞和Topo I蛋白的共同培养中产生的IL-10显著高于常规B细胞，而腹腔注射重组嵌合PD-1-Fc和PD-L2-Fc可抵消这种增强效应。这些结果表明，sPD-1和sPD-L2通过调节与T细胞和B细胞的同源相互作用促进SSc中的疾病发展。
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.