Mokuda Sho, Miyazaki Tatsuhiko, Ubara Yoshifumi, Kanno Masamoto, Sugiyama Eiji, Takasugi Kiyoshi, Masumoto Junya
Department of Immunology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Department of Pathology, Ehime University Proteo-Science Centre and Graduate School of Medicine, Shizukawa, Toon, Ehime, 791-0295, Japan.
Arthritis Res Ther. 2015 Sep 30;17:275. doi: 10.1186/s13075-015-0785-0.
Proto-oncogene survivin is a member of the inhibitor of apoptosis (IAP) family of proteins. The presence of serous antibodies against survivin in patients with systemic sclerosis has been previously reported; however, there are few reports regarding the pathophysiological relationship between survivin and systemic sclerosis. We herein investigated the expression and function of survivin in SSc patients.
We performed immunohistochemistry analyses to determine the expression of XIAP, cIAP and survivin in skin lesions from patients with SSc and non-SSc. The expression levels of survivin in peripheral blood mononuclear cells (PBMCs) obtained from SSc patients and healthy controls were evaluated using RT-PCR and flow cytometry. Additionally, the function of survivin was verified with overexpression experiments using monocyte-derived dendritic cells (Mo-DCs).
The expression patterns of both XIAP and cIAP were similar, while only the survivin expression differed between the SSc and non-SSc skin lesions. Survivin-overexpressing cells were detected in the SSc dermis frequently. The positive rate of survivin in SSc dermis (64.3%, 9/14) was higher than that in non-SSc dermis (11.2%, 1/9). Furthermore, survivin+ cells expressed CD1a, one of the DC markers. Real-time PCR and FACS analyses revealed that the survivin-WT (wild type) expression levels in PBMCs, in particular CD14+ monocytes, from SSc patients were higher than that from healthy controls. Additionally, the overexpression experiments showed that survivin-WT-overexpressing CD1a+ Mo-DCs have the characteristics of promoting cell cycle progression and decreasing apoptotic cells.
These findings suggest that dermal survivin+ CD1a+ cell infiltration may be a potential biomarker of SSc skin lesions. PBMCs and monocytes from SSc patients also overexpressed survivin; therefore, dermal survivin+ DC may be derived from peripheral blood monocytes. Additionally, survivin may be involved in dermal CD1a+ DC proliferation through cell cycle activation and resistance to apoptosis. Survivin may be an important molecule for the pathogenesis of SSc.
原癌基因生存素是凋亡抑制蛋白（IAP）家族的成员。先前已有报道系统性硬化症患者体内存在抗生存素的血清抗体；然而，关于生存素与系统性硬化症之间病理生理关系的报道较少。我们在此研究了生存素在系统性硬化症患者中的表达及功能。
我们进行了免疫组织化学分析，以确定X连锁凋亡抑制蛋白（XIAP）、细胞凋亡抑制蛋白（cIAP）和生存素在系统性硬化症患者和非系统性硬化症患者皮肤病变中的表达。使用逆转录聚合酶链反应（RT-PCR）和流式细胞术评估从系统性硬化症患者和健康对照者获取的外周血单个核细胞（PBMC）中生存素的表达水平。此外，通过使用单核细胞衍生树突状细胞（Mo-DC）的过表达实验验证了生存素的功能。
XIAP和cIAP的表达模式相似，而系统性硬化症和非系统性硬化症皮肤病变之间仅生存素表达存在差异。在系统性硬化症真皮中经常检测到生存素过表达细胞。系统性硬化症真皮中生存素的阳性率（64.3%，9/14）高于非系统性硬化症真皮（11.2%，1/9）。此外，生存素阳性细胞表达树突状细胞标志物之一CD1a。实时PCR和流式细胞术分析显示，系统性硬化症患者PBMC中，特别是CD14+单核细胞中的野生型（WT）生存素表达水平高于健康对照者。此外，过表达实验表明，过表达WT生存素的CD1a+Mo-DC具有促进细胞周期进程和减少凋亡细胞的特征。
这些发现表明，真皮中生存素阳性CD1a+细胞浸润可能是系统性硬化症皮肤病变的潜在生物标志物。系统性硬化症患者的PBMC和单核细胞也过表达生存素；因此，真皮中生存素阳性树突状细胞可能来源于外周血单核细胞。此外，生存素可能通过激活细胞周期和抵抗凋亡参与真皮CD1a+树突状细胞的增殖。生存素可能是系统性硬化症发病机制中的重要分子。
