Manetti Mirko, Pratesi Sara, Romano Eloisa, Bellando-Randone Silvia, Rosa Irene, Guiducci Serena, Fioretto Bianca Saveria, Ibba-Manneschi Lidia, Maggi Enrico, Matucci-Cerinic Marco
Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence, Italy.
Department of Experimental and Clinical Medicine, Section of Internal Medicine, Azienda Ospedaliero-Universitaria Careggi (AOUC), University of Florence, Florence, Italy.
PLoS One. 2017 Aug 10;12(8):e0183102. doi: 10.1371/journal.pone.0183102. eCollection 2017.
The mechanisms underlying endothelial cell injury and defective vascular repair in systemic sclerosis (SSc) remain unclear. Since the recently discovered angiogenic T cells (Tang) may have an important role in the repair of damaged endothelium, this study aimed to analyze the Tang population in relation to disease-related peripheral vascular features in SSc patients. Tang (CD3+CD31+CXCR4+) were quantified by flow cytometry in peripheral blood samples from 39 SSc patients and 18 healthy controls (HC). Circulating levels of the CXCR4 ligand stromal cell-derived factor (SDF)-1α and proangiogenic factors were assessed in paired serum samples by immunoassay. Serial skin sections from SSc patients and HC were subjected to CD3/CD31 and CD3/CXCR4 double immunofluorescence. Circulating Tang were significantly increased in SSc patients with digital ulcers (DU) compared either with SSc patients without DU or with HC. Tang levels were significantly higher in SSc patients with late nailfold videocapillaroscopy (NVC) pattern than in those with early/active NVC patterns and in HC. No difference in circulating Tang was found when comparing either SSc patients without DU or patients with early/active NVC patterns and HC. In SSc peripheral blood, Tang percentage was inversely correlated to levels of SDF-1α and CD34+CD133+VEGFR-2+ endothelial progenitor cells (EPC), and positively correlated to levels of vascular endothelial growth factor and matrix metalloproteinase-9. Tang were frequently detected in SSc dermal perivascular inflammatory infiltrates. In summary, our findings demonstrate for the first time that Tang cells are selectively expanded in the circulation of SSc patients displaying severe peripheral vascular complications like DU. In SSc, Tang may represent a potentially useful biomarker reflecting peripheral vascular damage severity. Tang expansion may be an ineffective attempt to compensate the need for increased angiogenesis and EPC function. Further studies are required to clarify the function of Tang cells and investigate the mechanisms responsible for their change in SSc.
系统性硬化症（SSc）中内皮细胞损伤和血管修复缺陷的潜在机制仍不清楚。由于最近发现的血管生成性T细胞（Tang细胞）可能在受损内皮的修复中起重要作用，本研究旨在分析SSc患者中Tang细胞群体与疾病相关外周血管特征的关系。通过流式细胞术对39例SSc患者和18例健康对照（HC）外周血样本中的Tang细胞（CD3 + CD31 + CXCR4 +）进行定量。通过免疫测定法评估配对血清样本中CXCR4配体基质细胞衍生因子（SDF）-1α和促血管生成因子的循环水平。对SSc患者和HC的连续皮肤切片进行CD3/CD31和CD3/CXCR4双重免疫荧光检测。与无指端溃疡（DU）的SSc患者或HC相比，有DU的SSc患者循环中的Tang细胞显著增加。晚期甲襞视频毛细血管镜（NVC）模式的SSc患者的Tang细胞水平显著高于早期/活动期NVC模式的患者和HC。比较无DU的SSc患者或早期/活动期NVC模式的患者与HC时，循环中的Tang细胞无差异。在SSc外周血中，Tang细胞百分比与SDF-1α和CD34 + CD133 + VEGFR-2 +内皮祖细胞（EPC）水平呈负相关，与血管内皮生长因子和基质金属蛋白酶-9水平呈正相关。在SSc真皮血管周围炎性浸润中经常检测到Tang细胞。总之，我们的研究结果首次表明，在表现出如DU等严重外周血管并发症的SSc患者循环中，Tang细胞选择性扩增。在SSc中，Tang细胞可能代表反映外周血管损伤严重程度的潜在有用生物标志物。Tang细胞扩增可能是为补偿血管生成增加和EPC功能需求而进行的无效尝试。需要进一步研究以阐明Tang细胞的功能，并研究SSc中其变化的机制。
