Department of Experimental Medicine, Sapienza University, Rome, Italy.
Department of Clinical Medicine, Sapienza University, Rome, Italy.
Front Immunol. 2021 Apr 19;12:651013. doi: 10.3389/fimmu.2021.651013. eCollection 2021.
Microvascular injury is considered an initial event in the pathogenesis of scleroderma and endothelial cells are suspected of being the target of the autoimmune process seen in the disease. EBV has long been proposed as a trigger for autoimmune diseases, including scleroderma. Nevertheless, its contribution to the pathogenic process remains poorly understood. In this study, we report that EBV lytic antigens are detected in scleroderma dermal vessels, suggesting that endothelial cells might represent a target for EBV infection in scleroderma skin. We show that EBV DNA load is remarkably increased in peripheral blood, plasma and circulating monocytes from scleroderma patients compared to healthy EBV carriers, and that monocytes represent the prominent subsets of EBV-infected cells in scleroderma. Given that monocytes have the capacity to adhere to the endothelium, we then investigated whether monocyte-associated EBV could infect primary human endothelial cells. We demonstrated that endothelial cells are infectable by EBV, using human monocytes bound to recombinant EBV as a shuttle, even though cell-free virus failed to infect them. We show that EBV induces activation of TLR9 innate immune response and markers of vascular injury in infected endothelial cells and that up-regulation is associated with the expression of EBV lytic genes in infected cells. EBV innate immune modulation suggests a novel mechanism mediating inflammation, by which EBV triggers endothelial cell and vascular injury in scleroderma. In addition, our data point to up-regulation of EBV DNA loads as potential biomarker in developing vasculopathy in scleroderma. These findings provide the framework for the development of novel therapeutic interventions to shift the scleroderma treatment paradigm towards antiviral therapies.
微血管损伤被认为是硬皮病发病机制中的初始事件，内皮细胞被怀疑是疾病中自身免疫过程的靶标。EBV 长期以来被认为是自身免疫性疾病（包括硬皮病）的触发因素。然而，其在发病机制中的作用仍知之甚少。在这项研究中，我们报告称，在硬皮病皮肤的真皮血管中检测到 EBV 裂解抗原，这表明内皮细胞可能是 EBV 感染在硬皮病皮肤中的靶标。我们表明，与健康 EBV 携带者相比，硬皮病患者的外周血、血浆和循环单核细胞中的 EBV DNA 载量显著增加，并且单核细胞是硬皮病中 EBV 感染细胞的主要亚群。鉴于单核细胞具有黏附在内皮细胞的能力，我们随后研究了单核细胞相关的 EBV 是否可以感染原代人内皮细胞。我们通过使用结合了重组 EBV 的人单核细胞作为穿梭物来证明内皮细胞可以被 EBV 感染，尽管无细胞病毒不能感染它们。我们表明，EBV 诱导受感染的内皮细胞中 TLR9 先天免疫反应和血管损伤标志物的激活，而上调与受感染细胞中 EBV 裂解基因的表达相关。EBV 先天免疫调节提示了一种新的机制，通过该机制 EBV 触发硬皮病中的内皮细胞和血管损伤。此外，我们的数据表明 EBV DNA 载量的上调可能是硬皮病中血管病变发展的潜在生物标志物。这些发现为开发新型治疗干预措施提供了框架，以将硬皮病的治疗模式转向抗病毒治疗。
