Innate Immune Modulation Induced by EBV Lytic Infection Promotes Endothelial Cell Inflammation and Vascular Injury in Scleroderma

Abstract

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.

Immunosuppressive Tumor Microenvironment and Immunotherapy of Epstein–Barr Virus-Associated Malignancies

“…Furthermore, EBERs can be detected in endothelial cells in EBV-infected tissues, implicating that EBERs released from EBV-infected cells can act on endothelial cells and promote angiogenesis by stimulating VCAM-1 expression [ 86 ]. Innate immune modulation induced by EBV lytic infection can also promote endothelial cell inflammation and vascular injury [ 87 ].…”

Laser Speckle Contrast Analysis: Functional Evaluation of Microvascular Damage in Connective Tissue Diseases. Is There Evidence of Correlations With Organ Involvement, Such as Pulmonary Damage?

“…Systemic sclerosis is characterized by structural and functional vasculopathy, where the peripheral microvascular involvement may manifest as Raynaud's phenomenon (RP) and/or digital ulcers (DU) (Domsic et al, 2014;Gaillard-Bigot et al, 2014;Sebastiani et al, 2014;Sulli et al, 2014b;Lambrecht et al, 2016;Morales-Cárdenas et al, 2016;Trombetta et al, 2016;Smith et al, 2018;Frech and Murtaugh, 2019;Bruni et al, 2020;Guigui et al, 2020;Farina et al, 2021;Gigante et al, 2021;Suliman et al, 2021). Frequently, RP is the earliest morphological and functional manifestation of SSc vasculopathy (Domsic et al, 2014;Gaillard-Bigot et al, 2014;Sulli et al, 2014b;Lambrecht et al, 2016; -Cárdenas et al, 2016;Trombetta et al, 2016;Frech and Murtaugh, 2019;Guigui et al, 2020;Farina et al, 2021;Gigante et al, 2021;Suliman et al, 2021). RP, secondary to SSc (SRP), is also the most common presenting feature of the disease, it is observed in 95% of scleroderma patients (Wigley et al, 1990;Wigley and Flavahan, 2016;Bruni et al, 2018).…”

“…It has been postulated that progressive deficiency in the vasodilatory capacity of the vessels, intimal fibroproliferation, thrombosis of the digital arteries and tissue ischemia may well be the underlying mechanisms that lead to persistent vascular involvement (Domsic et al, 2014;Wigley and Flavahan, 2016;Bruni et al, 2018;Ruaro et al, 2019a). Endothelial cell injury and activation lead to vascular dysfunction and vasospasm that may quickly obstruct the already limited blood flow of the vasculopathic digital arteries (Wigley et al, 1990;Roustit et al, 2010;Pauling et al, 2012;Della Rossa et al, 2013Wigley and Flavahan, 2016;Bruni et al, 2018Bruni et al, , 2020Wilkinson et al, 2018;Ruaro et al, 2019b;Farina et al, 2021). There is often a luminal narrowing of > 75% of digital arteries due to underlying intimal fibrosis and luminal occlusion caused by thrombi (Wigley et al, 1990;Wigley and Flavahan, 2016;Bruni et al, 2018;Farina et al, 2021).…”

“…Endothelial cell injury and activation lead to vascular dysfunction and vasospasm that may quickly obstruct the already limited blood flow of the vasculopathic digital arteries (Wigley et al, 1990;Roustit et al, 2010;Pauling et al, 2012;Della Rossa et al, 2013Wigley and Flavahan, 2016;Bruni et al, 2018Bruni et al, , 2020Wilkinson et al, 2018;Ruaro et al, 2019b;Farina et al, 2021). There is often a luminal narrowing of > 75% of digital arteries due to underlying intimal fibrosis and luminal occlusion caused by thrombi (Wigley et al, 1990;Wigley and Flavahan, 2016;Bruni et al, 2018;Farina et al, 2021).…”

“…Furthermore, degradation of the endothelial barrier occurs in response to perivascular inflammation and to reactive oxygen species generated by the ischemia-reperfusion injury, taking place in SSc patients' microvasculature. This phenomenon is a trigger to the endothelial barrier leading to opening of the endothelial junctions, inflammatory cells homing, sustained hyperpermeability and continuous vascular leak (Wigley et al, 1990;Wigley and Flavahan, 2016;Bruni et al, 2018;Farina et al, 2021).…”