Abstract
Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, excessive extracellular matrix deposition, and fibrosis of the skin and internal organs. Several infectious agents, including human herpesvirus-6 (HHV-6), have been suggested as possible triggering factors, but a direct association is still missing. We characterized 26 SSc patients for the presence of HHV-6 in tissues and blood, the anti-HHV-6 response, HLA-G plasma levels, and KIR typing. Given the prominent role of endothelial cells (EC) in SSc pathogenesis, along with HHV-6 tropism for EC, we also investigated the expression of pro-fibrosis factors in HHV-6 infected EC. Results showed the presence of HHV-6A in skin biopsies, and an increased virus load was associated with disease severity and poor natural killer (NK) response against the virus, particularly in subjects exhibiting a KIR2 phenotype. HLA-G plasma levels were significantly higher in HHV-6A/B-KIR2 positive SSc patients and in vitro HHV-6A infection-induced pro-fibrosis factors expression in EC, supporting its role in the development of the fibrosing process. Our data suggest an association between virus infection/reactivation and disease, opening the way to future studies to understand the mechanisms by which HHV-6A might contribute to the multifactorial pathogenesis of SSc.
Highlights
Systemic sclerosis (SSc) is a rare autoimmune disease representing one of the most severe connective tissue pathologies, characterized by vascular obliteration, immunological abnormalities, and excessive extracellular matrix deposition, which causes fibrosis of the skin and of internal organs [1]
We reported that HHV-6A/B infection modulates the expression of the tolerogenic human leucocyte antigen (HLA)-G in different cell types [36,37], and this molecule was reported to be differentially expressed in SSc patients compared to controls, both at the skin and blood level [38,39]
We investigated the presence and replicative state of HHV-6A and 6B in SSc patients both at the blood and tissue level, the immune responses against the virus, the host killer-cell immunoglobulin-like (KIR) type and HLA-G expression, and, as a proof of concept of HHV-6A and 6B involvement in fibrosis induction, the ability of HHV-6A/B infection to induce an aberrant expression of pro-fibrotic factors in vascular endothelial cells
Summary
Systemic sclerosis (SSc) is a rare autoimmune disease representing one of the most severe connective tissue pathologies, characterized by vascular obliteration, immunological abnormalities, and excessive extracellular matrix deposition, which causes fibrosis of the skin and of internal organs [1]. We reported that HHV-6A/B infection modulates the expression of the tolerogenic human leucocyte antigen (HLA)-G in different cell types [36,37], and this molecule was reported to be differentially expressed in SSc patients compared to controls, both at the skin and blood level [38,39]. Based on these observations, this study explored the possible association between HHV-6A/B infection and SSc development, including different sides of the hypothesis in the analysis. We report the results of our studies on the possible role of HHV-6A/B infection in the pathogenesis of SSc
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
