HHV-6A Infection and Systemic Sclerosis: Clues of a Possible Association

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.

Impact of Human Cytomegalovirus and Human Herpesvirus 6 Infection on the Expression of Factors Associated with Cell Fibrosis and Apoptosis: Clues for Implication in Systemic Sclerosis Development

“…The pattern of pro-fibrotic factors induced by HHV-6A in fibroblasts was similar but not completely superimposable with that observed in endothelial cells, where IL-4, TNFα, and MMP9 were similarly induced [ 15 ], but IL-5 was also increased, in contrast to what was detected in fibroblasts, suggesting that viral strategies depend, at least partly, on the cell type and microenvironment.…”

“…Recent studies have confirmed the high prevalence of beta-herpesvirus infection in SSc subjects, testified by both presence of the viruses at the tissue and/or blood level and by the detection of a significantly higher immune response against HCMV and HHV-6 in SSc patients compared to controls [ 15 , 16 , 26 , 59 ]. Furthermore, HHV-6A was shown to be capable of inducing the expression of pro-fibrotic factors in endothelial cells [ 15 ], but no information are available about the ability of both HHV-6 and HCMV to induce the expression of fibrosis- and apoptosis-associated factors in human dermal fibroblasts, that are one of the main target cells of the disease.…”

“…Additionally, oxidative stress has been evoked as an important element in the pathogenesis of SSc [ 11 , 12 ], as well as environmental factors [ 13 , 14 ]. Moreover, persistent/latent viral infections, such as human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) infections, have been evoked as possibly involved in the pathogenesis of SSc [ 13 , 15 , 16 ]. Both viruses belong to the Betaherpesvirinae subfamily, are genetically related, and have a worldwide distribution, sustaining primary infection usually early in life and then establishing a latent infection lifelong in the host.…”

“…Besides, HHV-6 was detected with high frequency in thyroid cells of subjects affected by Hashimoto’s autoimmune thyroiditis, a condition often preceding SSc disease [ 47 ], and its infection/reactivation has been associated to several autoimmune pathologies, including multiple sclerosis, Sjogren syndrome, rheumatoid arthritis, systemic lupus erythematosus, Purpura fulminans, severe autoimmune acquired protein S deficiency, and severe autoimmune hepatitis [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. More recently, HHV-6 was also detected with high frequency in the blood and skin tissue of SSc patients [ 15 ], who also exhibited an anti-U94 antibody titer significantly higher than controls, suggesting that SSc subjects may undergo multiple virus reactivations. Notably, HHV-6A, and not HHV-6B, was detected at the tissue level, confirming the different tropism and pathogenic action of the two species.…”

“…Notably, HHV-6A, and not HHV-6B, was detected at the tissue level, confirming the different tropism and pathogenic action of the two species. Furthermore, HHV-6A was shown to induce the expression of pro-fibrosis factors in infected vascular endothelial cells [ 15 ], suggesting its possible role in endothelial injury during SSc.…”