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

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.