Expression pattern of several miRNAs in SS tissue parallels the pattern generated when dermal fibroblasts and endothelial cells are infected by HHV-6A and CMV.
A recent review article summarizes evidence that two betaherpesviruses—HHV-6A and human cytomegalovirus (CMV)—may contribute to the pathogenesis of the autoimmune disease known as systemic sclerosis (SSc) or scleroderma.
SSc typically affects the skin and several internal organs, including the lungs, heart, esophagus, low gastrointestinal tract, and kidneys. In all these tissues, there is diffuse fibrosis, characterized by an extracellular matrix composed of collagen, elastin and fibronectin.
Previous research has linked both HHV-6 and CMV to SSc. HHV-6A nucleic acid and antigens have been found more often both in the tissue and in blood, and there is an unusually marked immune response toward viral antigens, particularly HHV-6-U94 and UCMV-UL94—compared to antibodies to those antigens in the healthy population.
The diseased tissues of people with SSc reveal dysregulated levels of microRNA (miRNA) expression. In particular, there is a significant downregulation of let-7 family miRNAs, particularly let-7a. The let-7 family miRNAs are highly conserved across animal species and were the first miRNAs identified in humans.
The review summarizes recent studies finding that in vitro infection of primary human dermal fibroblasts (cells central to SSc pathology) by HHV-6A alone, and by HCMV alone, induces a miRNA expression pattern that is associated with a rapid and sustained up-modulation of several profibrotic and pro-apoptotic factors. This alteration in miRNA expression patterns is even more marked by HHV-6A/CMV coinfection, and continued for 14 days.
The miRNAs that were upregulated by both viruses were miR-7, miR-let-7g, miR-92a. All these miRNAs are upregulated in SSc dermal fibroblasts, and are associated with fibrogenesis, excessive collagen accumulation and pulmonary involvement. HHV-6A and CMV infection also down-regulated several miRNAs that are downregulated in SSc tissue, including miR-let-7a, miR-10a, and miR-193.
This review provides some evidence linking both HHV-6A and CMV—two human betaherpesviruses—to the pathogenesis of systemic sclerosis. While the evidence linking HHV-6A to other diseases—including primary infertility, mesial temporal epilepsy and multiple sclerosis—is stronger than the evidence linking the virus to systemic sclerosis, it is sufficient to justify considerably more research.
Read the full article: Soffritti 2024