Pregnancy Is Associated with Impaired Transcription of Human Endogenous Retroviruses and of TRIM28 and SETDB1, Particularly in Mothers Affected by Multiple Sclerosis

Abstract

Accumulating evidence highlights the pathogenetic role of human endogenous retroviruses (HERVs) in eliciting and maintaining multiple sclerosis (MS). Epigenetic mechanisms, such as those regulated by TRIM 28 and SETDB1, are implicated in HERV activation and in neuroinflammatory disorders, including MS. Pregnancy markedly improves the course of MS, but no study explored the expressions of HERVs and of TRIM28 and SETDB1 during gestation. Using a polymerase chain reaction real-time Taqman amplification assay, we assessed and compared the transcriptional levels of pol genes of HERV-H, HERV-K, HERV-W; of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis associated retrovirus (MSRV); and of TRIM28 and SETDB1 in peripheral blood and placenta from 20 mothers affected by MS; from 27 healthy mothers, in cord blood from their neonates; and in blood from healthy women of child-bearing age. The HERV mRNA levels were significantly lower in pregnant than in nonpregnant women. Expressions of all HERVs were downregulated in the chorion and in the decidua basalis of MS mothers compared to healthy mothers. The former also showed lower mRNA levels of HERV-K-pol and of SYN1, SYN2, and MSRV in peripheral blood. Significantly lower expressions of TRIM28 and SETDB1 also emerged in pregnant vs. nonpregnant women and in blood, chorion, and decidua of mothers with MS vs. healthy mothers. In contrast, HERV and TRIM28/SETDB1 expressions were comparable between their neonates. These results show that gestation is characterized by impaired expressions of HERVs and TRIM28/SETDB1, particularly in mothers with MS. Given the beneficial effects of pregnancy on MS and the wealth of data suggesting the putative contribution of HERVs and epigenetic processes in the pathogenesis of the disease, our findings may further support innovative therapeutic interventions to block HERV activation and to control aberrant epigenetic pathways in MS-affected patients.

HERVs: Expression Control Mechanisms and Interactions in Diseases and Human Immunodeficiency Virus Infection

“…Strikingly, HERV dysregulated expression has been especially linked with neuro-inflammation and neuro-degeneration, with the most prominent examples of such implications being multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Regarding the role of HERVs in MS, HERV-W participation is highly considered a key player in the disease's development and progression, as HERV-W concentrations in MS patients demonstrate a parallel course to the disease in terms of its relapses and remissions [51], and the presence of increased HERV-W concentrations in the cerebrospinal fluid of MS patients early in their disease indicates a worse prognosis. Additionally, strong inter-viral interactions between HERV-W and the Epstein-Barr virus (EBV) are surmised for this effect, due to the strong correlations between the activation of HERV-W in vitro and in vivo [14].…”

“…Increased HERV-W and HERV-H during disease relapses, early detection of HERV-W in cerebrospinal fluid during early stages linked to worse prognosis [51,52] Amyotrophic Lateral Sclerosis HERV-K Env expression correlation to disease stage, severity, phenotype, and its link to neuroinflammation pathogenesis [54,55] Rheumatoid Arthritis…”