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Pregnant women with multiple sclerosis have lower expression levels of endogenous retroviruses

Dec 12, 2023 | Neuroscience (Featured)

Multiple sclerosis (MS) is a chronic inflammatory disease leading to demyelination and neurodegeneration of the central nervous system (CNS). It affects young people and women more than men. Pregnancy significantly improves the course of MS, and the beneficial effect of gestation on MS is highest in the third trimester. In this study, the researchers from Italy investigated the expression of human endogenous retroviruses (HERVs) in the placenta and peripheral blood of pregnant women diagnosed with MS, in healthy pregnant women, in the umbilical cord blood of their newborns, and in the blood of healthy non-pregnant women of childbearing age. They examined the transcription levels of the polymerase (pol) genes of the three HERV families, HERV-H, -K, and -W, as well as the envelope (env) genes of syncytin 1 (SYN1) and syncytin 2 (SYN2) and the multiple-sclerosis-associated retrovirus (MSRV). They also investigated tripartite motif 28 (TRIM28) and SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), regulators of the epigenetic mechanisms implicated in the activation of HERVs in MS.

The HERVs are relics of ancient infections, characterized by an RNA intermediate reverse-transcribed into a double-stranded DNA (dsDNA). This dsDNA, called a provirus, is capable of integrating into the host cell genome. Because of such endogenization and further fixation in the human population, HERVs have been vertically transmitted to offspring in a Mendelian fashion, constituting up to ~8% of the human genome. HERVs are stable components of the human transcriptome and exhibit differential expression across a diverse range of human tissues. During evolution, the accumulation of mutations blocked the capacity to produce infectious virions. However, some viral sequences are transcribed and encode proteins, such as syncytin 1 (SYN1) and syncytin 2 (SYN2). These proteins are involved in essential physiological functions, such as placental syncytiotrophoblast formation and maternal-fetal immunotolerance.

Epigenetic changes induce transitory or persistent variations in gene expression without altering the genetic code. Epigenetic mechanisms, like those regulated by TRIM 28 and SETDB1, are implicated in the activation of HERVs in MS. 

Several lines of research have demonstrated a link between aberrant expression of HERVs and autoimmune diseases. Numerous data indicate that HERV overexpression is involved in the initiation and maintenance of MS. Two highly homogeneous HERV-W-env proteins have been proposed as crucial elements, MSRV and SYN1. Previous studies have demonstrated that MSRV and SYN1 are upregulated in MS. In mice, MSRV-env induces autoimmunity to myelin proteins and causes experimental autoimmune encephalomyelitis, while SYN1 exerts robust immunosuppressive actions, contributing to the production of chemokines, cytokines, and C-reactive protein in glial cells.

 

About the study

The blood samples were collected from four groups of women, 20 pregnant women diagnosed with MS, 27 healthy pregnant women, 38 non-pregnant women of childbearing age, and another 20 non-pregnant women. The placental tissue samples were collected at delivery from 20 women diagnosed with MS and 27 healthy pregnant women.

The umbilical cord blood samples were also collected from the 22 neonates (6 males, 27%) born to mothers with MS and 27 neonates (10 males, 37%) born to healthy mothers.

The authors examined the transcription levels of the polymerase (pol) genes of the three HERV families, HERV-H, -K, and -W, as well as the envelope (env) genes of syncytin 1 (SYN1) and syncytin 2 (SYN2) and the multiple-sclerosis-associated retrovirus (MSRV). They also investigated tripartite motif 28 (TRIM28) and SET domain bifurcated histone lysine methyltransferase 1 (SETDB1).

The Results

The median age of the MS group was 33.9 (ranging from 31.4 to 37.7) and for healthy controls 39.1 (ranging from 33.2 to 41.3). The rate of preterm delivery (gestation < 37 weeks) was 25% in the MS group and 26% in the healthy controls.

Transcription levels in peripheral blood

The analysis of HERV transcription levels in the whole blood of mothers with MS, healthy mothers, and non-pregnant women of child-bearing age demonstrated significantly lower levels of HERV mRNA in pregnant women compared to nonpregnant women. In addition, nonpregnant women had significantly higher median transcription levels of TRIM28 and SETDB1 than both groups of mothers. 

Pregnant women with MS had significantly lower levels of HERV-K-pol, SYN2-env, MSRV-env, TRIM28, and SETDB1 compared to healthy pregnant women. 

Transcription levels in the placenta

Mothers affected by MS had significantly lower median transcription levels of the pol genes of HERV-H and HERV-K (but not for HERV-W), the env genes of SYN1, SYN2, MSRV, and TRIM28/ SETDB1 in the decidua basalis and chorion than healthy mothers. 

Transcription levels in umbilical cord blood of neonates

Neonates born to mothers with MS and those born to healthy mothers had comparable median transcriptional levels of every HERV tested, except HERV-W-pol which was significantly higher in the former. The median transcriptional levels of TRIM28 and SETDB1 were also comparable between the two groups of newborns.

Conclusion

This study has shown that gestation is characterized by lower expression levels of HERVs and TRIM28/SETDB1. The results showed significantly lower expression of HERVs and TRIM28/SETDB1 in pregnant women than in nonpregnant women at delivery. The impaired transactivation of HERVs was evident in the chorion and decidua basalis, and the peripheral blood of mothers with and without MS.

In addition, the expression of HERVs was reduced in pregnant women with MS compared to healthy pregnant women. However, reduced HERV activation in pregnant women seems to be a specific maternal feature, as it was absent from the umbilical cord blood of newborns.

The authors discussed the negative impact of estriol, progesterone, and corticosteroids on HERV expression. However, they emphasized that the different expression levels of HERVs and TRIM28/SETDB1 in the peripheral blood and placenta of mothers with MS compared to healthy mothers are difficult to explain by any hormone or other circulating factor.

The authors concluded that observed differences require further investigation. The cause of the impaired HERV transcription at delivery and its real clinical significance remains to be elucidated. Since pregnancy significantly improves the course of MS, the authors support the idea of innovative therapeutic interventions that should block HERV activation and control aberrant epigenetic pathways in patients with MS.

 

This article was published in Viruses.

 

 

Journal Reference

Tovo P-A, Marozio L, Abbona G, et al. Pregnancy Is Associated with Impaired Transcription of Human Endogenous Retroviruses and of TRIM28 and SETDB1, Particularly in Mothers Affected by Multiple Sclerosis. Viruses 2023, 15, 710.  https://doi.org/10.3390/v15030710

 

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