T-cell changes reflect pregnancy’s protective effects in MS

Changes in the gene activity within immune T-cells explain why women with multiple sclerosis (MS) improve during pregnancy, a study reports.

Gene activity changes during and after pregnancy were highly similar between MS patients and healthy women. Many of the genes whose activity was altered during pregnancy were associated with the sex hormone progesterone.

“What was possibly most striking is that we couldn’t find any real differences between the groups during pregnancy, as it seems that the immune system of a pregnant woman with MS looks roughly like that of a healthy pregnant woman,” Sandra Hellberg, PhD, the study’s co-first author and an assistant professor at Linköping University, Sweden, said in a university news release.

Further studies investigating the potential effect of progesterone “as add-on treatment in MS are highly needed,” the researchers wrote in “Prominent epigenetic and transcriptomic changes in CD4+ and CD8+ T cells during and after pregnancy in women with multiple sclerosis and controls,” which was published in the Journal of Neuroinflammation.

In MS, nerve function is impaired when the immune system mistakenly attacks the fatty insulation around nerve fibers, called the myelin sheath. As a result, nerves become inflamed and damaged, leading to neurological symptoms.

Women with MS show a marked decrease in disease activity during pregnancy, although symptoms worsen  after delivery.

In fact, “pregnancy is one of the most profound suppressors of disease activity, with a 70-80% reduction in relapse rate in the [third] trimester, thereby exceeding the effects of many currently available treatments,” the researchers wrote.

While the mechanisms behind this phenomenon are not clear, changes in the maternal immune system that are meant to tolerate the fetus, which also carries paternal genetic material, are thought to be a main contributing factor.

“A better understanding of how the modulation of the maternal immune system affects MS could provide insights into central disease mechanisms as well as facilitate the discovery of new treatment strategies,” the researchers wrote.

Because immune T-cells have been implicated in MS as key regulators of inflammation and nerve cell damage, the researchers focused on them as prime candidates for pregnancy-associated improvement.

Blood samples from 11 women with MS and seven unaffected women were collected before, during, and after pregnancy. Isolated T-cells were analyzed to identify the genes active during pregnancy and how they were switched on and off through epigenetic changes.

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Epigenetic changes are chemical modifications to genes that change their activity without changing their DNA sequence. The researchers focused on a type of epigenetic modification called DNA methylation that suppresses the activity of the target gene.

Results showed changes in gene activity and DNA methylation during and after pregnancy correlated well between patients and the unaffected women, who served as controls, indicating pregnancy induces similar effects on gene activity regardless of the presence of disease.

The greatest changes occurred during the third trimester and were reversed after delivery (post-partum) — “in agreement with the effect of pregnancy on the disease activity in MS,” the researchers wrote.

Many genes that were more active during pregnancy became less active post-partum and conversely, low-activity genes showed increased activity after pregnancy.

“We can see that the changes in the T cells mirror the amelioration in relapse frequency,” Hellberg said, adding “the biggest changes happen in the last third of pregnancy and this is where women with MS improve the most.”

“These changes are then reversed after pregnancy at the point in time when there is a temporary increase in disease activity,” Hellberg said. “It is important to stress that disease activity thereafter goes back to what it was prior to the pregnancy.”

Network analysis, a tool that identifies genes that interact extensively with the genes of interest, revealed that many genes whose activity reversed between the third trimester and post-partum were regulated by genes associated with progesterone, one of the main pregnancy hormones.

Progesterone has “pronounced anti-inflammatory properties,” the researchers wrote, noting its levels during and after pregnancy “coincide with the temporary improvement and worsening of disease activity in MS.”

“It has therefore been suggested to be one of the main drivers of the pregnancy-induced modulation of MS,” they said. “Our findings emphasize pregnancy as a potent modulator of central immune cells in the MS [development] and underscore the need for further studies investigating treatment strategies that can mimic the pregnancy milieu.”

“Such insights can be used to find alternative medication and find new biomarkers to be able to differentiate between subgroups of a disease,” added Mika Gustafsson, PhD, the study’s co-senior author and a professor of bioinformatics at Linköping. “We have used this strategy successfully for analysis in research into, for instance, allergy and multiple sclerosis.”

The research team is testing several hormones with the aim of mimicking the observed effects of pregnancy in T-cells and determine whether this can be a potential MS treatment strategy.