A molecule produced during pregnancy that controls immune cells could be linked to spontaneous abortions and preterm births, according to a study published today in eLife.
The findings could help pave the way for treatments to prevent the elevated inflammation and influx of immune cells into the womb linked to pregnancy complications.
“The evolutionary history of cell types, tissues and organ systems can help to explain the function or dysfunction of those tissues in health and disease,” explains lead author Mirna Marinić, Postdoctoral Scholar at the Department of Organismal Biology and Anatomy, University of Chicago, US. “We proposed that a mechanistic understanding of how pregnancy originated and diverged within and between species could provide unique clues into the origins of pregnancy disorders.”
To find the evolutionary information underlying pregnancy disorders, the researchers compared the activity of 21.750 genes between 27 different species, including 15 mammals with placentas (called Eutherian mammals), three marsupials, a platypus, two birds, five lizards and one amphibian.
Among those genes, one called HAND2 stood out, because it plays an essential role in facilitating the anti-oestrogen effect of the hormone progesterone. This oestrogen ‘silencing’ is essential for successful implantation of a fertilised egg into the womb. To see if HAND2 had evolved for this purpose, the team compared the activity levels of HAND2 in an opossum, which does not have the implantation stage in its pregnancy. As expected, levels of HAND2 decreased during pregnancy in the opossum, suggesting that the oestrogen silencing seen in humans does not occur. Measurements of oestrogen receptor activity in the opossum also confirmed that oestrogen was still active.
The team next looked at how the activity of HAND2 was controlled, and found that the molecule might be controlled by progesterone. Given that progesterone levels fluctuate throughout the menstrual cycle and pregnancy, they were intrigued to see if HAND2 levels did the same. Using published gene expression data from the womb and placenta, they found that HAND2 increased through the early and middle phase of the menstrual cycle, peaking in the late secretory phase. By contrast, in pregnancy, HAND2 decreases from the first trimester to when the baby reaches term. HAND2 was also dysregulated in the womb lining of women whose fertilised egg failed to implant successfully, and in those who had recurrent spontaneous abortion.
To find out how HAND2 might cause these complications, they looked at the genes it controls. They found that many of the downstream effects of HAND2 related to inflammation and the movement of immune cells. Specifically, one of the genes affected by faulty HAND2 is the immune molecule interleukin-15 (IL-15). This molecule increased during the menstrual cycle, and decreased during pregnancy, in a way that mirrored HAND2 activity. It was also found to be dysregulated in women with implantation failure. Taken together, the results suggest that HAND2 might control immune cells and inflammation, via IL-15, at different stages of pregnancy.
“We have shown that HAND2 has evolved to be expressed in the womb of mammals with placentas, to coincide with the evolution of suppressed oestrogen signalling which allows a fertilised egg to be implanted,” concludes senior author Vincent Lynch, Assistant Professor at the Department of Biological Sciences, University at Buffalo, New York, US. “Our results also suggest that HAND2 may help to control pregnancy length by promoting a progesterone-rich environment and influencing immune cells as the baby reaches term. The results provide important insights into the mechanisms that contribute to complications during pregnancy, which we can now build on further.”
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This study will be published as part of eLife’s Special Issue on evolutionary medicine. For more information, see https://elifesciences.org/inside-elife/bb34a238/special-issue-call-for-papers-in-evolutionary-medicine.
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