BIRMINGHAM, Ala. (WBRC) – Researchers at the University of Alabama at Birmingham (UAB) have identified an immune pathway that might help explain why some women develop a serious pregnancy complication.
The research, led by transplant surgeon Dr. Paige Porrett, found that an immune switch called NFAT helps uterine natural killer cells, known as uNK cells, remain in the uterus, becoming “tissue-resident.”
Those cells are critical for the development of a healthy placenta, a process called placentation.
Dr. Porrett said abnormalities in placentation can cause preeclampsia, a condition that impacts between 5-8% of all births in the United States.
She and her team compared uterine tissue samples of women who received uterine transplants against healthy control volunteer samples and found the transplant recipients had lower levels of uNK cells.
“We thought, ‘Aha, we’re really onto something potentially here,’ because no one has yet been able to, to our knowledge, establish the link that some of the pathology that we see in the animal models when these immune cells are reduced would actually also be driving potentially pregnancy complications in humans. So that was the first time we got really super excited about the finding.”
The next step was to identify why the uNK cells were lower in transplant recipients. To find that answer, the team used single-RNA sequencing.
“For each individual cell, we’re actually able to break it open and then label at the molecular level each of the individual RNA transcripts that’s inside the cell,” said Dr. Porrett.
That process results in libraries of RNA transcripts that are then sequenced and analyzed using computational algorithms.
“A key aspect of this work is that we compared these, all these millions of transcripts against millions of transcripts from healthy control volunteer samples. And so it’s really in that comparison between the transplant and the control that we were able to detect the differences which showcased to us that molecular pathway, the molecular pathways that were impacted potentially by the drug.”
That drug is called tacrolimus (TAC), an immunosuppressant that is commonly prescribed to transplant recipients.
“We use this drug TAC to block this molecule NFAT from actually going from inside one compartment of the cell into the nucleus. And what NFAT will do in an activated T cell is actually turn on a bunch of genes that will make a T cell essentially become activated and potentially harm the tissue that it’s in in the course of a transplant. And the reason I share all this is because this molecule NFAT has been appreciated to be really important in a T cell, a different type of immune cell,” explained Dr. Porrett.
“What we discovered, and this was, I call it again, unexpected, is that this molecule NFAT participates in uNK cells in their biology. And the thing that NFAT does in uNK cells apparently is to provide that signal that the cell needs to actually stay put in the tissue.”
She said it’s a “completely different biologic function” than what NFAT does in T cells.
“This could be potentially a pathway, or NFAT could be a molecule that impacts the residence of a lot of immune cells, too, even inclusive of T-cells so that information, while it might not be as important necessarily to explain why we have pregnancy complications, right, but this pathway, knowing it’s important in actually immune cell residence could be really important to a lot of other fields.”
She continued, “If you want to understand for example, how a T cell gets into the liver to fight an infection there, this molecule could be important potentially in helping that T cell stay put to fight an infection there.”
Dr. Porrett said these discoveries allow researchers to investigate more specific questions, and could ultimately lead to healthier outcomes for pregnant women, and a better understanding for how the immune system functions.
“This improvement in our knowledge will allow us to build better tests and better ways of detecting… to personalize the medical care we provide, right, so that we can identify patients at risk and then ultimately change the plan… so that we can decrease that risk and get them a better outcome,” she said.
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