A Stranger to Oneself: The Mystery of Fetal Microchimerism

ABOVE: During pregnancy, fetal cells make their way into maternal tissues where they can remain for decades. ©istock, Fly View Productions

In 1893, Georg Schmorl, a pathologist at the University of Leipzig, made an astonishing discovery during his studies of eclampsia, a serious complication of pregnancy. At the time, eclampsia was one of the most common causes of maternal mortality; it was poorly understood and effective treatments were non-existent.¹

To investigate the etiology of the disease, Schmorl took on the somewhat macabre task of performing autopsies on 17 women who had died from eclampsia. Although he identified abnormalities in many organs, it was in the examination of the lungs that he observed something “very peculiar:” large, multinuclear cells similar to those found in the placenta, an organ derived from embryonic cells.²

More than a century later, modern scientific techniques have enabled researchers to confirm that fetal cells enter maternal circulation as well as various tissue types throughout the body. This phenomenon, the presence of a small number of cells that are genetically different from the rest of the organism, is now known as microchimerism.  Pregnancy is thought to be the most common cause of microchimerism, and just as the mother obtains cells from her fetus, maternal cells also make their way into fetal tissues, where they may impact development of the brain and immune system.^3,4 However, microchimerism can also result from blood transfusions, organ transplants, and sharing the womb with another fetus.

In humans, scientists have identified chimeric cells in many maternal organs, including the kidney, liver, spleen, lung, heart, and brain. Although their numbers steeply decline postpartum, women can harbor them for decades after they have given birth.^5,6 However, scientists understand very little about their roles in maternal health—are they helpful, harmful, or merely a byproduct of maternal-fetal exchange of substances across the placenta?

In part, this knowledge gap is due to the fact that there are generally very few of these cells and they are difficult to detect, said Petra Arck, a maternal and fetal immunity researcher at University Medical Center Hamburg-Eppendorf. This rarity hinders their study and fuels skepticism among the scientific community.

“There’s a disbelief that rare cells matter,” said Amy Boddy, who studies evolution, human health, and microchimerism at the University of California, Santa Barbara. 

Scientists also linked this lack of knowledge to the general dearth of research on women’s health, especially during pregnancy.  “Pregnancy is very often seen as [a time when] we need to protect women from research, but not through research,” said Arck. “Which is why pregnant women are often left out of clinical trials, or vaccine trials, or anything else. This is why the field is not as advanced as it could be.”

“We just don’t know very much about women’s health in general,” Boddy similarly noted. Despite these challenges, microchimerism researchers have soldiered on. “I think there’s some pretty good evidence and support to show that these aren't cells that are just a byproduct [of pregnancy],” said Boddy. “There's function here, and we should figure out what that function is.” 

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Studies in humans have hinted that chimeric cells may play an important role in maternal health or function as indicators of disease. For example, during pregnancy, a greater number of fetal-origin cells in maternal blood was associated with preeclampsia and severe hypertension.^7,8 

Chimeric cells may be relevant long after pregnancy as well. The presence of these cells in maternal scar tissue has led researchers to hypothesize that they may be involved in healing and tissue regeneration.⁹ They have been spotted in the thyroids of women with Hashimoto’s disease, in which the body produces autoantibodies against thyroid proteins, implicating chimeric cells in the development of autoimmune disease.¹⁰ They’ve turned up in cancers of the lung, skin, cervix, and breast; researchers have variously hypothesized that these cells may exert antitumor effects via immunosurveillance or tumorigenic effects by promoting angiogenesis or other forms of tissue growth.¹¹ 

However, these studies are largely correlational: while researchers have caught the chimeric cells at the scene of the crime, so to speak, it’s much more difficult to determine their roles in these processes. Are the cells contributing to pathology, or are they trafficking to the site to fight disease, or have they simply been caught in the wrong place at the wrong time?

The answer is likely complicated: Anne Cathrine Staff, a maternal-fetal medicine researcher at Oslo University Hospital, hypothesizes that the number or characteristics of fetal chimeric cells both influences and is influenced by pathological processes. “We have to be really open when we are thinking about the framework for this instead of thinking in black and white,” she said. 

Figuring this out will require careful and methodical research to fill in the gaps left by earlier piecemeal efforts by scientists who identified these cells in various types of diseased tissue but were unable to investigate further due to the technological limitations of the time. “We need to get into the basics of microchimerism biology,” said Thomas Kroneis, who studies rare cells, including microchimeric cells, at the Medical University of Graz. Now, Kroneis and many other researchers are adopting newer technologies to revisit fundamental questions about the locations and identities of these not-quite-self cells, hoping to build a foundation of knowledge that will enable future mechanistic studies of their roles in health and disease processes.

The Y in the Ointment

In the absence of controlled, and unethical, breeding trials, human microchimerism is tricky to investigate. Historically, researchers have identified chimeric cells in maternal tissues using fluorescence in situ hybridization to label any errant Y chromosomes in women who had given birth to sons. However, this technique has some important limitations. First, researchers cannot use it to study chimerism in instances where children are female. This is problematic as Staff’s research suggests that the quantity of chimeric cells is greater when the fetus is female, indicating that differences in fetal sex may affect processes related to microchimerism.⁸

Perhaps more concerningly, this technique resulted in the puzzling finding that some women who had never given birth to sons still had male cells.¹² In one study, researchers found that the prevalence of male microchimerism was not significantly different in women with and without sons, nor did it seem to be affected by having a male twin, although it trended toward increased prevalence in women with older brothers.¹³

“The early studies looked for the Y chromosome, because that was the technology that was available,” said Boddy. “You could determine that those cells weren't from the mom, but you really couldn't determine if they were from the baby. We don’t know whose cells they are.” 

With technological advancements, research has become more sophisticated. “It's pretty standard now to genotype the mother and the baby, and then look for markers that don't overlap,” said Boddy. “We typically look at HLA [human leukocyte antigen], because we know that’s a variable region in the genome. Basically, we look for a unique baby ‘fingerprint,’ a region of DNA that the baby has that the mother doesn't.” This enables researchers to identify cells that don’t belong, but also be reasonably sure that they are in fact from the fetus, opening the door for a new generation of research into the complexities of microchimerism.

“It’s a super exciting time to be studying these cells because the technology is there,” said Boddy. 

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Everything Affects Everything: Microchimerism and the Immune System

Using these newer genotyping strategies in combination with animal studies, researchers are finally beginning to unravel the mysteries of fetal microchimerism, elucidating the complex ways that these cells interact with the mother’s immune system and the potential implications of this. For example, researchers demonstrated that in mice, fetal microchimeric cells are important to maintain regulatory T cell populations that help mothers tolerate the fetus.¹⁴ 

The more researchers learn, the more they come to appreciate just how complex these interactions truly are. From the early days of microchimerism research, scientists have suspected that whether chimeric cells help or harm the mother is dependent on disease context. Even within a single disease, however, the effects of chimeric cells are likely nuanced, and could be influenced by the genetic makeup of both the mother and her baby.

For example, autoimmunity researchers have identified certain HLA alleles that protect against rheumatoid arthritis (RA)—these alleles encode the five amino acid sequence ‘DERAA’. While DERAA is protective when the mother carries it, it increases the mother’s risk when carried by the fetus: among DERAA-negative women, having a DERAA-positive child increased the risk that they would later develop RA by about 70 percent.¹⁵

To determine whether fetal microchimeric cells were involved, a research group led by J. Lee Nelson at the Fred Hutch Cancer Center analyzed blood from DERAA-negative women with and without RA.¹⁶ They found DERAA-positive chimeric cells in 53 percent of women with RA, but in only six percent of healthy women. To investigate potential mechanisms, they cultured the women’s blood immune cells with cell lines that were either DERAA-negative or -positive. The women’s CD4+ T cells, which are important regulators of autoimmunity, displayed more markers of activation in the presence of the DERAA-positive cells, providing a possible mechanism by which HLA mismatches between mother and baby could contribute to autoimmunity.

“It’s so complicated, because it’s not just about the presence of the fetal cells in maternal tissues,” remarked Boddy. “It’s the genomic context that matters.”

In support of this idea, the immunogenetic similarity between mother and fetus may also play an important role in determining the extent to which fetal cells enter or persist in maternal circulation, although this research is still preliminary.¹⁷ 

If microchimerism affects the mother’s immune regulation, this could be relevant for a host of other diseases as well. Immune and inflammatory processes underlie diseases that affect essentially every organ system, including cardiovascular disease, which is the top killer of women in many countries. This has prompted Staff, whose work revealed a link between fetal microchimerism and severe hypertension during pregnancy, to investigate the links between microchimerism, inflammatory processes, and cardiovascular function.⁸ Since pregnancy-related hypertension is associated with a greater risk of subsequent cardiovascular disease, determining the nature of this connection—and how chimeric cells might be involved—could inform interventions that would benefit women not only during pregnancy but also for the remainder of their lives.¹⁸ 

Boddy and Kroneis are also interested in answering fundamental questions about the interactions of microchimerism and immunogenetics as part of the Microchimerism, Human Health and Evolution Project, which they cofounded. “One of our goals is to create a microchimerism atlas in a mouse model to map where these cells are going,” said Boddy. “Are they wandering aimlessly, or does it seem like they are directed towards certain tissues?”

“This is one of the most important aspects,” said Kroneis. “Instead of sampling an organ or sampling blood, we are establishing a mouse model where we will screen whole individuals using light sheet microscopy.” 

They will start by mapping these cells in inbred mouse strains—in which the mother and her pups would be genetically identical. “In this case, we would expect the fetal cells to just go everywhere because they will be ‘unseen’ [by the mother’s immune system],” said Kroneis. Then, researchers can cross breed different mouse strains to determine how the differences between maternal and fetal immune systems could influence the distributions of microchimeric cells, which could shed light the role of these cells in the development of immunological tolerance.

Microchimerism also provides an opportunity for scientists to answer basic questions about human immunology. “I see this as something that can help us to understand the big picture of immunology,” said Arck. “Pregnancy itself is an amazing natural experiment of immune tolerance.” Improving scientific understanding of fetal microchimerism could have important implications for the entire population, not just individuals who experience pregnancy. If researchers can figure out how the mother’s immune system establishes long-term tolerance of these non-self cells, for example, this might provide new therapeutic strategies to help the host immune system tolerate transplanted organs.

“I don't want to get into philosophy,” said Kroneis, “but this makes us think about the meaning of ‘self.’ Do we need to redefine ‘self’—in terms of the immune system—as being more than just the individual?” 

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