The true value of a human being is determined primarily by the measure and the sense in which he has attained liberation from the self.

Albert Einstein

As of late, I’ve been scrubbing up on an intriguing phenomenon called microchimerism, or more simply put: the hosting of small amounts of foreign cells inside one’s body. Though it may sound contradictory to what we know about our immune system – namely, that it’s our body’s defense mechanism against unwelcome “visitors” – microchimerism is actually quite common in humans. In its most recurrent form, microchimerism is what happens during gestation, when mother and fetus exchange cells via the umbilical cord. But more surprisingly, some groundbreaking studies have found that these cells may persist for many decades and can take root all over the body, affecting our immune system and health.

Successful pregnancies have been somewhat of an enigma for immunologists. Until recently, it was thought that the immune system is suppressed during pregnancy, so as to accept a fetus that has inherited half of its genetic material from the father. But it appears that the immune system is actually very active during pregnancy. Mother and child somehow develop a mutual “tolerance” that allows the fetus to develop in the womb, and that may last for a lifetime – although mothers and their teenage children may want to dispute this…

Recent studies have found that fetal cells (cells from the baby that keep clinging on to mom) may play an active role in the development of certain autoimmune diseases in the mother, but also in keeping breast cancer away. Similarly, maternal cells (cells from the mother that don’t want to part from the child) may also contribute to particular autoimmune diseases in the child, while on the bright side, could help repair damaged organs.

lab
lab at the Hematology Department of Erasmus Medical Center Rotterdam (photo: Marijke de Jong)

Autoimmune diseases occur when the immune system turns against the body’s own cells. Two decades ago, in a true eureka moment, one researcher observed that the symptoms are very similar to those in patients who suffer from transplant rejection after receiving a donor organ. And now, there is growing evidence that this is not a failing of the immune system, but rather a (proper) immune response against foreign cells residing inside the body – the fetal or maternal cells that were left behind during pregnancy.

But microchimerism does not only arise from pregnancies. It also happens when patients receive an organ, tissue or stem cells from a donor[1]. In fact, the engraftment of a donor transplant in a patient is reminiscent of that of a fetus developing inside the mother’s womb. Both are foreign to their “host”, yet if all ends well, are accepted and the reason for much happiness to their recipients!

Researchers are now pondering what mechanism enables so many women to deliver healthy babies, while many transplant patients suffer from severe immune responses which may end up being fatal. One assumption is that sexual contact prior to a pregnancy seems to condition the mother’s immune system to recognize and accept the father’s cells so that it won’t reject the fetus when conception occurs. By studying pregnancies, transplantation doctors hope to find clues for reducing complications in transplant patients. Likewise, gynecologists are turning to transplantation science for answers to what goes wrong when pregnancies end prematurely.

three pioneers in HLA research
Old photo of three pioneers in the research on HLA: Prof. Jon van Rood (Leiden University Medical Center), Prof. Rose Payne (Stanford University Medical Center), Prof. Paul Terasaki (UCLA) (photo: Jon van Rood).

The discovery in the 1950s and 1960s of the HLA (human leukocyte antigens – also known as tissue groups) system, the role it plays in transplant rejections and the observation that a mother develops immunity against the DNA that a fetus has received from the father (IPA – inherited paternal antigens), meant a major breakthrough in making transplantations safer and more successful. HLA is a protein that can be found on most of the body’s cells. It helps the immune system in identifying cells as “foreign” or “self” and whether to reject or accept them.

A mismatch in the HLA types of donor and patient can cause transplant rejection. But whereas a slight deviation in HLA type may not impede the successful engraftment of a donor organ, a good match is crucial when looking for a stem cell donor. In case of stem cell transplantation, a match of ten HLA is considered ideal. If the HLA type of the patient does not resemble that of the stem cell donor, the donor cells will lash out at the “foreign” host (also known as GVHD – Graft versus Host Disease).

chance of donor match in siblings
infographic: Soon-ok Heijmans

Since half of the HLA is inherited from the mother and half from the father, siblings are a patient’s best bet for a donor. But still, chances of a match are just 25 percent. Chances of an unrelated donor match are even slimmer, as there are over one hundred million HLA types yet less than 26 million stem cell donors registered worldwide.

On a more positive note though, this maddening diversity of the HLA system makes that we all respond differently to infections. This reduces the risk of total extinction of the human race in case a pandemic disease breaks out. And as bacteria, viruses, et cetera are different in different parts of the world, different ethnic groups carry different HLA types. This means that a patient has the best chance of finding a match in a donor of the same ethnic background.

plasma and stem cells
plasma (left) and stem cells collected from my sister the day before my stem cell transplantation (photo: Soon-ok Heijmans)

The advent of stem cell transplantation for patients with malignant blood disorders such as leukemia, prompted a pioneering transplantation surgeon two decades ago to observe that organ and stem cell transplantations offer mirror images of the same immune response. In patients who receive donor organs you don’t want an immune response, since it can lead to rejection of the organ or even the patient’s death. But in stem cell transplantation you do want an immune response, since this will attack the cancer cells and, hopefully, cure the patient.

However, this immune response has to be a controlled one, as donor cells should not go after the patient’s healthy cells in the process. So if the donor’s HLA type closely resembles that of the patient, the risk of Graft versus Host Disease will be greatly reduced. A stem cell transplant allows healthy donor cells to take over the patient’s failing immune system – which has already been destroyed by chemotherapy and radiation– and provide new ammunition to fight the cancer cells.

IPA-NIMA
(infographic: Soon-ok Heijmans)

Transplantation doctors thus need to tread very carefully to find the right balance. The “memory” of the “tolerance” that mother and child develop for each other during pregnancy – and that researchers got a first glimpse of more than half a century ago – provides an insight into how to get that balance right[2]. Because mother and fetus have learned to recognize and accept cells that are partly theirs – their immune system may have already been “primed” to accommodate cells that are similar but carry some genetic differences, such as the donor cells.

Immune cells that the mother has developed against the IPA of the fetus can be found in cord blood. Some hospitals now use these cells to treat leukemia patients when no matching stem cell donor can be found. And so, the humble umbilical cord not only nurtures new life in the womb, but also in patients who might otherwise die. Cord blood transplantation provides new hope, especially for patients of non-Caucasian descent – who are faced with a dearth of potential donors[3] – and patients of mixed descent – whose HLA is more mixed, making it extremely difficult to find a donor with that same rare HLA combination.

cord blood units Tokyo Cord Blood Bank
Staff at Tokyo Cord Blood Bank preparing cord blood units for transplantation (photo: Soon-ok Heijmans)

Currently, tests are under way to grow cells from cord blood in the lab, to make them more widely available to patients[4]. Some researchers are exploring tests to detect microchimerism, as a non-invasive indicator for transplant rejection, which may help in further fine-tuning the all critical donor match.

Others are investigating whether the “memory” of the “tolerance” that mother and child have developed in the womb can also be used to treat other types of cancer, although one can doubt this would be a “treat” for the cancer cells… Cancer cells are basically cells gone wild, which have developed after several mutations in their DNA. Their HLA differs from that of normal cells. Some researchers think that fetal cells may be better poised at “sniffing out” these abnormal cells at a much earlier phase, alerting the immune system before they can develop into full-blown cancers.

In another example, fetal and maternal cells have been found in patients with autoimmune diseases. Researchers hypothesize that these are – or at least act like – stem cells, since they had dispersed and integrated into organs, where they appeared to be restoring damaged tissue. The big question now is whether these cells can also be grown in the lab to develop all kinds of specialized cells that can be used in therapies for a host of diseases, either inhibiting the growth of malignant cells or eliminating them, or helping in restoring damaged tissues.

However, all of this may just be the tip of the iceberg, as researchers have only just begun to grasp the scope of the possible implications and applications of microchimerism. The incredibly complex relation between “self” and “foreign”, “acceptance” and “rejection”, “immune memory” and “tolerance”, and the role that microchimerism plays in all of this is challenging some long held notions in medicine, and has opened up a Pandora box of new mysteries that researchers are now trying to solve.

love my lab
One researcher surely loves his work (photo: Marijke de Jong)

And yet again, there is more to the story.

For one, researchers have found that fetal cells may survive for many decades, well into old age. And it appears that a pregnant woman not only gets affected by cells from her baby, but also by cells she inherited from her mother. Another surprising finding is the discovery of male cells in women who never gave birth to sons. These findings suggest that foreign cells may have also been bequeathed by a plethora of other relatives: a fraternal twin who was “absorbed” by the fetus, a pregnancy that never materialized, an older sibling, or even a maternal aunt or uncle who is older than the mother. There are even suggestions that cells may have been left by sex partners, although there is no evidence for this as of yet.

Maybe even more shocking is the discovery of male cells in women’s breasts and brains. This not only challenges our notion of what is male and female – and more generally – who we (think) we are, but also defies the belief that the brain barrier is impenetrable. However, the fact that male cells were discovered in women’s brains does not mean that they may not carry cells from female relatives too. It’s just that it’s much easier to detect the Y chromosome that is unique to men in a sea of X chromosomes that both men and women carry.

The picture becomes even more confounding when we look at two other phenomenons that are closely related to microchimerism: chimerism and mosaicism. Chimerism is microchimerism on a larger scale. Chimerism could lead to unexpected problems, as an American woman called Lydia Fairchild experienced. Fairchild nearly had her children taken away from her, when a standard maternity test to apply for welfare assistance showed that she could not possibly be the mother. In the end, it turned out that she was chimeric, and that the DNA of her blood differed from that of her cervix, which – fortunately – did match her children’s DNA.

lab
lab at the Hematology Department of Erasmus Medical Center Rotterdam (photo: Marijke de Jong)

In contrast to (micro)chimeric persons – who harbor cells from other people – mosaic persons start out with their own DNA, which changes over time in some of the cells. As a result, the DNA in neighboring cells will look slightly different, creating a mosaic like pattern. An example of mosaicism can be found in people who are born with cells carrying XX chromosomes as well as cells with XY chromosomes. A condition that may not always be directly visible from the outside, but that may become an issue when the outside world wants to label them as “male” or “female”.

Though most people who are (micro)chimeric or mosaic will probably remain happily unknowing about this for the rest of their life, it does give food for thought on some ethical and legal issues. An example could be forensic testing of chimeric crime suspects or gender testing of female athletes, but also surrogacy and the new UK law that allows for the DNA of a father and mother to be combined with the healthy mitochondria of a female donor to prevent genetic diseases from being passed down from mother to child.

But if all of this seems quite complicated, the full picture is even far more complex. Each answer seems to raise many new questions, and maybe by the time you have read this article, some of the information may have already become outdated. At present, more research is needed to find definitive answers that can be translated into clinical applications, and it should not be surprising if more surprising results pop up in due course.

research continues
And the research continues… (photo: Marijke de Jong)

Concluding a long and complex story, we may be more than just ourselves, maybe literally carrying our family with us. Whether we find this comforting or unnerving, it surely does put the way we think about ourselves and about our relationships in a different perspective. Perhaps it’s no coincidence that the people who can hurt or love us most are our kin. It’s just a reflection of what we have experienced in the womb – sometimes lashing out at each other, and at other times providing healing and protection. And for always, connected through the traces we have left.

But perhaps the most important lesson that we can draw from the interaction between microchimerism and our immune system is to remain open for what we don’t know. To keep learning and expanding ourselves. And if we make an effort to get to know others, we will find enough room in our minds and hearts to allow those whom we considered as “outsiders” in, and to see them as a part of ourselves.

Soon-ok Heijmans

blood sisters
blood sisters (drawing: Soon-ok Heijmans)

[1] For clarity’s sake, in this article I use the term stem cell transplantation (SCT) to mean both bone marrow transplantation (BMT) and SCT, as the difference is just in how and from where the stem cells are collected. In BMT – which was developed much earlier than SCT – these stem cells are extracted by surgical procedure under general anesthesia. An SCT is less invasive. The stem cells are “harvested” from the blood – more similar to blood donation – after they are induced into the bloodstream. Doctors may still prefer BMT over SCT, such as when the donor’s veins are hard to access or when the stem cells cannot be induced properly into the bloodstream.

Unlike other cells in the body, stem cells have the ability to divide and develop into all kinds of cells with one specific function. The stem cells that are referred to in this article are the blood stem cells. Blood stem cells reside in the bone marrow – the spongy lining inside our bones. They have the amazing ability to churn out 2.4 million new blood cells each second: red blood cells that transport oxygen in the body, platelets that help in healing wounds, and – very important for a SCT – white blood cells that fight infections. By producing exactly those cells that the body needs to repair and replace damaged or faulty cells, they play a vital role in keeping us up and running.

[2] Just as the mother develops immunity against the earlier mentioned IPA (inherited paternal antigens) of the fetus, the child develops immunity against the cells that it has not inherited from the mother (NIMA – non-inherited maternal antigens). As of yet, not much is known about the role and impact of NIMA.

nitrogen tank with cord blood
nitrogen tank with cord blood units at Tokyo Cord Blood Bank (photo: Soon-ok Heijmans)

[3] Most registered donors can be found in North America and Europe, which have the longest history – as well as the funding, facilities, infrastructure, and legal framework – for stem cell transplantation. SCT’s are very expensive because patients need to be hospitalized in an isolation room for months, and then there are additional costs for testing, preparing, storing and transporting the cells – which may have to be shipped in from overseas if no suitable donor can be found domestically. Unfortunately – due to a lack of awareness and cultural sensitivities – ethnic minorities are still under-represented in stem cell donor registries.

[4] One cord blood unit is usually insufficient to treat an adult patient. In most cases two units are needed. The storage of cord blood is very costly, as the cord blood units have to be frozen and may have to be preserved for several years in nitrogen tanks in a climate controlled, sterile environment.

(main image: drawing of the blood circulation of a fetus in an old Dutch medical handbook)

A list of publications that were consulted for this article can be found at: https://theliminallifeblog.wordpress.com/2016/02/15/a-primer-on-microchimerism/

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