As Many Exceptions As Rules: You And Mom Are Never Apart

Biology concepts – chimeras, microchimerism, autoimmunity, tolerance, self, rejection, graft vs. host disease, HLA, Rh factor

Medicine can now accomplish many types of transplants –

face, hand, multiple organs. What we can’t do yet is a head

transplant, although they speculated on it in this 1962 movie,

The Brain That Wouldn’t Die. A scientist goes looking for an

appropriate body for his girlfriend’s head.

Modern medicine and science have developed treatments that we would have thought impossible 40-50 years ago. Gene therapies, gamma knife radiation, and organ transplants are just a few amazing advances. Need a new kidney? That’s routine nowadays. How about a liver and a set of lungs – we can do that too. We can grow you a new ear on your back!

We all know about the dangers of organ transplant; the replacement organ isn’t yours, so your body might try to destroy it (immune rejection). Your cells have human leukocyte antigen (HLA) proteins in a pattern that identifies you; cells with a different pattern of HLAs is non-self and will be attacked by your immune system (see this post).

In order to reduce the chance of organ rejection, doctors look for a donor that has similar HLAs to the recipient. You have six different HLA proteins on each cell (A, B, C, DP, DQ, DR). For just A, B, and C, you have over 25 billion possible combinations, although some are rare and some are much more common.

The take home message is that the closer the match between donor and recipient, the less chance there will be of rejection. Over time, science has found out that A, B and DR are the most important for organ rejection – of course you have two alleles of each, one from mom and one from dad, so it can still be tough to find a six antigen match.

For two siblings, there is a 50% chance that they will have three alleles (antigens) match, and a 25% chance that all or none will match. For a non-related donor, a six-antigen match is about 1 in 100,000. Of course, nothing is guaranteed; six antigen matches have been rejected, while some zero antigen matches have worked out perfectly.

Graft versus host disease is a bad way to go. There are cramps,

vomiting diarrhea, liver problems, rashes, itching, breathing

problems, chronic pain. It is basically rejection that just keeps

going. The chances go way up if the donor and recipient are not

related. Here we see the tissue injury and inflammation

in the skin.

Let’s consider the other direction – what if the transplant rejects the recipient? This can be a deadly problem call graft-versus host disease (GVHD). The immune cells remaining in the donated organ attack the recipient. This is more probable in bone marrow transplants, because you are delivering a new immune system to a recipient. GVHD is a bad way to go.

Now let’s try to mesh our discussion of rejection and GVHD with what we talked about last week – some dizygotic twins carry cells from each other; they are chimerics. Dizygotic (DZ) twins are no more related to each other than any two siblings, and they often can’t donate organs for one another. So, why doesn't a chimeric person reject some of his/her own cells, just like in rejection or GVHD?

We talked about many cases of people with different genetic profile cells in their body – this would mean they had different HLA profiles as well, yet they're not rejecting each other. There must be more to it.

Just when does a body decides what is self and what is non-self is important in why chimerics don’t attack, or are attacked by, their twin’s cells. The fetus starts to develop T lymphocytes around 14 weeks of gestation and this is much after the formation of chimeras.

The immune system develops tolerance to self over time, and a chimera has different cells before tolerance is determined. The developing fetus sees the chimeric cells as self. But can you think of a situation where the organism already has decided what is self and then cells with a different profile show up? It’s a lot like a transplant, but it’s naturally occurring. The answer - pregnancy.

Gestational immune tolerance is where the mother’s body

leaves her slightly immunosuppressed in order to protect the

baby. That is completely different from my intolerance for bad

portraiture. Does he really need to be shirtless? Did this

picture need to be taken at all?

Why doesn’t a mother see her fetus, who has a different genetic profile, as non-self and attack the baby? Well, in some cases she does – it is most often when she is Rh- and the baby is Rh+. Rh is a blood cell antigen like A, B, and O. If you don’t have the Rh antigen, you likely make anti-Rh antibody. If the blood of an Rh+ baby mixes with mom’s (birth canal during delivery, miscarriage, injury), then mom’s anti-Rh could attack the baby’s blood.

This is especially dangerous in the next pregnancy, if that next baby is also Rh+. The mom has been sensitized and antibodies will cross the placenta and attack the baby’s RBCs. Mom is given RhIg (anti-anti-Rh antibodies; think about it) to bind up her anti-Rh antibodies and keep them from attacking the baby. Yes, antibodies cross the placenta; that’s how babies have a bit of immunity immediately after they are born. They start to make their own antibodies about 3-6 months after delivery (except IgM, they make a little of this in the womb).

Most people believe that the placenta is a barrier that keeps all the mom’s immune cells (not just the Rh recognizing ones) from attacking the genetically different baby. And to a certain extent this is correct. The placenta is an immune privileged site. Most things don’t get through and this protects the baby from the mom’s immune system. It works well enough that some women can choose to be a gestational surrogate – an egg from a different mom, fertilized with a male gamete, is transferred to her and she carries the baby to delivery. The baby is nothing like her genetically, but the pregnancy most often goes off without a hitch.

The legal issues in surrogacy are many, mostly because money

and kids are involved. If the surrogate uses her own eggs it is

called natural surrogacy, but if a donor egg or the prospective

mother’s egg is used, it’s called gestational surrogacy,

But if we say most cells don’t traffic through the placenta, then some do, right? And this is our “exception that isn’t an exception” for today – microchimerism.

In just about every pregnancy (maybe every one) some of mom’s cells end up n the fetus and some of the fetus’ cells end up in mom. The number is low, less than 1% of the baby’s cells will be genetically mom’s, so it is called microchimerism.

Some of the cells that get through are likely to be stem cells, and since we can find them in people many years later, they must take up residence and live there – this isn’t like getting a blood transfusion and having a few cells that are different genetically for just a short time. The cells can live there at least 40 years (probably longer). There are different types of microchimerism, depending on where the cells come from and where they end up, and they might have a big impact on health. Let’s look at the types –

Fetal Cell Microchimerism (FCM) – It is a well known fact that women who give birth are less likely to have breast cancer. The reasons for this are a bit up in the air, but one hypothesis is that reproductive hormones increase your chance of breast cancer, and women who have had a baby had an interruption of those hormone cycles while they carried the baby. This reduces their overall chance (breast feeding prolongs the disruption, so it might reduce chances even more).

The easiest way to discover microchimerism? Look for a Y

chromosome in women who have given birth to boys (X on the

left, Y on the right). One recent study found Y DNA in a new

mom’s brain! And microchimerism may mean something.

A 2014 study found higher FCM in mom leads to longer survival

– less cancer and less heart disease.

But there is another hypothesis; one that concerns fetal cells in the mother. One report showed that mother’s that did get breast cancer after a pregnancy had significantly lower FCM – mom’s with more cells from their baby in their own system were less likely to get breast cancer. Is it a correlation or a cause? Too early to tell. But the thought is that the fetal cells put the mom’s immune system on higher alert and they are then more likely to recognize the breast cancer cells and destroy them.

There may be other effects as well. The first studies on FCM and mom’s health were done while investigating scleroderma, an autoimmune disease. Scleroderma hits more post-menopausal women, after they have had kids. Early studies found that women with scleroderma were more likely to have higher levels of FCM, and they found that the fetal cells were often in the skin, where scleroderma strikes.

So, is FCM helping or hurting mom? A later study stated that FCM might actually protect mom from scleroderma, but that if the women had cells from their own mothers they were more likely to contract scleroderma. And a newer study of maternal thyroid autoimmune disease found that the healthy controls had more FCM than in women with Grave’s disease or Hashimoto’s thyroiditis. The fetal cells were also more likely to be in the vessels and the thyroid follicle cells. Are they there to repair damage from the immune system? Or to induce more tolerance?

Microchimerism could be a great thing for people who have

lost a mother or lost a child. Their cells are alive in you, so

when we say that they will always be with you – it’s true. I find

that very comforting.

So the answer is, we’re not sure if FCM helps or hurts. It probably depends on more than just presence/absence of cells; it might be environment, immune state of individual, source and type of cells that persist.

Maternal microchimerism (MMc) - Yes, you read that correctly above, babies (even when grown up and are moms themselves) can harbor cells from their mothers. In some babies, this may not work out so well. It may be why they end up with juvenile (type I) diabetes, since some studies show kids with diabetes have more MMc.

Mom’s stem cells might infiltrate the pancreas and differentiate to become the islet cells that make insulin. This may induce an immune reaction to mom’s cells which then, through molecular mimicry (one looks enough like the other), switches to an attack on the baby's own islet cells. It can’t just be from attacking the mom’s cells as islets because not every islet cell is from mom – there must be a switch in the attack to cells that look similar.

A 2014 study says that while FCM should promote fitness in

the baby and MMc should promote mom’s fitness, but there

can also be issues when it comes to limited resources and

sibling rivalry. More FCM could put off another pregnancy

and keep more food for the first baby. There be more as well

in tying the mother more to one offspring than the other.

Twin microchimerism – we talked last week about how some twins can exchange hematopoietic (blood) stem cells or other cells and become isolated chimeras – this is a type of microchimerism too. But the effects are limited because this is when they are developing tolerance.

Maternal Transfer Microchimerism – This is the weird one. Imagine cells transferred from baby to mom. Then later mom gets pregnant again, and some of the cells of the first baby end up in the second baby. Now the siblings are microchimeras to each other. One study showed that DZ twins with two placentas and two amniotic sacs still had cells from one another – they must have been passed through the mother.

Another study showed a woman who had not given birth had cells of different profile, but not her mom’s cells; they were from an older sibling. The cells must have moved from sibling to mom to her. And yet another paper found male (XY) cells in umbilical blood of female child – they could only have gotten there by transmaternal passage. Are we all carrying cells from somebody else??

Next week – the weirdness of DZ twins continues. Just what determines if two babies are twins? Over the next three posts we'll see that no decent definition exists.

Cirello V, Rizzo R, Crippa M, Campi I, Bortolotti D, Bolzani S, Colombo C, Vannucchi G, Maffini MA, de Liso F, Ferrero S, Finelli P, & Fugazzola L (2015). Fetal cell microchimerism: a protective role in autoimmune thyroid diseases. European journal of endocrinology / European Federation of Endocrine Societies, 173 (1), 111-8 PMID: 25916393

Ye J, Vives-Pi M, & Gillespie KM (2014). Maternal microchimerism: friend or foe in type 1 diabetes? Chimerism, 5 (2), 21-3 PMID: 25093746

Kamper-Jorgensen, M., Hjalgrim, H., Andersen, A., Gadi, V., & Tjonneland, A. (2013). Male microchimerism and survival among women International Journal of Epidemiology, 43 (1), 168-173 DOI: 10.1093/ije/dyt230

Haig, D. (2014). Does microchimerism mediate kin conflicts? Chimerism, 5 (2), 53-55 DOI: 10.4161/chim.29122

Eun, J., Guthrie, K., Zirpoli, G., & Gadi, V. (2013). In Situ Breast Cancer and Microchimerism Scientific Reports, 3 DOI: 10.1038/srep02192

For more information or classroom activities, see:

HLA system –

http://ghr.nlm.nih.gov/geneFamily/hla

http://www.merckmanuals.com/professional/immunology-allergic-disorders/biology-of-the-immune-system/human-leukocyte-antigen-hla-system

http://web.stanford.edu/dept/HPS/transplant/html/hla.html

https://www.seattlecca.org/client/documents/The-Science-Behind-HLA-Typing_8460_0.pdf

https://www.youtube.com/watch?v=8tmprN33f6s

https://bethematch.org/for-patients-and-families/finding-a-donor/hla-matching/

http://www.uptodate.com/contents/human-leukocyte-antigens-hla-a-roadmap

https://www.youtube.com/watch?v=L4bT7zb8U6c