Are your children always on your mind? They may be IN your mind

Hmm. Do I have any cells in there?
On Mother’s Day this year, we told you why, if you have biological children, those children are literally a part of you for life thanks to a phenomenon called microchimerism. When a woman is pregnant, some of the fetal cells slip past the barrier between mother and fetus and take up residence in the mother. What researchers hadn’t turned up in humans before now was that some of those cells can end up in the mother’s brain. Once there, according to a study published today in PLoS ONE, they can stick around for decades and, the researchers suggest, might have a link to Alzheimer’s disease. Note that is a big “might.”

The easiest way to tell if a fetal cell’s made it into a maternal tissue is to look for cells carrying a Y chromosome or a Y gene sequence (not all fetuses developing as male carry a Y chromosome, but that’s a post for another time). As you probably know, most women don’t carry a Y chromosome in their own cells (but some do; another post for another time). In this study, researchers examined postmortem brain tissue from 26 women who had no detectable neurological disease and 33 women who’d had Alzheimer’s disease; the women’s ages at death ranged from 32 to 101. They found that almost two thirds (37) of all of the women tested had evidence of the Y chromosome gene in their brains, in several brain regions. The blue spots in the image below highlight cells carrying these “male” genes a woman’s brain tissue.

Photo Credit: Chan WFN, Gurnot C, Montine TJ, Sonnen JA, Guthrie KA, et al. (2012)
Male Microchimerism in the Human Female Brain. 
PLoS ONE 7(9): e45592. doi:10.1371/journal.pone.0045592

The researchers also looked at whether or not these blue spots were more (or less) frequent in the brains of women with Alzheimer’s disease compared to women who’d had no known neurological disease. Although their results hint at a possible association, it wasn’t significant. Because the pregnancy history of the women was largely unknown, there’s no real evidence here that pregnancy can heighten your Alzheimer’s risk or that being pregnant with or bearing a boy can help or hinder. As I discuss below, you can end up with some Y chromosome-bearing cells without ever having been pregnant.

Also, age could be an issue. Based on the reported age ranges of the group, the women without Alzheimer’s were on average younger at death (70 vs 79), with the youngest being only 32 (the youngest in Alzheimer’s group at death was 54). No one knows if the women who died at younger ages might later have developed Alzheimer’s. 

Indeed, most of this group–Alzheimer’s or not–had these Y-chromosome cells present in the brain. The authors say that 18 of the 26 samples from women who’d had no neurologic disease were positive for these “male” cells–that’s 69%–while 19 of the 33 who had Alzheimer’s were. That’s 58%. In other words, a greater percentage of women who’d not had Alzheimer’s in life were carrying around these male-positive cells compared to women who had developed Alzheimer’s. The age difference might also matter here, though, if these microchimeric cells tend to fade with age, although the researchers did get a positive result in the brain of a woman who was 94 when she died.

Thus, the simple fact of having male-positive cells (ETA: or not enough of them) in the brain doesn’t mean You Will Develop Alzheimer’s, which is itself a complex disease with many contributing factors. The researchers looked at this potential link because some studies have found a higher rate of Alzheimer’s among women who’ve been pregnant compared to women who have not and an earlier onset among women with a history of pregnancy. The possible reasons for this association range from false correlation to any number of effects of pregnancy, childbearing, or parenting.

Nothing about this study means that migration of fetal cells to the brain is limited to cells carrying Y chromosomes. It’s just that in someone who is XX, it’s pretty straightforward to find a Y chromosome gene. Finding a “foreign” X-linked gene in an XX person would be much more difficult. Also, a woman doesn’t have to have borne a pregnancy to term to have acquired these fetal cells. As the authors observe, even women without sons can have these Y-associated cells from pregnancies that were aborted or ended prematurely or from a “vanished” male twin in a pregnancy that did go to term. 

In fact, a woman doesn’t even have to have ever been pregnant at all to be carrying some cells with Y chromosomes. Another way you can end up with Y chromosome cells in an XX chromosome body is–get this–from having an older male sibling who, presumably, left a few cellular gifts behind in the womb where you later developed. As the oldest sibling, I can only assume I could have done the same for the siblings who followed me. So, if you’ve got an older sibling and have been pregnant before–could you be a double microchimera? 

But wait. You could even be a triple microchimera! This microchimerism thing can be a two-way street. If you’re a woman with biological children, those children already carry around part of you in the nuclear DNA you contributed and all of the mitochondria (including mitochondrial DNA) in all of their cells. Yes, they get more DNA from you than from the father. But they might also be toting complete versions of your cells, just as you have cells from them, although fetus–>mother transfer is more common than mother–>fetus transfer. The same could have happened between you and your biological mother. If so, a woman could potentially be living with cells from her mother, older sibling, and her children mixed in with her own boring old self cells.

The triple microchimera thing might be a tad dizzying, particularly the idea that you could be walking around with your mother’s and sibling’s cells hanging out in You, a whole new level of family relationships. But if you’re a biological mother, perhaps you might find it comforting to know that a cellular part of you may accompany your child everywhere, even as your child is always on your mind–and possibly in it, too.

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Leaky gut and wonky immune response might be double whammy leading to inflammatory bowel disease (in mice)

A case of ulcerative colitis, a form of inflammatory bowel disease.
Photo via Wikimedia Commons. Credit: Samir.

A two-hit punch in the gut might explain why some people find themselves alone among their closest relatives in having inflammatory bowel disease (IBD). The double gut punches come in the form of a compromised intestinal wall coupled with a poorly behaved immune system, say Emory researchers, whose work using mice was published in the journal Immunity. IBDs include ulcerative colitis and Crohn’s disease, the latter of which is slightly more common in women.

An inflamed gut is the key feature of IBD, which affects about 600,000 people in the United States each year. Typical symptoms include bloody diarrhea, fever, and cramps, which can come and go with bouts of severe inflammation punctuating relatively calm periods. The going explanation for these disorders is a wonky immune system, but some breach of the barrier that keeps your gut contents in their place is also implicated. Researchers also have identified a link between bouts of gastroenteritis–known around my house as “throw-up” illnesses–and development of IBD. What’s remained unclear is how people who have these so-called “leaky guts” don’t develop a disease like Crohn’s when a close family member with a leaky gut does.

These hints in humans led the Emory investigators to examine the interaction of a compromised gut and the immune system in mice. The mice in the study had ‘leaky’ gut walls because they lacked a protein that usually ties cells together into water-tight sheets. Without these proteins sealing up the intestinal lining, bacteria and other components can make their way their deeper into the intestinal wall, triggering chronic inflammation.

The thing is, these mice with their leaky guts don’t develop colitis spontaneously, a situation, the investigators hypothesized, that  reflects families full of people with leaky guts but rarely IBD.  Permeable intestines alone aren’t enough. Some other dysfunction related to the immune system, they figured, must pile onto that leakiness and bring on the inflammatory disorder.

If you’re an immunologist–which I am not–an obvious choice for investigation is a class of immune cells called T cells. These cells come in a dizzying array of types, but one way to narrow them down relies on a protein that some but not all of them make. Pulling out the T cells that make this protein, says Timothy Denning, PhD, a mucosal immunologist at Emory and study author, is “the simplest way” to start examining the immune system involvement because these cells play a ton of roles in balancing different immune responses. So, they first collected the T cells carrying this protein from the mouse intestines.

“There are good and bad” versions of T cells carrying these identifier molecules, though, says Denning, so the next step was to find the “good” ones that might be protecting mice in spite of their sieve-like intestinal linings. To achieve that goal required some fancier lab moves. “We stimulated the cells and looked at the cytokines (immune signaling molecules) they make,” explains Charles Parkos, MD, PhD, an experimental pathologist and mucosal immunologist at Emory and also a paper author. “We found that the cells in the mice that were better protected predominantly secreted TGF-beta, a prototypic marker for ‘good’ cells.”

One of the things T cells do with TGF-beta is to talk to B cells, another class of immune cell. B cells take responsibility for remembering what’s attacked you in the past and marshaling forces if it attacks again. Also, when B cells are stimulated, explains Parkos, one way they respond is to release proteins–antibodies–that target the offending invaders. In the gut, the kind of antibody the B cells make in response to the TGF-beta message is immunoglobulin A, or IgA. This antibody “keeps bacteria in check,” says Denning, and also probably “broadly neutralizes lots of different microorganisms” in the intestines, adds Parkos.

The Emory-based team found that when the leaky-gut mice also had an IgA deficiency, they became more open to the types of immune cells that cause gut inflammation. The animals also were far more susceptible to colitis triggered by a chemical treatment in the lab and had much worse disease. Without the IgA, the mice couldn’t dampen inflammation triggered by bacteria slipping through the intestinal breaches. The results of this two-step physiological fail, in mice, at least: severe inflammatory  gut disease.

Denning cautions that these results in mice don’t suggest a rush to TGF-beta or IgA treatment for inflammatory diseases. “TGF-beta has many effects and on many different cell types, and too much is not a good thing because it’s known to play a role in fibrosis and cancer,” says Denning. “If your child had IBD, the last thing you’d want to do is to give TGF-beta.” Much more work has to be done, he adds, for a better understanding of the implications of these results before anyone starts talking about therapies. Parkos agrees. “To our knowledge, administration of TGF-beta is not a viable therapy.”

The same applies for IgA, Denning says. “We couldn’t just take any old B cells and get them to make IgA and put it in and hope that it would do something,” he says. The reason, he explains, is because B cells make many different types of IgA molecules specific to foreign invaders they encounter, a process that happens on the spot, not in a lab dish. “We need to understand much more about the basic mechanisms, but we do believe that these pathways would be critical to induce in people who are more susceptible to IBD, such as first-degree relatives.”

Some research groups are conducting trials to treat IBDs with helminth worms–intestinal parasites–on the hypothesis that their presence would induce a balance in the immune system and tamp down an overactive inflammatory response. The balance in this case is supposed to be between two competing aspects of the immune system, called Th1 and Th2. But one issue in these intestinal inflammatory disorders, says Denning, is that Crohn’s is linked to Th1 hyperactivity while ulcerative colitis is associated with Th2.

Yet the worms appear to show some beneficial effects in both disorders, in spite of the different involvement of Th1 and Th2. The TGF-beta signaling effect on IgA that the Emory group identified operates by a third component, tentatively identified as Th3. Both Denning and Parkos are intrigued by the possibility that the presence of helminths might trigger this pathway, rather than influencing Th1 or Th2, explaining why worm treatment has sometimes proved useful for both Crohn’s and ulcerative colitis.

As for why IBD arises, the researchers hope their findings answer some questions. “There are different camps in the IBD community,” says Parkos. “Some say immune system, some say barrier, others say genetics or environment.” What they have with their results, he says, is evidence showing that a leak alone is not enough and that a wonky immune system alone is not enough. But the double-whammy of a leaky gut and an absence of immune protection “dramatically increase susceptibility to disease, and that helps explain why diseases are so complicated,” he says.

The use of parasitic worms for these inflammatory diseases arose from the concept of the hygiene hypothesis, the idea that we’re too clean in the modern developed world, leading to an immune imbalance that can include chronic inflammation and autoimmune disorders. Asked about any links between the hygiene hypothesis and this pathway to IBD they identified in mice, Denning says, “It’s not obviously all about the parasites. That’s just one key thing–it’s probably an exposure to a lot of different types of things in your gut and airways.” He describes the immune system as being a thermostat that registers a specific set-point early on based on these exposures. This set-point, he says, is lower in people who grow up in developed countries like the United States and leads to a “trigger-happy immune system that is ready to fire much more easily.”

That doesn’t mean that a worm infection or just being dirty will prevent your developing IBD. That said, these immunologists both have the same general advice for parents regarding their children. “Being too clean is not a good thing,” they agree. As immunologists, he adds, “We feel exactly the opposite. Go play in the dirt.”