Meet your parasite

I found out about my first little parasite during a completely routine primary care physical. While I’d been off birth control for about 2 months, my partner and I hadn’t intended to actually start trying for a few months at the soonest. To top it off, my period (which usually comes every 5 weeks or so) wasn’t even late by my standards. But the, “Just to be safe, let’s pee in the cup and check” test quickly became, “So, it’s positive,” and the world went into a tailspin. After settling down out of the confusion, laced with joy, wrapped in disbelief, and sprinkled with mild terror, I realized I had one underlying, burning concern: Why isn’t my body kicking this parasite out??

Now, don’t get me wrong. I’m very, very glad that my body was keeping this particular parasite safe and cozy in my uterine lining. I felt a period-cramp style twinge every so often during those first few weeks that I imagined is the little apple-seed sized tadpole baby-to-be snuggling down a little bit farther. In reality, these cramps are from the uterus stretching in accommodation of the rapidly expanding embryo. But why in the world was my body, which fights tooth and nail to get the tiniest bit of bad out of it (hello, airport hotdogs; sorry, airplane bathroom), allowing this particular foreign body to stick around? I know how immune systems work, and I know that half of the DNA in this embryo comes from my partner, not me. It is by definitely a foreign invader. Why wasn’t my body acting accordingly? I felt suddenly the same (irrational) fear I have in airplanes: if I realize I don’t know how the plane is staying aloft, will it do a Wylie-Coyote-looks-down-off-a-cliff maneuver and plummet? If my brain realizes my body should be evicting this parasite, will it mount an attack?

The answer, clearly, is no. At least not most of the time. But to explain why, we have to take a trip back in time to about 180 million years ago, before marsupial mammals (like kangaroos and opossums — the ones that carry their babies in pouches) and placental mammals (those that grow their babies in a placenta inside the uterus — like us) split into their separate evolutionary lineages. This common ancestor of all mammals likely gave birth extremely early on, like we see modern marsupials do today. There would have been a very brief window (about 12 days) where the developing embryo attached to mom, but then when it would try to implant itself in the lining of the uterus, the mother’s body would ‘reject’ it, sending it crawling out the birth canal and into the famous pouch. There, the embryo would finish developing while getting nutrients from nipples instead of directly from mother’s blood supply.

In placental mammals, this process begins in the same way. However, when the embryo attaches itself to the uterine wall — called implantation– the inflammatory attack-response seen in marsupials does not happen. Instead, the cells lining the uterus during — and just following — ovulation (a layer called the decidua) surround the embryo in a protective cellular hug. Eventually, the decidua is replaced by the placenta. (By the way, if you’re not pregnant, the decidua has nothing to hug and is what your body sheds during your period). The decidua's hug at implantation represses the production of a signaling molecule called IL-17 which, when present, beckons the immune cells responsible for inflammation and uterine contractions (which ultimately expel the tiny, tiny embryo into the pouch in marsupials). One of the reasons for extremely early miscarriages is failure on the part of these decidual cells to repress IL-17 production, and the body shoos the little mass out the door.

How do the decidual cells know to repress IL-17? What if some actual foreign body got into the lining of a uterus — would the decidual cells get confused and protect it from the body’s natural immune response? No, thankfully; the embryo itself is doing some critical self-advocacy during those first weeks. Researchers have measured the cellular communication between maternal and fetal embryo cells and found that the embryonic cells send a signal to the decidual cells cueing them to suppress IL-17 production (among other things)[1]. Think of it like the tiny baby-to-be (chemically) screaming “STOP! It’s just meeeeee!”

This immune-suppressing signal from the embryo cells comes from many places, but potentially chief among them in the activity of the HLA-G gene[2]. Almost every person in the world has the same form of the HLA-G gene and so we all express the same protein when the gene is active. This protein seems to be key in suppressing the maternal immune response and letting the embryo get cozy [4].

The implantation of the embryo also seems to change the very genetics of the decidua’s cells. Specifically, it ‘mutes’ certain genes that are normal responsible for recruiting T-cells, the storm troopers of the immune system, from swarming to and attacking the implanted embryo[3]. But not all t-cells are killers. Some, called regulatory t-cells, act more like moderators or negotiators, talking mom’s killer t-cells down from gobbling up the baby-to-be.

I’d like to pause on that for a moment: not only is this tiny, tiny embryo coming in and beckoning for mom’s blood supply, but it’s also changes the actually genes expressed within mom’s cells. Miracle of life, indeed.

So what cues the presence of the peacekeeper t-cells? The answer certainly surprised me: paternal antigens, foreign material from the sperm itself, seems to play a key role in cueing peacekeeper t-cells [5]. More on this next time.

References:

1. Evolution of embryo implantation was enabled by the origin of decidual cells in eutherian mammals CHAVAN, AR*; GRIFFITH, OW; MAZIARZ, J; PAVLICEV, M; TZIKA, A; MILINKOVITCH, M; FISHMAN, R; KOREN, L; WAGNER. Accessed at: http://www.sicb.org/meetings/2018/schedule/abstractdetails.php?id=1213

2. Vento-Tormo, Roser, et al. “Single-cell reconstruction of the early maternal–fetal interface in humans.” Nature 563.7731 (2018): 347.

3. P. Nancy, E. Tagliani, C.-S. Tay, P. Asp, D. E. Levy, A. Erlebacher. Chemokine Gene Silencing in Decidual Stromal Cells Limits T Cell Access to the Maternal-Fetal Interface. Science, 2012; 336 (6086): 1317 DOI: 10.1126/science.1220030

4. Lynge Nilsson, Line, Snezana Djurisic, and Thomas Vauvert F. Hviid. “Controlling the immunological crosstalk during conception and pregnancy: HLA-G in reproduction.” Frontiers in immunology 5 (2014): 198.

5. Williams Z. Inducing tolerance to pregnancy. N Engl J Med (2012) 367:1159–61.10.1056/NEJMcibr1207279