To survive in utero, the fetus must resist an onslaught by the mother's immune system that, most researchers agree, recognizes the father's share of the embryo as foreign and sometimes rejects it. Now, endocrinologists have determined that the principal soother of the maternal immune system is the same master hormone that commands the body's stress response. The results could help explain some infertility and recurring miscarriages.
Immunologists have long speculated that hormone changes early in pregnancy somehow alter the mother's immune system, but they couldn't pinpoint the mechanism. In the early 1990s, pediatric endocrinologist George Chrousos and his colleagues at the National Institute of Child Health and Human Development in Bethesda, Maryland, came across a clue. They found that corticotropin-releasing hormone (CRH), secreted by the hypothalamus to induce secretion of stress hormones by the pituitary and the adrenal glands, also appeared around sites of inflammation in adults. The correlation was so striking that the researchers decided to see whether CRH played a role in fetal implantation, which initially resembles an inflammation.
Chrousos's group looked for CRH in human trophoblast cells, special cells that help form the placenta, in petri dishes. Not only did the cells churn out CRH, they also harbored cell surface receptors for the hormone. CRH, in turn, triggered production of the cell surface protein FasL; trophoblasts expressing FasL then form a protective shield of sorts around the embryo by forcing any attacking immune cells to self-destruct. This suggested that blocking CRH should reduce the number of implanted fetuses--which, the team reports in the November issue of Nature Immunology, is indeed the case. When the researchers administered antalarmin, a CRH blocker, to pregnant rats during the first 6 days after conception, the number of implanted embryos was reduced by up to 70%. Chrousos thinks a potential cause of unexplained infertility or recurring early miscarriages in women might be due to a lack of CRH to prevent immune rejection.
While some scientists continue to question whether the fetus does kick off a maternal immune response, others are fascinated by Chrousos's findings. "Nobody has ever shown how FasL is induced" in the developing placenta, says reproductive immunologist Scott Kauma of the Virginia Commonwealth University in Richmond. "This adds to the importance of neuroendocrine hormones as key factors in regulating the maternal immune response" during pregnancy.