By David N. Leff

Every man, woman and child on earth today came into this world as an enemy alien. From the vantage point of a pregnant mother's immune defenses, we all started life as illegal immigrants.

Here's how clinical and research immunologist Hector Molina, at Washington University in St. Louis, interprets this paradox: "There has always been a mystery why an embryo within its mother's womb survives, since half of the embryo's proteins are derived from the father. They should be considered strange to the mother, except for fetomaternal tolerance - the ability of the mother's immune system to recognize, or at least tolerate, the person of the developing embryo for the sake of the future baby's survival."

Molina added, "The molecular mechanisms involved in this maternal tolerance are not very well established. My colleagues and I have at least characterized one of the mechanisms by which the immune system of the mother respects the survival of her embryo. That's by expressing a set of proteins that control one arm of the immune system, namely the complement system.

"It turns out," he continued, "that without one of these proteins, Crry, the complement cascade attacks the embryo as if it were something strange and hostile to its mother. In mice, this causes the developing fetus to be dismantled, and its tissue reabsorbed by the dam - which is equivalent to a miscarriage in humans. We have characterized this complement-controlling protein in vivo," he went on, "and shown that you have to express it especially on the surface of the placental cells in order for the embryo to survive."

Molina is senior author of a paper in the current issue of Science, dated Jan. 21, 2000, titled: "A critical role for murine complement regulator Crry in fetomaternal tolerance."

Crry stands for "complement receptor-related gene Y." It and its gene were discovered elsewhere a decade ago, but the protein's function remained unknown.

KO Mice Helpless To Control Complement

"We were also able to clone the gene," Molina told BioWorld Today, "express it in cells, and demonstrate that this Crry has an important function in complement regulation. Mouse cell lines expressed a lot of it, and we found that without the expression of Crry, complement was deposited on the surface of cells, and these cells died by complement activation."

So, to test this in vitro finding in vivo, and determine the role of these proteins that regulate complement activation, he and his co-authors generated a mouse model deficient in the expression of that Crry protein. "To our surprise," Molina recounted, "these mice didn't survive embryo development; they all died within the uterus.

"And we found," he continued, "that indeed, very early in their pregnancy, these embryos were exposed to a lot of complement on the surface of those placental cells that are derived from the embryo. By expressing this protein, the embryo was defending itself from any maternal complement attack. And this complement was doing its job - attracting a lot of inflammatory cells, especially neutrophils, which are among the first lines of defense against bacteria. But instead of attacking invading pathogens, the neutrophils were attacking the placenta."

Molina explained how incoming sperm, fresh from ejaculation, escape this fate:

"Sperm also express a lot of these complement regulatory molecules," he pointed out, "because the vagina, as well as the uterine lining, contains a lot of complement, which is a frontline immune-defense molecule. The vagina, being potentially open to the environment, is full of complement, probably to avoid infection. So if bacteria make contact with the vaginal lining, complement completely destroys it.

"A sperm cell also has on the surface of its membrane the same complement-curbing proteins that we have found in the placenta. So when it contacts the vaginal fluid, which is full of complement, it can protect itself from attack."

Molina noted, "In fact there are some conditions of infertility in which researchers have found antibodies against sperm. And antibodies are among the most potent activators of complement."

Looking to the future, he said, "One of the plans we have now is to see whether our Crry-lacking KO mouse model also applies to humans. It turns out that pregnant women have in the placenta a lot of these regulatory molecules that control complement activation. We want to see whether in woman who have multiple miscarriages, the level of these proteins on the placenta is diminished, or even absent."

He and his co-authors "are also trying to determine how we can avoid the deposition of this complement on the surface of the placental cells by actually injecting the Crry protein in soluble form into pregnant mice, to see whether the pregnancy can survive.

First Target: Spontaneous Abortions

"If we find a correlation in humans between the absence of these proteins and increased miscarriages, we could suggest providing the equivalent human proteins - DAF and MCP - to a mother, and see whether her pregnancy can survive as well."

"Women who suffer from a variant of systemic lupus erythematosus have a very high incidence of miscarriages. And there are some preliminary data," Molina observed, "in which it seems that some of these spontaneous abortions are induced by complement. So one of our ideas - also in the future - is that it may be reasonable to think that we can treat these miscarriages with those proteins, provided to the mother in soluble form."

His clinical focus also extends to "multiple miscarriages that have no explanation, in which the mother otherwise is healthy. It could be," he speculated, "that for some reason, within the placental cells, the level of those complement-regulating proteins is diminished.

"A lot of pharmaceutical companies," Molina pointed out, "are working with these molecules, as a way of controlling inflammation in human diseases. Not only in the placentas but also, for instance, myocardial infarction, stroke and other inflammatory conditions, such as rheumatoid arthritis. "I think this is an exciting moment for complement research," he observed. "We have here a nice mouse model in which we can screen the different complement regulatory molecules that are actually under scrutiny with the pharmaceutical companies. We can use this protein to test whether by controlling complement regulation, we can control human diseases - which is basically what it's all about."