St. Louis, Jan. 21, 2000 -- A mother's immune system must be kept in check so that it does not attack her baby, which contains foreign genetic material. Yet no comprehensive explanation has emerged about how this process, called fetomaternal tolerance, occurs.
A research team now has evidence that an immune system protein called Crry (complement receptor-related gene Y) is crucial for fetomaternal tolerance in mice. Its absence unleashes a destructive attack by the immune system. This causes the developing fetus to be dismantled and its tissue to be reabsorbed by the mother, which is equivalent to a miscarriage in humans. "Without this single molecule, complement components of the mouse immune system are activated, resulting in embryonic death," says Hector D. Molina, M.D., principal investigator of the study published in today's Science.
Molina, an assistant professor of medicine and pathology, led the team at Washington University School of Medicine in St. Louis that performed the research. Postdoctoral fellow Chenguang Xu, M.D., and technician Dailing Mao, are lead authors of the article. The team also plans to investigate the role of similar proteins in miscarriages in women.
The rodent Crry protein regulates a branch of the immune system called the complement system, which helps destroy foreign material such as infectious organisms. Crry prevents complement proteins called C3 and C4 from marking cells for immune-system destruction.
Molina's team found that mice that should have given birth to some offspring lacking Crry had smaller litters instead. When the researchers examined similar mice during their 19-day gestation period, they detected complement activity in Crry-free embryos. On the seventh day, outer embryo cells and cells of the developing placentas bore activated complement proteins. Moreover, immune cells called neutrophils had invaded these complement-bound tissues and were entering the Crry-free embryo.
Similar embryos analyzed on the ninth and 10th days of gestation also were undersized, as were the placentas, which are partially derived from embryonic tissue. By the 10th day, there were fewer embryos that lacked Crry. This suggested that the protein's absence had permitted the immune system to destroy embryos, leading to miscarriage.
Molina's team tested this theory by examining mouse embryos lacking both Crry and complement factor C3, which helps activate most components of the complement system. Without C3, Crry's absence had no effect Ð all the embryos developed normally.
Molina suggests that mouse embryos missing only Crry become starved of nutrients as the placenta is destroyed. "It appears that the mother has to constantly control complement activation Ð especially on the surface of the placenta Ð for an embryo to survive," he says.
Two placental proteins perform Crry's duties in humans: decay accelerating factor and membrane cofactor protein. Their role in miscarriage has not been addressed previously, though. "Using the mouse studies as a framework, we can jump to human studies and see whether miscarriages in women also involve complement regulation," Molina says.
The effort will focus on women who have autoimmune diseases such as lupus erythematosus and multiple miscarriages. Molina's team and investigators elsewhere will try to determine whether such women have diminished levels of the Crry-like regulatory proteins and thus might benefit from supplemental therapy. Molina also will study animal models to determine how inadequate activation of C3 in the absence of Crry influences diseases such as lupus.
Note: Molina is fluent in both Spanish and English. Also, high-resolution, color images of a normal mouse embryo and one that lacks Crry are available upon request.
Xu C, Mao D, Holers VM, Palanca B, Cheng A, Molina H. A Critical Role for Murine Complement Regulator Crry in Fetomaternal Tolerance. Science, 286 (5451), 498-502. Jan. 21, 2000.
This research was supported by a grant from the National Institute of Allergy and Infectious Diseases and by a Veterans Administration Merit Award.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.
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