Immune cells in fetters
A new study demonstrates that immune cells formed during fetal development are immature and largely ineffectual. The findings explain why neonates are so susceptible to infection, and why the risk is even greater for premature infants.
Pathogens that are otherwise relatively innocuous can cause serious infections in the newborn, and the risk is inversely proportional to the degree of maturity at birth. Up to 60% of highly premature babies, i.e., those born prior to the end of the 25th week, contract septicemia caused by bacterial infection, and approximately one million premature infants succumb to the condition each year. Their vulnerability is partly attributable to the fact that the neonatal immune system is functionally immature, and consequently less effective in fighting infections.
Immune reactions on screen
Researchers led by LMU’s Professor Markus Sperandio at the Walter Brendel Center Experimental Medicine, in collaboration with Professor Ulrich von Andrian’s group at Harvard Medical School in Boston, have developed a new model system that allows them to investigate immune function at the cellular level in the living fetus. “Because suitable experimental models have not been available up to now, relatively little is known about fetal immunology. Our system represents an important step forward, as it allows us to study the basis for the relative weakness of immune responses in premature infants,” says Sperandio.
The latest findings made with this new model, which have just appeared in the journal “Blood”, show that, in the young fetus, white blood cells (leukocytes) are unable to function correctly. In mature animals and adult humans, leukocytes orchestrate immune responses against invading pathogens by migrating from the bloodstream to sites of inflammation in the tissues. To do so they first interact with endothelial cells forming the inner surfaces of blood vessels. This is followed by leukocyte rolling along the endothelial surface. Eventually, leukocytes become firmly attached by means of specific cell-surface proteins, and finally transmigrate (penetrate) into the infected tissue.
Functional flaws in neonatal leukocytes
“In earlier stages of fetal development, however, the leukocytes are essentially inactive. They first acquire the ability to migrate into tissues near the end of the gestation period,” Sperandio explains. Thus, fetal leukocytes examined on day 14 of the 21-day gestation period in mice – equivalent to about 24 weeks in humans – were unable to leave the vasculature. In contrast, on day 18, the researchers observed many murine leukocytes rolling along and adhering to endothelial cells.
Similar studies on cord blood, which were recently reported by the same authors in the Journal of Leukocyte Biology, confirmed that a similar maturation process occurs during human fetal ontogeny. Here too, the ability of leukocytes to reach infected tissues was dependent on developmental age. Thus, leukocyte adhesion was largely absent in highly premature infants, in accordance with their gestational age at birth.
“In highly premature babies, the immune system operates with the handbrake on, so to speak,” says Sperandio, “and that is why bacterial growth can proceed essentially unhindered.” The researchers now plan to study the regulation of leukocyte function during fetal development in more detail and at the genetic level. Their objective is to identify the genetic switches that constrain the function of the fetal immune system. Sperandio is hopeful that these studies will lead to clinical advances. “In the longer term, we aim to develop therapeutic approaches that allow us to activate the leukocytes on demand. This strategy may reduce the incidence of infections and the rate of mortality among premature infants,” he says.
(Blood 2013) göd