New explanation for infection susceptibility in newborns
Cells that allow helpful bacteria to safely colonize the intestines of newborn infants also suppress their immune systems to make them more vulnerable to infections.
The study, which appears online Nov. 6, in Nature, could prompt a major shift in how medicine views the threat of neonatal infections – and how researchers go about looking for new strategies to stop infection, say scientists at Cincinnati Children's Hospital Medical Center.
Until now, the prevailing view has been that newborn infants are susceptible to infection because their immune system cells are immature or underdeveloped.
"The first few days after birth represent a critical developmental period when a baby's immune system must adapt to many new stimulants. This includes environmental microbes that are not present in the womb, but immediately colonize tissues such as the intestine and skin.
"Our findings fundamentally change how we look at neonatal susceptibility to infection by suggesting it is caused by active immune suppression during this developmental period, as opposed to the immaturity of immune cells."
Sing Sing Way, MD, senior investigator, physician, Division of Infectious Diseases, Cincinnati Children's Hospital
CD71+ are immune suppressive cells which are precursors to mature red blood cells — found in newborn mice and human umbilical cord blood. CD71+ cells prevent an over reactive immune response in infants as they adapt to their new microbe-filled world. tThey do this through expression of an enzyme called arginase-2 — essential to suppress immune cells. This process is vital to developing infants' intestines as it prevents the onslaught of inflammation response to colonizing bacteria which help digestion.
Researchers used a series of laboratory tests in human blood cells and mouse models to show how immune suppression in newborns extends beyond the intestines to affect other parts of the body. Although newborn vulnerability to infection is well known, Way began his study because earlier research had shown that compromised immunity in infant mice varies significantly on specific experimental conditions. This led the authors to hypothesize that there must be a better explanation for compromised immunity in neonates besides pointing to immature immune cells.
The scientists transferred adult immune system cells in bulk from adult mice into newborn mice to see if this would boost neonatal immunity during exposure to infection. Instead of enhancing immunity, researchers said the production of protective immune system cytokines in the adult cells remained blunted in the newborn mice. Similar results were observed when adult immune cells were mixed with neonatal cells in laboratory cultures.
In a complementary experiment, researchers transferred newborn immune system cells into adult mice exposed to infection. In the adult mice, the neonatal immune cells produced the protective cytokine TNF-alpha, which helps ramp up the immune system's protective response against infection.
Way and his colleagues said the benefits of CD71+ immune suppression to allow healthy bacterial colonization of intestines are essential, and this outweighs the threat of systemic infant infections. But the researchers stressed the importance of follow up studies to develop new strategies for protecting newborns from systemic infections. The goal would be to offer this protection while still allowing CD71+ cells to do their job in helping develop healthy intestines.
One strategy being explored by investigators in their ongoing research is possible modulation or control of immune suppression by CD71+ cells. The authors were careful to emphasize that far more follow up study is needed before direct application of their findings to human infants.
Newborn infants are highly susceptible to infection. This defect in host defence has generally been ascribed to the immaturity of neonatal immune cells; however, the degree of hyporesponsiveness is highly variable and depends on the stimulation conditions1, 2, 3, 4, 5, 6, 7. These discordant responses illustrate the need for a more unified explanation for why immunity is compromised in neonates. Here we show that physiologically enriched CD71+ erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after co-culture with neonatal splenocytes. Neonatal CD71+ cells express the enzyme arginase-2, and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with L-arginine overrides immunosuppression. In addition, the ablation of CD71+ cells in neonatal mice, or the decline in number of these cells as postnatal development progresses parallels the loss of suppression, and restored resistance to the perinatal pathogens Listeria monocytogenes and Escherichia coli8, 9. However, CD71+ cell-mediated susceptibility to infection is counterbalanced by CD71+ cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition10, 11. Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Thus, CD71+ cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. This finding challenges the idea that the susceptibility of neonates to infection reflects immune-cell-intrinsic defects and instead highlights processes that are developmentally more essential and inadvertently mitigate innate immune protection. We anticipate that these results will spark renewed investigation into the need for immunosuppression in neonates, as well as improved strategies for augmenting host defence in this vulnerable population.
Funding for the study came from the National Institute of Allergy and Infectious Diseases (R01AI087830, R01AI100934), the National Heart Lung and Blood Institute (R01HL103745) and the Burroughs Wellcome Fund.
About Cincinnati Children's:
Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report's 2013 Best Children's Hospitals ranking. It is ranked #1 for cancer and in the top 10 for nine of 10 pediatric specialties. Cincinnati Children's, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at http://www.cincinnatichildrens.org. Connect on the Cincinnati Children's blog, via Facebook and on Twitter.
Original press release: http://www.cincinnatichildrens.org/news/release/2013/infant-immunity-nature-11-06-2013/