Overview: Research reveals how the early days of maternal-provided immunity works and what this could mean for preventing death and disability for a wide variety of infectious diseases. The findings could enable the development of new therapies and improved vaccines that mimic the elevated maternal antibodies.
Source: Children’s Hospital of Cincinnati
Scientists discovered years ago that newborn babies depend on immune components passed on from their mothers to survive the onslaught of pathogens that enter their bodies as soon as they are born.
Ultimately, children develop their own immune systems, built by surviving natural exposure to viruses and bacteria, and supplemented by a phalanx of established childhood vaccines.
But in the meantime, one of the most important gifts a mother gives to keep their babies safe is antibodies.
Now, a far-reaching study published on June 8, 2022, in Nature, provides a startling explanation of how those early days of maternal-provided immunity actually work — and what that information could mean for preventing death and disability from a wide variety of infectious diseases.
The findings suggest that researchers could mimic the boosted antibodies that mothers expect to make new drugs to treat diseases, as well as improved vaccines to prevent them.
“For many years, scientists believed that antibodies cannot get into cells. They don’t have the necessary machines. And so infections caused by pathogens that live solely in cells were thought to be invisible to antibody-based therapies,” says Sing Sing Way, MD, PhD, Division of Infectious Diseases at Cincinnati Children’s.
“Our findings show that pregnancy changes the structure of certain sugars attached to the antibodies, allowing them to protect babies from infection by a much wider range of pathogens.”
“The mother-child dyad is so special. It’s the intimate bond between a mother and her baby,” says John Erickson, MD, PhD, Division of Neonatology and lead author of the study.
Both Way and Erickson are part of the Cincinnati Children’s Center for Inflammation and Tolerance and the Perinatal Institute, which strives to improve outcomes for all pregnant women and their newborns.
Erickson continues: “This special bond begins when babies are in the womb and continues after birth. I am thrilled to see the closeness between mothers and their babies in our newborn care units. This discovery paves the way for groundbreaking new therapies that could specifically target infections in pregnant mothers and newborn babies. I believe these findings will have far-reaching implications for antibody-based therapies in other areas as well.”
How mothers make superantibodies
The new study identifies what specific sugar is changed during pregnancy, as well as how and when the change occurs. During pregnancy, the “acetylated” form of sialic acid (one of the sugars attached to antibodies) shifts to the “deacetylated” form. This very subtle molecular change allows immunoglobulin G (IgG) – the body’s most abundant type of antibody – to take on an extensive protective role by boosting immunity through receptors that specifically respond to deacetylated sugars.
“This change is the light switch that allows maternal antibodies to protect babies from infection in cells,” Way says.
“Mothers always seem to know best,” Erickson adds.
Revved-up antibodies can be produced in the lab
Using advanced mass spectrometry techniques and other methods, the research team compared key biochemical differences between antibodies in virgin mice and pregnant mice. They also identified the enzyme naturally expressed during pregnancy that is responsible for this transformation.
Furthermore, the team successfully restored lost immune protection by supplying lab-grown stocks of the antibodies from healthy pregnant mice to pups born to mothers that had been genetically engineered to lack the ability to remove acetylation from antibodies to enhance protection.
Hundreds of monoclonal antibodies have been produced as potential treatments for a variety of conditions, including cancer, asthma, multiple sclerosis, as well as hard-to-shake viral and bacterial infections, including new treatments that are rapidly being developed for COVID-19. Some are already FDA-approved, many more are in clinical trials, and some have not shown strong results.
Way says the molecular change of antibodies that occurs naturally during pregnancy could be replicated to alter how antibodies stimulate the immune system to fine-tune their effects. This could potentially lead to improved treatments for infections caused by other intracellular pathogens, including HIV and respiratory syncytial virus (RSV), a common virus that poses serious risks to infants.
Another reason to speed up vaccine development
“We’ve known about the many far-reaching benefits of breastfeeding for years,” says Erickson. “An important factor is the transfer of antibodies into breast milk.”
The study shows that the molecular switch persists in nursing mothers, so that antibodies with an increased protective scope are also transferred to infants through breast milk.
In addition, Way underlines the importance of receiving all available vaccines for women of childbearing age, as well as the need for researchers to develop even more vaccines against infections that mainly affect women during pregnancy or newborn babies.
“The immunity has to be in the mother for it to be passed on to her child,” Way says. “Without natural exposure or immunity primed by vaccination, when that light switch flips during pregnancy, there’s no electricity behind it.”
About the study
An antibody-sialic acid modification patent has been filed by the Cincinnati Children’s Hospital with first author Erickson and senior author Way as inventors (PCT/US2022/018847).
In addition to Erickson and Way, the study is in Nature co-authored 9 researchers from Cincinnati Children’s and the University of Cincinnati: Alexander Yarawsky, BS, Jeanette LC Miller, PhD, Tzu-Yu Shao, BS, Ashley Severance, PhD, Hilary Miller-Handley, MD, Yuehong Wu, MS , Giang Pham, PhD, Yueh-Chiang Hu, PhD, and Andrew Herr, PhD.
Contributors also included experts from the University of Georgia, Ohio State University, Cornell University and the Roswell Park Comprehensive Cancer Center in Buffalo.
Financing: Funding sources included grants from the National Institutes of Health (F32AI145184x, K12HD028827, DP1AI131080, R01AI145840, R01AI124657, U01AI144673, T32DK007727, R24GM137782, R01GM094363, and R01AI162964); the HHMI Faculty Scholar’s Programme; the Burroughs Wellcome Fund; the March of Dimes Foundation Ohio Collaborative; and GlycoMIP, a National Science Foundation Materials Innovation Platform, funded through collaboration agreement DMR-1933525.
About this immunology research news
Original research: Closed access.
†Pregnancy allows for antibody protection against intracellular infectionby John Erickson et al. Nature
Pregnancy allows for antibody protection against intracellular infection
Adaptive immune components are believed to play a non-overlapping role in host antimicrobial defense, with antibodies targeting pathogens in the extracellular environment and eliminating T cells infection in cells. Relying on antibodies for vertically transmitted immunity from mothers to babies may explain neonatal susceptibility to intracellular infections.
Here we show that pregnancy-induced post-translational antibody modification allows protection against the prototypic intracellular pathogen. Listeria monocytogenes†
Susceptibility to infection was reversed in neonatal mice born to preconceptually primed mothers who had a L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice.
While maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for the acquisition of protective functions by antibodies, instead requiring sialic acid acetylesterase to deacetylate terminal sialic acid residues on IgG variable region. N-bound glycans. deacetylated L. monocytogenes-specific IgG-protected neonates via the sialic acid receptor CD22
, which suppressed IL-10 production by B cells, leading to antibody-mediated protection. Viewing the maternal-fetal dyad as a conjoined immunological unit reveals protective roles for antibodies against intracellular infection and sophisticated adaptations to enhance host defenses during pregnancy and early life.
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