Summary: Study reveals how early days of maternally provided immunity work and what it could mean to prevent death and disability from a wide range of infectious diseases. The results could allow the development of new therapies and improved vaccines that mimic raised maternal antibodies.
Source: Cincinnati Children’s Hospital
Scientists discovered years ago that newborns depend on immune components transferred from their mothers to survive the onslaught of pathogens that begin to invade their bodies as soon as they are born.
Eventually, children develop their own immune system, built through surviving natural exposures to viruses and bacteria, and augmented by a phalanx of well-established childhood vaccines.
But in the meantime, it’s one of the most important gifts of a mother who protects her baby: antibodies.
Now, a large study published on June 8, 2022, in Nature, provides a startling explanation of how these early days of maternally provided immunity really worked – and what this information could mean in preventing death and disability from a wide range of infectious diseases.
The results suggest that researchers may be able to mimic the boosted antibodies expectant mothers produce to create new drugs to treat diseases as well as improved vaccines to prevent them.
“For many years, scientists believed that antibodies could not penetrate inside cells. They don’t have the necessary machines. Thus, infections caused by pathogens that live exclusively inside cells were considered invisible to antibody-based therapies,” says Sing Sing Way, MD, PhD, Division of Infectious Diseases at Cincinnati Children’s.
“Our results show that pregnancy alters the structure of certain sugars attached to antibodies, allowing them to protect babies against 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 first author of the study.
Way and Erickson are both part of the Cincinnati Center for Children’s Inflammation and Tolerance and Perinatal Institute, which strives to improve outcomes for all pregnant women and their newborns.
Erickson continues, “This special connection begins when babies are in the womb and continues after birth. I love seeing the closeness between mothers and babies in our neonatal care units. This discovery paves the way for pioneering new therapies that can specifically target infections in pregnant women and newborns. I believe these findings will also have far-reaching implications for antibody-based therapies in other fields.
How mothers make super antibodies
The new study identifies which 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) changes to the ‘deacetylated’ form. This very subtle molecular change allows immunoglobulin G (IgG) – the body’s most common type of antibody – to take on an expanded protective role by stimulating immunity through receptors that respond specifically to deacetylated sugars.
“This change is the light switch that allows maternal antibodies to protect babies against infection inside the cells,” says Way.
“Mothers always seem to know best,” adds Erickson.
Accelerated antibodies can be produced in the lab
Using advanced mass spectrometry techniques and other methods, the research team identified key biochemical differences between antibodies from virgin mice and those from pregnant mice. They also identified the enzyme naturally expressed during pregnancy responsible for this transformation.
Additionally, the team was able to restore lost immune protection by providing supplies of lab-grown antibodies from healthy pregnant mice to puppies born to mothers whose genes were altered to lack the ability to eliminate antibody acetylation to improve protection.
Hundreds of monoclonal antibodies have been produced as potential treatments for various disorders, including cancer, asthma, multiple sclerosis, as well as hard-to-shake viral and bacterial infections, including rapidly developing new treatments for COVID. -19. Some are already FDA approved, many more are in clinical trials, and some haven’t shown solid results.
Way says the molecular alteration of antibodies that occurs naturally during pregnancy can be replicated to change 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 accelerate vaccine development
“We’ve known for years about the many tremendous benefits of breastfeeding,” says Erickson. “A major factor is the transfer of antibodies into breast milk.”
The study shows that the molecular switch persists in breastfeeding mothers, so the antibodies with enhanced protective range are also transferred to babies through breast milk.
Additionally, Way says the findings underscore 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 are particularly important in women during pregnancy or in newborns.
“Immunity has to exist in the mother for it to be transferred to her child,” says Way. “Without natural exposures or vaccine-primed immunity, when that switch goes on during pregnancy, there’s no electricity behind it.”
About the study
A patent on antibody modification of sialic acid was filed by Cincinnati Children’s Hospital with first author Erickson and senior author Way as inventors (PCT/US2022/018847).
Besides Erickson and Way, the study of Nature was co-authored by 9 Cincinnati Children’s and University of Cincinnati researchers: 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 Roswell Park Comprehensive Cancer Center in Buffalo.
Funding: Funding sources included grants from the National Institutes of Health (F32AI145184x, K12HD028827, DP1AI131080, R01AI145840, R01AI124657, U01AI144673, T32DK007727, R24GM137782, R01GM094363, and R01AI162964); the HHMI Faculty Scholarship Program; the Burroughs Welcoming Fund; collaboration with the March of Dimes Foundation Ohio; and GlycoMIP, a National Science Foundation Materials Innovation Platform funded by cooperative agreement DMR-1933525.
About this immunology research news
Original research: Access closed.
“Pregnancy allows antibody protection against intracellular infection” by John Erickson et al. Nature
Pregnancy allows antibody protection against intracellular infection
Adaptive immune components are thought to exert non-overlapping roles in host antimicrobial defense, with antibodies targeting pathogens in the extracellular environment and T cells clearing infection inside cells. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections.
Here, we show that pregnancy-induced post-translational antibody modification affords protection against the prototypical intracellular pathogen. Listeria monocytogenes.
Susceptibility to infections was reversed in newborn mice born to preconceptually primed mothers possessing L. monocytogenes-IgG specific or after passive transfer of antibodies from primed pregnant, but not virgin, mice.
Although maternal B cells were essential for producing IgGs that provide the vertically transferred protection, they were indispensable for the acquisition of antibodies of the protective function, which instead required sialic acid acetyl esterase to deacetylate the terminal sialic acid residues on the variable region of IgG. NOT-linked glycans. Deacetylated L. monocytogenes-newborns protected by specific IgG via the CD22 sialic acid receptor
, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the mother-fetus dyad as an attached immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defense during pregnancy and early life.
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