In the past, components of adaptive immunity were thought to play non-overlapping roles in antimicrobial host defense, with antibodies targeting pathogens in the extracellular environment and T cells responsible for eliminating intracellular infections. However, a recent study has shattered this perception. Researchers at Cincinnati Children’s Hospital Medical Center published a research paper in Nature titled: Pregnancy enables antibody protection against intracellular infection.
The study found that pregnancy-induced post-translational antibody modifications enable maternal antibodies to protect infants from Listeria-mediated intracellular infection. Based on this discovery, scientists can develop new drugs to treat diseases and improve vaccines to prevent diseases by simulating the “super antibodies” produced by pregnant women.
Dr. Sing Sing Way, the corresponding author of the study, said: “for many years, scientists believed that antibodies cannotget inside cells. However, the findings suggest that pregnancy changes the structure of certain sugars attached to antibodies, which allows them to get inside cells and protect the baby from a wider range of pathogens. ”
Using methods such as mass spectrometry, the research team first compared the key biochemical differences of antibodies between unmated and pregnant mice, thus determining which specific glycosyl chain modifications of antibodies change during pregnancy, and how and when this change occurred. The team found that sialic acid, a sugar chain on antibodies, changes from acetylation to deacetylation during pregnancy. This very subtle molecular change makes Immunoglobulin G (IgG) respond specifically to the modification of deacetylated sugar chains through the sialic acid receptor CD22, thus stimulating the immune system more strongly and playing a more powerful protective role. “This change acts like a light switch, turning on during pregnancy, allowing maternal antibodies to protect the baby from intracellular infection,” explained the paper’s first author, Dr. John Erickson.
Deacetylated anti-Lm antibodies protect via CD22-mediated suppression of B cell IL-10 production. (Erickson, 2022)
Further research found that this change was driven by Sialic Acid Acetylesterase (SIAE), which is naturally expressed during pregnancy. In addition, the research team also constructed female mice lackingSIAE gene, which were unable to remove the acetylated modification of the sialic acid sugar chain in the antibody after pregnancy, and their pups were also unable to resist the intracellular infection of Listeria. However, when the researchers fed the pups with milk from normal mother mice, they successfully restored immune protection.
Today, more than 200 monoclonal antibodies have been approved by the FDA to treat a variety of diseases, including cancer, autoimmune diseases, multiple sclerosis, and refractory viral and bacterial infections including COVID-19. In addition, many more monoclonal antibodies are in clinical trials, some of which have not shown strong therapeutic effects. Dr. Sing Sing Way said: “The molecular changes in antibodies that naturally occur during pregnancy can be widely used to alter the way antibodies stimulate the immune system to fine-tune its effects. This could lead to improved treatments for infections by other intracellular pathogens, including human immunodeficiency virus (HIV) and respiratory syncytial virus (RSV). “In addition, these findings underscore the importance of vaccinating women of childbearing age, as pregnant women who receive the vaccine can pass on antibodies to their infants through breastfeeding, making them passively immune to infection.”
Overall, the study breaks previous cognitions and proves that maternal antibodies can also protect infants from intracellular infections, paving the way for groundbreaking new treatments that can specifically target infections in pregnant women and newborns. At the same time, these findings will have far-reaching implications for antibody therapy in other areas.
Reference
Erickson, J.J., et al. Pregnancy enables antibody protection against intracellular infection. Nature 606, 769–775 (2022). https://doi.org/10.1038/s41586-022-04816-9