COVID-19’s wide range of symptoms has been a particularly challenging piece of the disease’s puzzle to figure out. For children, the situation is even more complicated as they almost exclusively experience mild or asymptomatic COVID-19. But children who contract COVID-19 are at risk for a rare but serious syndrome called multisystem inflammatory syndrome in children (MIS-C). Severe cases of MIS-C can lead to cardiac disease and ventricular failure and require hospitalization and intense medical support.
In a recent study, researchers identified immune mechanisms that result in these disparate clinical phenotypes in children could provide critical insights into COVID-19 pathogenesis. More specifically, they found specific types of antibodies that may be driving these different responses, including one specific to severe disease in adults and another specific to MIS-C in children.
Their work is published in Nature Medicine, in the article, “Humoral signatures of protective and pathological SARS-CoV-2 infection in children.”
“We noticed children who developed MIS-C after COVID disease or exposure had high levels of a specific type of antibody called IgG,” said Lael Yonker, MD, director of the Massachusetts General Hospital Cystic Fibrosis Center. “Normally, IgG acts to control an infection, but with MIS-C, the IgG is triggering activation of immune cells, which may be driving the severe illness seen in MIS-C.”
Specifically, explained Yonker, IgG antibodies interact with cells called macrophages, which live throughout the body’s tissues. If there are too many IgG bodies activating these macrophages, this could cause inflammation in many different organs and systems, which is seen in MIS-C. These high levels of IgG antibodies were only found in children who developed MIS-C after contracting or being exposed to COVID-19.
Yonker, a pediatric pulmonologist at Massachusetts General Hospital (MGH) and assistant professor at Harvard Medical School (HMS), runs a biorepository that collects samples from pediatric cystic fibrosis patients. When the pandemic hit, she began to collect samples from children with mild cases of COVID-19. When Yonker and other pediatricians began seeing children hospitalized with what is now called MIS-C, which typically onsets three to six weeks after developing COVID-19, she quickly began collecting those samples too. She wanted to understand how a mild case of COVID-19 could lead to severe MIS-C weeks after recovery.
Seeking a detailed understanding of the immune response, Yonker teamed up with Galit Alter, PhD, professor at HMS and an immunologist in the department of infectious diseases at MGH. Alter’s team used her unique “systems serology” technology to carefully perform a detailed comparison of the immune responses in children—17 with MIS-C and 25 with mild COVID-19—to the responses of 26 adults with severe disease and 34 adults with mild disease.
“We were expecting the children’s immune responses to look drastically different from the adults’, regardless of the severity of disease,” said Alter. “But instead, we found that adults with mild COVID-19 and children with COVID-19 had remarkably similar immune responses. It was only the adults with severe COVID-19 whose immune responses looked different.”
For adults with severe COVID-19, Alter explained, they saw increased levels of IgA antibodies, which interact with a type of immune cells called neutrophils and cause the neutrophils to release cytokines. If there are too many IgA antibodies, the neutrophils may be pushed to release too many cytokines, which could contribute to a cytokine storm, one of the symptoms of severe COVID-19.
In both cases, the study shows, it may be a high level of a specific type of antibody causing the disease severity. “In MIS-C, high levels of IgG antibodies may be activating macrophages, which can drive inflammation in organs throughout the body,” said Yannic Bartsch, PhD, the study’s first author and a research fellow at the Ragon Institute. “In adults with severe COVID-19, high levels of IgA antibodies could be driving neutrophils to release too many cytokines, with the potential of causing a cytokine storm.”
Identifying the immune mechanisms of multiple, distinct responses to the same virus is the first step to understanding why it mounts different responses in divergent populations. Discovering how the immune system’s response shapes the disease and its outcome in both children and adults can help researchers develop treatments that can prevent or modulate the immune response, keeping its protective functions but lessening the unintentional, yet harmful, ones.