Antibodies developed in immune response may influence COVID-19 outcomes

Levels of specific antibodies developed in the immune response may influence novel coronavirus (COVID-19) outcomes in both children and adults, according to new research from Massachusetts General Hospital (MGH), the Ragon Institute of MGH, Massachusetts Institute of Technology, and Harvard University published in the journal Nature Medicine.

COVID-19 may be caused by a single virus, but it has a variety of presentations that make treatment difficult, the researchers said. Children, for example, almost exclusively experience mild or asymptomatic COVID-19, while adults can develop severe or even fatal COVID-19. 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, the researchers said.

The research team wanted to understand why COVID-19 can lead to such distinctly different outcomes in different populations. They identified 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. Specifically, 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, according to the study.

Researchers Galit Alter, PhD, core member of the Ragon Institute of MGH, MIT and Harvard, and Lael Yonker, MD, director of the Massachusetts General Hospital Cystic Fibrosis Center teamed up for the study. When the pandemic hit, Yonker began to collect samples from children with mild cases of COVID-19. When she 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 Alter, who is also a 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.

For adults with severe COVID-19, the researchers 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, it may be a high level of a specific type of antibody causing the disease severity, according to the study.

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, the researchers said. 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.

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