Although most children who are infected with SARS-CoV-2, the virus that causes COVID-19, experience mild symptoms, a very few develop a hyperinflammatory syndrome due to a specific reaction by their immune systems, according to a recent study co-led by Cedars-Sinai.

The syndrome, known as multisystem inflammatory syndrome in children (MIS-C), is a rare but serious condition in some pediatric COVID-19 patients that can produce persistent fever, abdominal pain, diarrhea, heart problems, rash and severe inflammation affecting many bodily systems. The symptoms resemble toxic shock syndrome, a rare, life-threatening disease triggered by bacteria.

The study found that children with MIS-C were unique because of differences in their T cells—immune cells that help the body fight infection. T cells have receptors on their surfaces that help them recognize invading pathogens. In most people these receptors are quite diverse. However, in this study, it was found that children with MIS-C are more likely to have a limited or single type of T cell receptor. Further, this skewing correlated with the severity of MIS-C and development of a severe and sometimes fatal immune response, known as a cytokine storm, in COVID-19 patients.

"Our findings shed important new light on the mysteries of MIS-C," said Moshe Arditi, MD, director of the Pediatric Infectious Diseases and Immunology Division at Cedars-Sinai. He was corresponding and co-senior author of the study, published in the Journal of Clinical Investigation.

T cell receptor skewing also occurs in toxic shock syndrome as a reaction to so-called bacterial superantigens. To find out if a similar process was driving T cell receptor skewing in MIS-C, the investigators used computer modeling. This approach identified a potentially strong interaction between a specific T cell receptor type and a protein on SARS-CoV-2, the virus that causes COVID-19.

A prior study co-led by Arditi and Ivet Bahar, PhD, at the Pittsburgh School of Medicine discovered that a protein in SARS-CoV-2 is structured like a superantigen. Now the scientists have evidence that children who develop MIS-C have an immune response similar to that raised against superantigens.

"Future investigations are needed to characterize the phenotype and functional properties of T cells involved in this process, in order to provide a complete understanding of how MIS-C develops and progresses," said Arditi, professor of Pediatrics and Biomedical Sciences and the GUESS?/Fashion Industries Guild Chair in Community Child Health.

The other co-senior authors of the study were Bahar from the University of Pittsburgh School of Medicine, and Mascha Binder, MD, from Martin Luther University Halle-Wittenberg in Germany.

Arditi has continued to contribute to this important line of research, including a study published May 25 in the Journal of Clinical Investigation that uncovered how viral particles in the gut help instigate MIS-C.

Funding: Research reported in this publication was funded by the National Institutes of Health under award numbers P41 GM103712, R01 AI072726 and 3RO1AI072726-10S1.