A pioneering study by a collaborative team from several institutions has revealed a critical mechanism behind multisystem inflammatory syndrome in children (MIS-C), a severe COVID-19 complication, offering new insights into this condition and its potential links to other autoimmune diseases.
This research, conducted by a team comprising experts from UC San Francisco, Chan Zuckerberg Biohub San Francisco, St. Jude Children’s Research Hospital, and Boston Children’s Hospital, provides new insights into this complex condition and its potential links to other autoimmune diseases.
Some children who initially showed few or no symptoms, during the early stages of the Covid-19 pandemic, later experienced a sudden and severe onset of MIS-C, a condition marked by widespread inflammation across multiple organ systems that often led to organ failure. While many of them got cured following aggressive treatment, the underlying cause of MIS-C had remained unclear—until now.
The study, published in Nature, reveals that the immune systems of children with MIS-C targeted a component of the coronavirus that closely resembles a protein found in various human tissues, including the heart, lungs, kidneys, brain, skin, eyes, and gastrointestinal tract. This similarity triggered a catastrophic autoimmune response, causing the body to attack its own tissues.
A critical care fellow at UCSF and lead author of the study, Dr. Aaron Bodansky, expressed optimism about the findings, saying: "Thanks to our world-class team, we've pinpointed how children develop this mysterious disease. We hope this approach will advance our understanding of similar autoimmune diseases, such as multiple sclerosis and type 1 diabetes."
The study builds on the work of Dr. Adrienne Randolph, a critical care pediatrician at Boston Children’s Hospital, who had tracked MIS-C cases through a national network of pediatric ICUs. She observed a surge in cases approximately 30 days after peaks in Covid-19 infections, underscoring the crucial link between the viral infection and the onset of MIS-C.
To delve deeper into the phenomenon, UCSF researchers employed Phage Immunoprecipitation Sequencing (PhIP-Seq) to screen blood samples for autoantibodies—antibodies that mistakenly attack the body’s own tissues instead of external threats. They discovered that one-third of MIS-C patients had autoantibodies targeting SNX8, a human protein found in various immune cells.
A significant breakthrough occurred when researchers found that SNX8 closely resembles a portion of SARS-CoV-2’s N protein, providing a clear connection between the virus and the autoimmune response seen in MIS-C. The team discovered that antibodies from MIS-C patients specifically targeted the part of the N protein that resembled SNX8.
In addition to autoantibodies, the study identified the involvement of T cells, which detect and destroy infected cells. The researchers found that certain T cells in MIS-C patients targeted both SNX8 and the viral N protein, a discovery crucial to understanding how the immune system’s mistaken targeting of SNX8 led to severe inflammation and tissue damage.
While most children with MIS-C have since recovered, and cases have become less frequent, especially among vaccinated individuals, the findings have broader implications for autoimmune disease research.
By identifying the specific immune response mechanisms involved in MIS-C, researchers aim to pave the way for new approaches to studying and treating other autoimmune conditions.
"This paper is special because it actually finds the smoking gun—what made these kids so sick," says Dr. Joe DeRisi, president of Chan Zuckerberg Biohub San Francisco and corresponding author of the study. "It opens the door to understanding why so many of these post-infectious, inflammatory autoimmune events occur."
This study marks a significant advancement in understanding autoimmune diseases and offers hope for more effective treatments in the future.