The immune system is the body’s most important defense against disease. It does its essential work by producing proteins called antibodies, which scour the body for disease-causing bacteria, viruses, and other pathogens.
But sometimes the immune system malfunctions and produces autoantibodies (Abs), proteins that mistakenly target the body’s own tissues instead of finding and destroying illness-causing invaders. This is the case in some COVID-infected people, in whom autoantibodies are linked to severe illness, persistent symptoms, and an increased risk of new-onset autoimmune disease.
This sideways immune response has long been recognized in COVID-19, but what’s been unclear is how this errant process gets set in motion.
Now, a new study in Immunity sheds light on the immune cells responsible for producing autoantibodies in COVID-infected people and helps explain the molecular process that drives them.
“Our goal was to understand why some people produce autoantibodies after SARS-CoV-2 infection while others do not,” says Jim Heath, PhD, senior author and president of the Institute for Systems Biology (ISB) in Seattle, in an ISB news release. “By combining multiple layers of biological data, we were able to pinpoint the immune cells responsible and identify the regulatory mechanisms that distinguish them.”
DN2 cells overrepresented in high-autoantibody group
For the study, ISB researchers and their partners analyzed data from 209 COVID-infected participants. From this cohort, the researchers selected 12 age-matched women with markedly different autoantibody levels (autoantibody prevalence is higher in women and older adults).
The team classified the women into two groups—a low-autoantibody group (autoAb-low) and a high-autoantibody group (autoAb-high)—for in-depth analysis. Data were collected before the emergence of the Omicron variant (April 2021) and before participants had been vaccinated. A separate group of 101 participants was used to validate key results.
According to the findings, a subset of immune cells known as atypical memory B cells were more likely to develop into autoantibody-secreting cells in participants in the autoAb-high group than in those in the autoAb-low group.
Our findings suggest that SARS-CoV-2 infection can activate an immune program that closely resembles those involved in established autoimmune disorders, helping explain why some individuals experience autoimmune complications following infection.
Plus, the researchers found, a subtype of atypical memory B cells known as double-negative 2 (DN2) B cells were overrepresented in the high-autoantibody group. DN2 cells have been linked to autoantibody production and may play a role in other autoimmune diseases like lupus.
“A clear difference between autoAb-high and autoAb-low individuals was the enrichment of innate sensing pathways, particularly in DN2s,” write the researchers.
“Our findings suggest that SARS-CoV-2 infection can activate an immune program that closely resembles those involved in established autoimmune disorders, helping explain why some individuals experience autoimmune complications following infection,” lead author Dan Yuan, PhD, of ISB, says in the news release.
While the current study focused on autoantibody responses following SARS-CoV-2 infection, the findings have broader implications. “Our findings point to specific immune pathways that could become future therapeutic targets," Yuan says in the release. "By understanding how these cells become activated, we move closer to interventions that could prevent or reduce harmful autoimmune responses following infection."
