Researchers at the Institute for Systems Biology (ISB) and their collaborators have traced harmful autoantibody production following SARS-CoV-2 infection to a distinct population of B cells. By integrating single-cell, proteomic, genetic, clinical, and laboratory data, the team found that these...
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NEWS RELEASE 28-AUG-2026
ISB researchers identify immune cells that drive harmful autoantibody responses after COVID-19
Multi-omics study uncovers a key cellular pathway linking viral infection to autoimmune responses and points toward future therapeutic targets
Peer-Reviewed Publication
INSTITUTE FOR SYSTEMS BIOLOGY
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SEATTLE — When the immune system encounters a virus, it produces antibodies designed to recognize and eliminate the invader. But in some people infected with SARS-CoV-2, the virus that causes COVID-19, the immune response goes awry, producing autoantibodies — antibodies that mistakenly attack the body's own tissues.
Scientists
have long known that these autoantibodiesare associated with severe COVID-19, Long COVID, and an increased risk of developing autoimmune disease. What has remained unclear is where these harmful antibodies come from.
Researchers at the Institute for Systems Biology (ISB) and their collaborators have now identified the immune cell population responsible for producing them and uncovered the molecular program that drives this response. The findings provide new insight into how viral infections can trigger autoimmune responses and identify biological pathways that could one day become targets for new therapies.
The study, published in the journal
Immunity and led by researchers in
ISB’s Heath Lab, combined multiple cutting-edge technologies to analyze immune responses from participants enrolled in ISB's longitudinal INCOV study of COVID-19. Rather than relying on a single experimental approach, the team integrated single-cell RNA sequencing, chromatin accessibility profiling, plasma proteomics, proteome-wide autoantibody profiling, clinical data, laboratory experiments, and genetic analyses to build a detailed picture of how B cells respond during infection.
"Our goal was to understand why some people produce autoantibodies after SARS-CoV-2 infection while others do not," said
ISB President and Professor Dr. Jim Heath, senior author of the paper. "By combining multiple layers of biological data, we were able to pinpoint the immune cells responsible and identify the regulatory mechanisms that distinguish them."
A Distinct Population of B Cells
The research identified a subset of B cells — known as atypical memory cells — as the primary precursors of autoantibody-producing cells during SARS-CoV-2 infection. While these cells are a normal part of the immune system, the researchers found that individuals with high levels of autoantibodies adopted a markedly different biological program.
Laboratory experiments demonstrated that atypical memory cells from these individuals were especially prone to maturing into antibody-secreting cells that produced autoantibodies. At the same time, the researchers observed that patients with higher autoantibody levels tended to have weaker virus-neutralizing antibody responses, suggesting that this altered response may come at the expense of protective antiviral immunity.
Connecting COVID-19 and Autoimmunity
One of the study's most striking findings was how closely the major subset of atypical memory B cells, called DN2 cells, resembled immune cells previously implicated in autoimmune diseases such as systemic lupus erythematosus.
The researchers found that DN2 cells from patients with elevated autoantibodies showed increased activity in immune signaling pathways controlled by Toll-like receptor 7 (TLR7), along with changes involving the transcription factors T-bet and XBP1. Together, these pathways appear to prime the cells to produce autoantibodies.
Genetic analyses strengthened the connection. Among all B-cell populations examined, DN2 cells showed the strongest enrichment for inherited genetic risk associated with multiple autoimmune diseases, including lupus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, type 1 diabetes, and primary biliary cirrhosis.
“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,” said Dr. Dan Yuan, lead author of the study.
Beyond COVID-19
Although the study focused on COVID-19, the implications extend well beyond a single virus.
The work suggests that infection can reveal underlying immune tendencies that, in genetically susceptible individuals, favor the production of autoantibodies. Understanding this process may ultimately improve scientists' ability to identify patients at higher risk for autoimmune complications and guide development of therapies that interrupt these harmful immune responses before they become established.
"Our findings point to specific immune pathways that could become future therapeutic targets," said Yuan. "By understanding how these cells become activated, we move closer to interventions that could prevent or reduce harmful autoimmune responses following infection."
While additional studies will be needed to determine whether directly targeting these pathways can improve patient outcomes, the researchers say the work provides one of the clearest pictures to date of how infection-induced autoantibody production begins.
“The study also demonstrates the power of ISB's systems biology approach,” Heath said. “By integrating diverse molecular datasets with clinical information and functional experiments, we were able to move beyond identifying associations to uncover the cellular mechanisms that drive disease.”
This study involved collaborative work by scientists at ISB, the University of Washington, Fred Hutchinson Cancer Center, Stanford University, Swedish Medical Center, and Providence.
About ISB
The Institute for Systems Biology (ISB) is a collaborative, cross-disciplinary, non-profit biomedical research organization based in Seattle. We focus on some of the most pressing issues in human health, including aging, brain health, cancer, chronic illness, infectious disease, and more. Our science is translational, and we champion sound scientific research that results in real-world clinical impacts. ISB is an affiliate of Providence, one of the largest not-for-profit healthcare systems in the United States. Follow us online at
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JOURNAL
Immunity
DOI
10.1016/j.immuni.2026.08.002
SUBJECT OF RESEARCH
People
ARTICLE TITLE
A Distinct Effector B Cell Population Drives Autoantibody Production in SARS-CoV-2 Infection
ARTICLE PUBLICATION DATE
28-Aug-2026
