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COVID-triggered autoimmunity may be mostly temporary
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Brian Katzowitz
Rosemary Pitrone
Antibodies and antibody background and Immunoglobulin concept as t cells attacking contagious virus cells and pathogens as a 3D illustration.

In a new study, Emory researchers isolated thousands of antibody-secreting cells from COVID-19 patients who were in intensive care at Emory hospitals. They explored in detail what COVID-19-generated autoantibodies react against, both during acute infection and later.

New findings on COVID-19-triggered autoimmunity have implications for both the treatment of acute infection and for people with long COVID, in which self-targeted antibodies have emerged as a key characteristic.

It appears that during a severe COVID-19 infection, the immune system sabotages itself by generating a wide variety of autoantibodies: proteins that are usually tools for defense, but in this situation, attack the body’s own tissues.

The results are published in Nature.

During acute infection, COVID-19 patients’ immune systems resemble those of people with diseases such as lupus or rheumatoid arthritis, for whom autoantibodies contribute to symptoms such as fatigue, skin rashes and joint pain. However, after the storm passes, the autoantibodies decay and are mostly removed from the body over time. This was the case for most hospitalized patients who then recovered.

“The immune system can make mistakes under duress,” says Emory immunologist Matthew Woodruff, PhD, who is co-first author of the paper. “It temporarily loses sight of the viral target and produces self-targeting antibodies. Often the situation will eventually resolve and cause no further disease.”

For a moderate number of people with long COVID —about one third —their levels of some types of autoantibodies fall but remain elevated above normal for months after the initial infection. Follow-up studies are now underway to understand just how long these misdirected immune responses may last.

Testing for autoantibodies during acute infection may enable identification of some patients who need early intervention to head off problems later. One type of antibody (against carbamylated proteins) seems to closely correlate with overall autoimmunity. In addition, therapies that deplete autoantibody activity may improve longer-term recovery outcomes, the Emory investigators suggest.

Critically, high levels of autoantibodies were also observed in hospitalized patients with bacterial pneumonia, suggesting the triggering of autoimmunity is not limited to SARS-CoV-2 infection and occurs in other settings during intense inflammation. This finding may influence scientific understanding of post-viral chronic illnesses more broadly.  

In the Nature paper, researchers led by Ignacio Sanz, MD, and F. Eun-Hyung Lee, MD, isolated thousands of antibody-secreting cells from seven COVID-19 patients who were in intensive care units (ICUs) at Emory hospitals. They explored in detail what COVID-19-generated autoantibodies react against, both during acute infection and later.

In addition, researchers looked for markers of autoimmunity in a larger group of COVID-19 ICU patients and outpatients, comparing them to people who were in intensive care because of bacterial pneumonia. Researchers also obtained samples from people with lupus, along with patients from Emory’s post-COVID clinics.

“We were trying to address the question: what is the origin of the autoantibodies?” Sanz says.

That is, are they newly generated early during the course of infection from inexperienced naïve B cells? Or were the immune cells capable of making the observed autoantibodies already existing in the immune system memory and let loose by the infection?

“It appears that new generation of autoreactive clones from naïve cells is a dominant mechanism in acute severe infection,” he says. “What we see is a broad breakdown of tolerance, at least temporarily.”

Woodruff, an instructor in Sanz’s lab, and Richard Ramonell, MD, a former fellow in Lee's lab and in pulmonary and critical care medicine at Emory University Hospital, co-first authored the work. In some of the experiments, Emory researchers collaborated with the biotech company Exagen, using technology developed by Exagen to probe clinical autoimmune profiles.

Sanz says that the question of whether autoantibodies — or perhaps, lingering autoreactive cells — contribute to persistent symptoms needs to be tested in a larger group of COVID-19 patients. Autoimmunity is not thought to be the only mechanism for long COVID symptoms. Sanz and Lee’s laboratories continue to examine people with severe COVID-19 and those who recovered, as well as outpatients, including those with long-haul symptoms. 

“This is something we are going to have to follow,” he says. “We also need to compare this to other viral infections that have been associated with autoimmunity.”

“It will be important to know exactly how much these misdirected antibodies are contributing in patients with debilitating symptoms of long COVID. Since more than half of patients that we tested had signs of autoreactivity, there may be a wide opportunity to intervene if these antibodies really are pathogenic.” 

Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology and a Georgia Research Alliance Eminent Scholar. Lee is associate professor of medicine and director of Emory’s Asthma/Allergy Immunology program.

The research was supported by the National Cancer Institute (SeroNet, U54CA260563), the National Institute of Allergy and Infectious Diseases (U19AI110483 — Emory Autoimmunity Center of Excellence, P01AI125180, R37AI049660, R01AI121252, U01AI141993) and the National Heart Lung and Blood Institute (T32HL116271).

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