In people with severe COVID-19, the immune system goes temporarily berserk and generates a wide variety of autoantibodies: proteins that are tools for defense, but turned against the body’s own tissues.
During acute infection, COVID-19 patients’ immune systems resemble those of people with diseases such as lupus or rheumatoid arthritis. However, after the storm passes, the autoantibodies decay and are mostly removed from the body over time, according to a study of a small number of patients who were hospitalized and then recovered.
In a preprint posted on medRxiv, Emory immunologists provide a view of the spectrum of what COVID-generated autoantibodies react against, both during acute infection and later. Note: the results have not yet been published in a peer-reviewed journal.
The findings on COVID-19-triggered autoimmunity may have implications for both the treatment of acute infection and for long-haulers, in whom autoantibodies are suspected of contributing to persistent symptoms such as fatigue, skin rashes and joint pain.
During acute infection, testing for autoantibodies may enable identification of some patients who need early intervention to head off problems later. In addition, attenuation of autoantibody activity by giving intravenous immunoglobulin (IVIG) – an approach that has been tested on a small scale — may help resolve persistent symptoms, the Emory investigators suggest.
Researchers led by Ignacio Sanz, MD and Frances Eun-Hyung Lee, MD, isolated thousands of antibody-secreting cells from 7 COVID-19 patients who were in ICUs at Emory hospitals. They also looked for markers of autoimmunity in a larger group of 52 COVID-19 ICU patients.
A recent paper from Emory pathologist Cheryl Maier and colleagues provides more evidence for autoantibodies in critically ill COVID-19 patients. Autoantibodies are signs that the immune system attacking the body itself, and are features of diseases such as lupus and rheumatoid arthritis. They have been proposed as an explanation for the severity of some acute COVID-19 cases, as well as continued symptoms in long COVID.
Generally, antibodies are a good thing, and a major goal of COVID-19 vaccination is to drive the immune system to generate protective antibodies against the coronavirus. With autoantibodies and COVID, the idea is that intense inflammation coming from viral infection is causing immune cells to become confused. Not every COVID-19 patient’s immune system goes off the rails, but the train wreck seems to happen more often in COVID-19.
However, in the current paper in Cell Reports Medicine, autoantibodies were also found in most control samples from intensive care unit patients with pneumonia or sepsis, who are experiencing a state of systemic inflammation comparable to severe COVID-19.
“It’s a reminder that autoantibodies are not necessarily unique to COVID,” Maier says. “They may be more dramatic in COVID, but we see autoantibodies associated with other severe diseases too.”
Maier is medical director for Emory’s Special Coagulation Laboratory, and her team came to the autoimmunity question from a side angle. They were investigatingblood clots and hyperviscosity in COVID-19 patients, and wanted to check whether high concentrations of antibodies might be an explanation. Antibodies are proteins, after all, and if someone’s blood is full of them, they thicken it.
Post-acute is a confusing term, because it includes both people who were hospitalized with COVID-19, sometimes spending weeks on a ventilator or in an intensive care unit, as well as members of the long COVID group, who often were not hospitalized and did not seem to have a severe infection to begin with.
COVID-19 infection can leave behind lung or cardiac damage that could explain why someone would have fatigue and shortness of breath. But there are also signs that viral infection can perturb other systems of the body, leading to symptoms such as “brain fog” (cognitive/memory problems), persistent pain and/or loss of smell and taste.
One goal for the workshop was to have experts discuss how to design future studies, or how to take advantage of existing studies to gain insights. A major clue on what to look for comes from Emory immunologist Ignacio Sanz, who spoke at the conference.
Sanz’s research has shown similarities between immune activation in people hospitalized at Emory with severe COVID-19 and in people with the autoimmune disease lupus. In lupus, the checks and balances constraining the immune system break down. A characteristic element of lupus are autoantibodies: antibodies that recognize parts of the body itself. Their presence in COVID-19 may be an explanation for the fatigue, joint pain and other persistent symptoms experienced by some people after their acute infections have passed.
For details on Sanz’s research, please see our write-up from October, their Nature Immunology paper, and first author Matthew Woodruff’s explainer. The Nature Immunology paper’s results didn’t include measurement of autoantibodies, but a more recent follow-up did (medRxiv preprint). More than half of the 52 COVID-19 patients tested positive for autoantibodies at levels comparable to those in lupus. In those with the highest amounts of the inflammatory marker CRP, the proportion was greater.
“It could be that severe viral illness routinely results in the production of autoantibodies with little consequence; this could just be the first time we’re seeing it,” Woodruff writes in a second explainer. “We also don’t know how long the autoantibodies last. Our data suggest that they are relatively stable over a few weeks. But, we need follow-up studies to understand if they are persisting routinely beyond infection recovery.”
Sanz’s group was looking at patients’ immune systems when both infection and inflammation were at their peaks. They don’t yet know whether autoantibodies persist for weeks or months after someone leaves the hospital. In addition, this result doesn’t say what is happening in the long COVID group, many of whom were not hospitalized.
It makes sense that multiple mechanisms could explain post-COVID impairments, including persistent inflammation, damage to blood vessels or various organs, and blood clots/mini-strokes.
Anthony Komaroff from Harvard, who chaired a breakout group on neurology/psychiatry, said the consensus was that so far, direct evidence of viral infection in the brain is thin. Komaroff said that neuro/psych effects are more likely to come from the immune response to the virus.
There were breakout groups for different areas of investigation, such as cardiovascular, and gastrointestinal. Emory Vaccine Center director Rafi Ahmed co-chaired a session for immunologists and rheumatologists, together with Fred Hutch’s Julie McElrath.
Reports from the breakout groups Friday emphasized the need to design prospective studies, which would include people before they became sick and take baseline samples. Some suggestions came for taking advantage of samples from the placebo groups in recent COVID-19 vaccine studies.