New research offers evidence that autoimmunity—in which the body’s immune system targets its own tissues—is a driver in some cases of Long COVID.
Why COVID-19 sometimes leads to Long COVID still confounds doctors, but researchers have several hypotheses to explain its often-debilitating symptoms. These include lingering SARS-CoV-2 remnants, the reactivation of latent viruses as the Epstein-Barr virus, infection-induced tissue damage, and autoimmunity.
Now, in this new study, when researchers transferred antibodies from patients with Long COVID into healthy mice, the animals began exhibiting symptoms including heightened pain sensation and dizziness. The study is among the first to show a causal link between antibodies and Long COVID symptoms. It was posted as a preprint on medRxiv on June 19.
“We’re very excited to have a mechanism to study and learn more about so we can help people with specific reported symptoms,” says Akiko Iwasaki, PhD, Sterling Professor of Immunobiology and the study’s principal investigator at Yale School of Medicine.
We believe this is a big step forward in trying to understand and provide treatment to patients with this subset of Long COVID.
Akiko Iwasaki, PhD
Several factors prompted Iwasaki’s team to zero in on autoimmunity as one of Long COVID’s drivers. First, there was the persistent nature of the condition. “This suggested to us that there is some chronic triggering of an immune response that is pathogenic,” she says.
Second, women between the ages of 30 and 50 are among the most susceptible to Long COVID. Women in this age group also face a greater risk of autoimmune diseases in general. Finally, in earlier research, Iwasaki’s team detected significant levels of autoantibodies in individuals who were infected with SARS-CoV-2. “All of these things were pointing to the possibility of autoimmune responses being one of the triggers of Long COVID,” Iwasaki says.
Human antibodies induced Long COVID symptoms in mice
In their latest study, Iwasaki’s team analyzed blood samples from patients in the Mount Sinai-Yale Long COVID study. This cohort of over 215 Long COVID patients is part of a collaboration between Iwasaki and David Putrino, PhD, professor in the Department of Rehabilitation and Human Performance at Icahn School of Medicine at Mount Sinai in New York City. As part of this joint effort, Putrino’s clinic obtained blood samples from patients enrolled in the study. Iwasaki’s laboratory then purified antibodies from the blood and transferred them into healthy mice.
Next, the researchers led by Keyla Sá, a postdoctoral fellow in Iwasaki’s lab, conducted multiple behavioral experiments to look for Long COVID symptoms. While many of these experiments found no significant difference between the experimental and control mice, a few revealed striking changes in those that received antibodies.
In one such experiment, researchers placed the mice on a heated plate and measured how long it took for them to react. Some mice that received antibodies reacted significantly more quickly to the heat, indicating a heightened sensitivity to pain. The researchers went back and identified the patients whose antibodies had been injected into the mice. Interestingly, these patients reported pain as one of their Long COVID symptoms.
Another experiment was the rotarod test, in which researchers placed mice on a rotating cylinder to measure coordination and balance. Mice that received antibodies were more likely to struggle to stay on the apparatus. Once again, when the researchers looked at the source of these antibodies, they learned that they were mostly from patients who reported suffering from dizziness.
The mice also underwent a grip strength test, in which researchers measured the force applied by the animals to a grid apparatus. A group of mice were found to have reduced muscle strength if they received antibodies from patients reporting tinnitus and headache. Thus, antibodies capable of impairing muscle function are found in patients with these symptoms. How exactly these antibodies cause pathology needs more studies.
Treatments targeting autoimmunity may help some Long COVID patients
Developing diagnostic tools and therapies for Long COVID will require knowledge of its underlying disease mechanisms. The new study offers important evidence that autoimmunity is one of these contributors. Recently, the autoimmunity hypothesis has been further supported by a research group in the Netherlands led by Jeroen den Dunnen, DRS, associate professor at Amsterdam University Medical Center, which posted a preprint a couple of weeks earlier also showing a link between patients’ Long COVID antibodies and corresponding symptoms in mice. “We believe this is a big step forward in trying to understand and provide treatment to patients with this subset of Long COVID,” says Iwasaki.
Intravenous immunoglobulin (IVIg) is commonly used as treatment for various autoimmune disorders such as lupus, for example—antibodies from healthy human donors are given to patients in the hope that they will alleviate or reduce symptoms. This therapy may also have promise in treating cases of Long COVID caused by autoimmunity. A 2024 Yale-led study led by Lindsey McAlpine, MD, instructor at YSM and first author, and Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology and principal investigator, suggests that this type of treatment may be beneficial in treating small fiber neuropathy associated with Long COVID. (Small fiber neuropathy, a condition in which patients suffer numbness or pain in their hands or feet, occurs in some cases of Long COVID.) Iwasaki hopes that future clinical trials may show potential in treating some of the other painful symptoms of the disease.
Furthermore, researchers are developing other biologics, or drugs produced from living organisms, that may also help Long COVID patients, including FcRn inhibitors. FcRn is a receptor that binds to antibodies and recycles them. Through blocking this receptor, these drugs can reduce levels of circulating antibodies. This type of drug was recently approved by the Food and Drug Administration (FDA) for the treatment of myasthenia gravis, another kind of autoimmune disease.
The study also offers insights for developing diagnostic tools to identify which patients will benefit from these kinds of treatments. “Targeted therapy is going to be key for each of these subsets of Long COVID,” says Iwasaki. “This study demonstrates that we can identify people with pathological antibodies.”
Future studies to focus on autoimmunity pathogenesis in Long COVID and new therapeutics
In future studies, Iwasaki hopes to explore further why and how autoantibodies cause disease in Long COVID. She also hopes to conduct randomized clinical trials for testing therapeutics targeting autoimmunity. In addition to IVIg and FcRn inhibitors, she believes there are a range of promising treatments for reducing antibodies, including B cell depletion therapy and plasmapheresis.
Unfortunately, it’s highly unlikely that a single drug could cure everyone with Long COVID, she says. While this study focuses on autoantibodies, the disease likely has multiple underlying causes, and different subtypes will require different treatments. Iwasaki is also working closely with Harlan Krumholz, MD, Harold H. Hines, Jr. Professor of Medicine (Cardiology), on the Yale Paxlovid for Long COVID (PAX LC) Trial. This trial is testing the lingering virus hypothesis by investigating the efficacy of a 15-day course of the antiviral Paxlovid in treating Long COVID.
There are many avenues for future studies, but in the meantime, Iwasaki is excited about her team’s promising results. “Seeing this one-to-one correlation of antibodies that cause pain from patients who reported pain is really gratifying to me as it suggests a causal link,” she says. “It’s a first step, but I think it’s a big one.” Iwasaki’s team is currently expanding these antibody transfer studies to other post-acute infection syndromes including myalgic encephalomyelitis/chronic fatigue syndrome.