Antibodies From Long COVID Patients Provide Clues to Autoimmunity Hypothesis

Promising new research supports that autoimmunity—in which the immune system targets its own body—may contribute to Long COVID symptoms in some patients.

As covered previously in this blog, researchers have several hypotheses to explain what causes Long COVID, including lingering viral remnants, the reactivation of latent viruses, tissue damage, and autoimmunity.

Now, in a recent study, when researchers gave healthy mice antibodies from patients with Long COVID, some of the animals began showing Long COVID symptoms—specifically heightened pain sensitivity and dizziness. It is among the first studies to offer enticing evidence for the autoimmunity hypothesis. The research was led by Akiko Iwasaki, PhD, Sterling Professor of Immunobiology at Yale School of Medicine (YSM).

“We believe this is a big step forward in trying to understand and provide treatment to patients with this subset of Long COVID,” Iwasaki said.

Iwasaki zeroed in on autoimmunity in this study for several reasons. First, Long COVID’s persistent nature suggested that a chronic triggering of the immune system might be at play. Second, women between ages 30 and 50, who are most susceptible to autoimmune diseases, are also at a heightened risk for Long COVID. Finally, some of Iwasaki’s previous research had detected heightened levels of antibodies in people infected with SARS-CoV-2.

Mice given antibodies show signs of Long COVID symptoms

Iwasaki’s team isolated antibodies from blood samples obtained from the Mount Sinai-Yale Long COVID study. They transferred these antibodies into mice and then conducted multiple experiments designed to look for changes in behavior that may indicate the presence of specific symptoms. For many of these experiments, mice that received antibodies [the experimental group] behaved no differently than mice that had not [the control group].

However, a few experiments revealed striking changes in the behavior of the experimental mice. These included:

1. Pain sensitivity test: Some experimental mice were quicker to react after being placed on a heated plate.
2. Coordination and balance test: Some experimental mice struggled to balance on a rotarod (rotating rod) compared to control mice.
3. Grip strength test: Some of the experimental mice applied less force with their paws.

Among the mice that showed behavioral changes, the researchers identified which patients their antibodies came from and what symptoms they had experienced. Interestingly, of the mice that showed heightened pain, 85% received antibodies from patients that reported pain as one of their Long COVID symptoms. Additionally, 89% of mice that had demonstrated loss of balance and coordination on the rotarod test had received antibodies from patients who reported dizziness. Furthermore, 91% of mice that showed reduced strength and muscle weakness received antibodies from patients who reported headache and 55% from patients who reported tinnitus. More research is needed to better understand this correlation.

The autoimmunity hypothesis has recently been further supported by a research group in the Netherlands led by Jeroen den Dunnen, DRS, associate professor at Amsterdam University Medical Center, which also found a link between patients’ Long COVID antibodies and corresponding symptoms in mice.

Treatments for autoimmunity may help some Long COVID patients

Diagnosing and treating Long COVID requires doctors to understand what causes the disease. The new study suggests that treatments targeting autoimmunity, such as B cell depletion therapy or plasmapheresis, might alleviate symptoms in some patients by removing the disease-causing antibodies.

Intravenous immunoglobulin (IVIg) is another therapy used for treating autoimmune diseases like lupus in which patients receive antibodies from healthy donors. While its exact mechanism is still unclear, the treatment can help modulate the immune system and reduce inflammation. Could this treatment help cases of Long COVID that are caused by autoimmunity?

A 2024 study led by Lindsey McAlpine, MD, instructor at YSM and first author, and Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology at YSM and principal investigator, found that IVIg might help improve small fiber neuropathy—a condition associated with numbness or painful sensations in the hands and feet—caused by Long COVID. Iwasaki is hopeful that future clinical trials might reveal the benefits of this treatment in helping some of the other painful symptoms of the diseases.

Other drugs are also in the pipeline, such as FcRn inhibitors. FcRn is a receptor that binds to antibodies and recycles them. Blocking this receptor could help bring down levels of circulating antibodies in the blood. An FcRn receptor was recently approved by the FDA for treating myasthenia gravis, another kind of autoimmune disease.

The study could also help researchers create diagnostic tools for evaluating which patients have Long COVID induced by autoimmunity so that doctors can identify who is most likely to benefit from treatments such as these.

Iwasaki plans to continue researching why and how autoantibodies might cause Long COVID, as well as conduct randomized clinical trials on promising treatments. She is also conducting similar antibody transfer studies in other post-acute infection syndromes, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

In the meantime, she 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.”

Isabella Backman is associate editor and writer at Yale School of Medicine.

The last word by Lisa Sanders, MD:

I am very excited by this research, which suggests that at least some of the symptoms of Long COVID are driven by autoimmunity. If so, then this suggests that there may be a way to test for some versions of Long COVID. And if we could identify the patients who have an autoimmune-driven disease, we have treatments to try that have been used with success in other autoimmune diseases. Many of the autoimmune diseases are treated with medications that suppress the immune system. These are powerful medicines that can leave an individual at risk for infection, so they must be thoughtfully applied to patients with evidence of immune system involvement.

I feel as though every blog post here ends with the possibility of better testing and better treatment, but what makes this different is that it points in a very specific direction and leads to the kind of specific questions that help get to useful answers. Which antibodies are involved? Which cells? And finally, can we develop treatments that are specific to those antibodies or to their targets? These are exciting questions, which will, I hope, lead to useful answers.

Read other installments of Long COVID Dispatches here.

If you’d like to share your experience with Long COVID for possible use in a future post (under a pseudonym), write to us at: LongCovidDispatches@yale.edu

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