Long COVID antibodies induce persistent pain-like symptoms in mice

A new study coordinated by researchers at UMC Utrecht and Amsterdam UMC shows that antibodies from Long COVID patients can induce persistent pain-like symptoms in mice. This provides evidence for a potential causal role of autoantibodies in Long Covid. These findings open the door to the development of targeted antibody-based therapies for Long COVID in the future.

A growing body of evidence suggests that Long COVID (or post-COVID syndrome), a condition affecting more than 10 percent of people after a SARS-CoV-2 infection, may be driven by the immune system turning against the body. Now, new research coordinated by UMC Utrecht and Amsterdam UMC provides some of the strongest functional evidence yet that autoantibodies (antibodies that mistakenly target the body's own tissues) could play a causal role.

Long COVID is known for its wide range of symptoms, including extreme fatigue, post-exertional malaise (PEM), pain, and cognitive dysfunction ('brain fog'). Despite its prevalence, the biological mechanisms behind the condition remain poorly understood. Previous studies have hinted at immune dysregulation and the presence of autoantibodies, but whether these molecules actively drive symptoms has remained unclear.

Antibodies that transfer symptoms

In the study, researchers injected immunoglobulin G (IgG) - a major class of antibodies – derived from blood of 34 patients with Long COVID, into mice. The result was striking as the animals developed persistent pain-like hypersensitivity. This effect lasted for at least two weeks. Even more notable, IgG collected from the same patients two years later reproduced the same symptoms when administered to mice.

This finding suggests that the underlying disease mechanism may persist long after the initial infection, potentially explaining why many patients experience long-term symptoms."

Prof. Niels Eijkelkamp, PhD, co-study lead, Center for Translational Immunology, UMC Utrecht

Distinct biological subgroups

To better understand the condition, researchers analyzed blood samples from Long COVID patients and identified distinct subgroups based on markers of brain injury (GFAP, NFL) and immune activation (interferon-β). These subgroups displayed unique molecular signatures in large-scale protein analyses. When autoantibodies from these different groups were tested in mice, they produced distinct patterns of symptoms. Co-study lead Jeroen den Dunnen, PhD (Center for Infection and Molecular Medicine, Amsterdam UMC) added: "This finding supports the idea that Long COVID is not a single condition but a heterogeneous disease with different biological drivers."

A landscape of autoimmunity

The team also found that Long Covid patients carry elevated levels of autoantibodies that target a wide range of the body's own proteins, from those involved in immune regulation, nerve signaling, and metabolism. Many of these autoantibodies persisted for years and differed between the specific patient subgroups. "What's is really striking", say both co-leads of the study, "is that three independent research groups have recently reported similar findings, adding confidence to the emerging autoimmune signature of Long COVID". In addition, in other diseases with overlapping symptoms, patient-derived antibodies can also induce symptoms in animal models, such as fibromyalgia, pointing to shared immunological pathways.

Toward targeted treatments

While the study has limitations, including its relatively small size, single-center design and the use of pooled samples, it provides compelling evidence that IgG autoantibodies may actively contribute to Long COVID symptoms. The results also point toward new treatment strategies. Therapies that are able to remove or neutralize harmful antibodies, such as immunoadsorption, plasmapheresis or targeted immunotherapy, could offer relief, particularly if tailored to specific biological subtypes.

As researchers continue to unravel the complexity of Long COVID, this study marks an important step toward understanding and potentially treating this persistent and often debilitating condition.