Amsterdam institute for Immunology and Infectious diseases

A preprint by researchers from the Amsterdam Institute for Immunology and Infectious diseases, in collaboration with the University Medical Center Utrecht, Sanquin, and Vrije Universiteit Amsterdam, on bioRxiv has led to exceptional attention, with both Science and Nature featuring news articles about it on their websites. What findings have our researchers uncovered about Long COVID?

Scientists estimate that around 10–20% of people infected with the SARS-CoV-2 coronavirus will develop Long COVID, a severe condition characterized by symptoms such as intense fatigue, debilitating brain fog, and chronic pain that persist for at least three months after the initial infection. Affecting at least 65 million people worldwide, the causes of Long COVID remain poorly understood, and there are currently no proven treatments.

"Autoimmunity is frequently observed in Long COVID patients. But until now, the main unanswered question remained: is the relationship between autoantibodies and Long COVID causal?" says Jeroen den Dunnen, an infectious disease researcher at Amsterdam UMC. "In other words, do autoantibodies cause Long COVID symptoms, or are they simply generated in response to the infection?" Den Dunnen and his colleagues conducted the latest study to find an answer.

Research Methods and Findings

To explore this mechanism, den Dunnen and his colleagues collected IgG antibodies — the most common type found in human bodily fluids — from the blood of 34 people (analyzing plasma from 31 of them). The participants, who averaged 43 years old, developed Long COVID after mild SARS-CoV-2 infections during the first two years of the pandemic. Most experienced fatigue and chronic pain, requiring time off work.

The researchers divided the participants into groups based on the concentrations of various inflammatory proteins in their blood: those with markers of neuroinflammation, those with immune signaling proteins called interferons (often present after a viral illness), and a third group with neither of these signatures. They pooled the immunoglobulin G (IgG) antibodies from members of each group and injected each mouse with one of the pools.

Mice injected with IgG from the neuroinflammation and interferon subgroups showed heightened pain sensitivity, with the effect appearing especially quickly in the interferon group. Mice injected with IgG from the third group exhibited reduced walking distance a day after the injection, which researchers suggested could be related to high levels of muscle-related proteins in these patients’ blood. Mice injected with IgG from healthy control participants showed no changes in behavior.

Implications and Future Research

In summary, current research indicates that antibodies taken from individuals with Long COVID can heighten pain sensitivity and decrease movement in mice when administered to them. These findings suggest that antibodies could contribute to certain Long COVID symptoms, though the precise mechanism is still unclear and requires validation through larger studies.

In the coming period, Dr. den Dunnen and colleagues will continue this line of research with three main objectives: 1) further investigating the pathophysiology to determine which proteins, cells, or tissues are recognized by these autoantibodies and how this recognition causes symptoms; 2) utilizing the animal model for long COVID they have created to test potential therapies; and 3) developing an objective diagnostic test for long COVID by identifying specific autoantibodies, which would be the first of its kind.

For more information contact Jeroen den Dunnen (j.dendunnen@amsterdamumc.nl) or read the scientific preprint below.

Chen, H. J., Appelman, B., Willemen, H., Bos, A., Prado, J., Geyer, C. E., ... & den Dunnen, J. (2024). Transfer of IgG from Long COVID patients induces symptomology in mice.bioRxiv, 2024-05.

Read the news article on the website of Nature here.

Read the news article on the website of Science here.

Amsterdam UMC researchers involved

Hung-Jen (Oliver) Chen¹, Postdoctoral Scientist

Brent Appelman¹, PhD Candidate Infectious Diseases

Amelie Bos¹, Postdoctoral Researcher

Chiara E. Geyer¹, PhD Candidate

Mads Larsen^1,2, PhD Candidate

Eline Schüchner¹, Master student Biomedical Sciences

Marije K. Bomers³, Internist-infectiologist

Ayesha H.A. Lavell³, Scientist Physician

Joost Wiersinga¹, Professor of Medicine

Michèle van Vugt¹, Professor of Internal Medicine

Jeroen den Dunnen¹, Principal Investigator

1. Center for Experimental and Molecular Medicine, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands

2. Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands

3. Department of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, location VUMC, Amsterdam, Netherlands

Funding

This project was supported by the Patient-Led Research Collaborative of Long COVID (grant ID: C1), Stichting Long-COVID consortium grant, the Netherlands Organization for Health Research and Development (ZonMw, grant number 10430142210001).