Are the immune system's own antibodies responsible for long COVID?

Long COVID, also known as the post-COVID condition, includes as many as 200 symptoms that persist months after a severe, mild or asymptomatic SARS-CoV-2 infection.

Dave Yasvinski 3 minute read November 30, 2021
Hand punch fighting a virus, novel coronavirus, covid-19, vector illustration.

It is estimated that roughly 150,000 Canadians have experienced symptoms of long COVID. GETTY

The enduring symptoms of a COVID-19 infection commonly referred to as long COVID may be caused by the immune system’s own antibodies that have learned to mimic the virus.

The possible explanation, presented in The New England Journal of Medicine, would come as welcome news to the roughly 25 per cent of people who have experienced lingering symptoms of infection long after the virus has cleared their system. The rationale builds on the Network Hypothesis offered by Nobel Laureate Niels Jerne, which deals with in the manner in which the immune system regulates its own antibodies.

According to Jerne, after the immune system launches an antibody response to an antigen such as COVID-19, these same antibodies later prompt a new antibody response toward themselves that clears them from the body. These secondary antibodies — known as anti-idiotype antibodies — are capable of mimicking the initial antigen as they bind to and remove the first responders.

“A fascinating aspect of the newly formed anti-idiotype antibodies is that some of their structures can be a mirror image of the original antigen and act like it in binding to the same receptors that the viral antigen binds,” said William Murphy, co-author of the article and the Vice Chair of Research and Distinguished Professor of Dermatology and Internal Medicine at the University of California, Davis. “This binding can potentially lead to unwanted actions and pathology, particularly in the long term.”

Because anti-idiotype antibodies can bind to the same ACE2 receptors as the virus, they can interfere with the other, normal functions of these receptors. “Given the critical functions and wide distribution of ACE2 receptors on numerous cell types, it would be important to determine if these regulatory immune responses could be responsible for some of the off-target or long-lasting effects being reported,” Murphy said. “These responses may also explain why such long-term effects can occur long after the viral infection has passed.”

This process could also explain some of the off-target — or unexpected physiological responses — people around the world have had to the vaccines that were created to curb the spread of the virus. As the global scientific community turned its attention to rapidly producing a protective response to COVID-19, early studies were focused more on the ability of a vaccine to eliminate the virus than other long-term considerations.

“With the incredible impact of the pandemic and our reliance on vaccines as our primary weapon, there is an immense need for more basic science research to understand the complex immunological pathways at play,” Murphy said. “This need follows to what it takes to keep the protective responses going, as well as to the potential unwanted side effects of both the infection and the different SARS-CoV-2 vaccine types, especially as boosting is now applied,” Murphy said.

“The good news is that these are testable questions that can be partially addressed in the laboratory and, in fact, have been used with other viral models.”

Long COVID, also known as the post-COVID condition, encompasses a range of as many as 200 symptoms that persist months after a severe, mild or asymptomatic SARS-CoV-2 infection, according to the Ontario COVID-19 Science Advisory Table. It is estimated that roughly 150,000 Canadians have experienced symptoms of long COVID, according to Fahad Razak, the lead author of the report, with vaccination decreasing the chances of developing the condition. The most common symptoms of long COVID include fatigue, pain, anxiety, depression, shortness of breath and difficulty sleeping.

Dave Yasvinski is a writer with