‘Long COVID’: MSK Scientists Search for Potential Autoimmune Causes

Michael Roehrl

Michael Roehrl

Approximately 10% of people who contract COVID-19 will develop lingering symptoms — fever, fatigue, blood clots, or brain fog — that can last for months. The underlying cause of “long COVID” is not yet known, but one hypothesis is autoimmune reactions.

An autoimmune reaction occurs when our immune system begins to attack parts of our own body. For unclear reasons, certain markers on normal cells (called antigens) are perceived by our immune system as foreign or dangerous. As a result, the body makes antibodies against these “autoantigens,” which leads to inflammation and other problems.

The diverse symptoms associated with long COVID may mean that infection with the SARS-CoV-2 virus is leading to the creation of a variety of autoantibodies that affect different parts of the body.

“It turns out that many of the acute and long-term side effects of COVID-19 are not caused by the viral infection itself,” says Michael Roehrl, an attending pathologist in the Department of Pathology, an affiliate member in the Human Oncology and Pathogenesis Program, and Director of the Precision Pathology and Biobanking Center at Memorial Sloan Kettering. “There is now enormous interest in understanding what’s going on at the level of the immune system as a way to account for these symptoms.”

There is now enormous interest in understanding what's going on at the level of the immune system as a way to account for these symptoms.
Michael H. A. Roehrl physician-scientist

Dr. Roehrl got interested in the subject during the COVID-19 lockdown, when his lab was closed, and he couldn’t go into work. Dr. Roehrl’s wife, Julia Wang, is also a scientist, and their teenagers are computational whizzes, so they all teamed up on a study, which was recently published in the Journal of Autoimmunity.

A Real Eye-Opener

To identify potential autoantigens related to SARS-CoV-2 infection, the scientists used a method they had previously developed in a different context. It involves measuring which proteins in the body bind to (or have an affinity for) a normal molecule in the skin called dermatan sulfate (DS). Proteins with a strong affinity for DS have a high likelihood of being autoantigens.

When the scientists performed DS-affinity analysis on a line of human lung cells commonly used to study COVID infection, they identified 348 potential autoantigens. By searching the literature, they discovered that 291 (83.6%) of these potential autoantigens are also found at abnormal levels in COVID-19 patients.  

“That was a real eye-opener,” Dr. Roehrl says. “That’s a much higher percentage than you would expect at random.”

They took their analysis further. They looked in medical databases and found that many of these autoantigens are already implicated in other autoimmune responses.

Dr. Roehrl and his coauthors hope their atlas of COVID-19 autoantigens will serve as a resource to investigators studying the autoimmune basis of long COVID.

Many Mysteries Remain

Why would viral infections create autoantigens out of the body’s normal proteins? Like all viruses, SARS-CoV-2 relies on the molecular machinery of the cells it infects to copy itself and spread. In the process, the virus can alter the amounts, location, and binding partners of normal human proteins. These changes can result in the immune system seeing these proteins as foreign.  

While this process isn’t unique to SARS-CoV-2, there could be something about this virus that makes it more likely to create autoantigens, which would explain why COVID-19 symptoms linger longer than those of other common viral infections.

“There’s clearly something we don’t quite understand about this infection yet,” Dr. Roehrl says.

Even why certain normal human proteins become autoantigens is not well understood. “That’s one of the big Holy Grail questions in all of immunology,” he adds.

It’s not that the proteins become genetically altered and look obviously different from the original, he explains. Scientists know this from studying the autoantigens in autoimmune conditions, such as rheumatoid arthritis, lupus, and type 1 diabetes. More likely, he says, it has to do with what the proteins are binding to in the context of inflammation or dying cells. 

That’s why the DS-affinity method that Dr. Roehrl and his colleagues developed is useful: It helps scientists make a pretty good guess about which proteins are likely to become autoantigens, without fully understanding the biology. In another recent paper, published in Frontiers of Immunology, Dr. Roehrl and colleagues provide evidence to explain why DS-affinity makes a good predictor — it has to do with the way the antigens bound to DS interact with B cells, which make antibodies.

This work was partially supported by Curandis, the National Institutes of Health (grant R21 CA251992 and Cancer Center Support Grant P30 CA008748), and a Cycle for Survival Innovation Grant. Dr. Roehrl is a member of the Scientific Advisory Boards of Trans-Hit, Proscia, and Universal DX. Dr. Wang is the founder and Chief Scientific Officer of Curandis.