Severe COVID Clues: Autoantibodies, Gene Mutations

Sept. 25, 2020 — Since the beginning of the COVID-19 pandemic, scientists have struggled to find out why some people who get COVID-19 develop severe disease, and others are infected but don’t notice symptoms.

Now, new research from the National Institutes of Health and other institutions suggests that some people have antibodies that are misguided, called autoantibodies, that attack the immune system instead of attacking the virus that causes COVID-19. Others may have a genetic mutation that makes their immune system less able to fight the virus.

Both groups fall short in mounting effective immune responses that rely on what’s called type I interferon, a group of proteins needed to protect cells and the body from viruses.

In one study, researchers found that among nearly 660 people with severe COVID-19, many had variations in 13 genes linked with the body’s defense against the virus that causes influenza. More than 3.5% completely lacked a functioning gene. When the researchers looked further, they found that immune cells taken from those 3.5% could not produce any detectable type I interferons when exposed to the coronavirus that causes COVID-19.

The innate immune system, sometimes called the general immune system, is the body’s first line of defense against germs and other foreign invaders. The adaptive immune system, sometimes referred to as the specialized immune system, takes over if the innate immune system can’t do the job and attacks the specific germ causing the trouble.

In research that looked at about 1,000 patients who had severe COVID-19 pneumonia, more than 10% had autoantibodies against interferon when they first became infected. And 95% of these were men, who have been found in other research to be more likely to get a severe infection.

Expert Perspective

“The most shocking thing [about the research] is that that many people are making autoantibodies that block type 1 interferon,” says Shane Crotty, PhD, a professor at the Center for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology in California. He was not involved in the new research but has published recently on COVID.

“What this is showing is that there are people, almost all men, for unclear reasons, who have these autoantibodies against their own antiviral proteins, the type 1 interferon. Then when these people get coughed on [by infected people], they really run into trouble. Their own body is preventing an innate immune response.”

Much of the research published on COVID has dealt with the innate immune response, he says. He compares the innate response to a kind of burglar alarm that is set off before the adaptive immune system kicks in. “An early response by our innate immune system is important to stop this virus.”

People can be tested for these autoantibodies, Crotty says. Of the research, he says: “This is really valuable information to have. The more you can potentially categorize patients, the more likely you come up with treatments [that are tailored].”


Shane Crotty, PhD, professor, Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA.

Science: “Auto-antibodies against type I IFNs in patients with life-threatening COVID-19.”

Science: “Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.”
News release, National Institutes of Health: “Scientists discover genetic and immunologic underpinnings of some cases of severe COVID-19.”

NCBI Bookshelf: “The innate and adaptive immune systems.” 

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