Autoantibodies against type I interferons associated with increased risk of dying from COVID-19

In the quest to determine which individuals have the greatest risk of a severe disease course if they develop COVID-19 , researchers have found that the presence of specific autoantibodies significantly increases the risk of hospitalisation and the need for oxygen or ventilatory support and is also associated with an increased risk of dying.

Autoantibodies are antibodies that mistakenly target and react or interfere with a person’s own signalling proteins, called type I interferons, which are necessary for a good antiviral response.

This increased risk of dying from COVID-19 therefore seems unrelated to whether a person has diabetes or has other risk factors for severe disease.

The recognition of how autoantibodies can lead to a severe COVID-19 disease course opens the possibility of more precisely identifying the people who are at greatest risk. The discovery will also enable healthcare professionals to identify people who can avoid a severe and potentially fatal disease course through a special therapy that removes the autoantibodies from the blood.

“Our next step is to determine how we can use this discovery clinically to help people with COVID-19,” explains a researcher behind the study, Trine Mogensen, Professor, Department of Infectious Diseases, Aarhus University Hospital and Department of Biomedicine, Aarhus University.

The research has been published in Proceedings of the National Academy of Sciences of the United States of America.

The body attacks its own immune system

Researchers from Europe, the United States, Japan and South America have collaborated in a large global consortium, the COVID Human Genetic Effort, with the aim of learning more about the genetics and immunology behind COVID-19.

Several hundred doctors including paediatricians, epidemiologists, immunologists and others are participating in the consortium.

The researchers collected blood samples from thousands of people and examined them for autoantibodies against type I interferons.

Interferons play an important role in the immune system’s antiviral response, helping to activate the immune cells that attack viruses.

Sometimes, however, the immune system turns on itself, developing autoantibodies against type I interferons and thereby neutralising the antiviral defences. The same mechanism happens in autoimmune diseases, such as when the immune system attacks cells in the pancreas, leading to the development of type 1 diabetes.

The researchers investigated whether the presence of autoantibodies against type I interferons in the blood of people with COVID-19 is associated with a more severe disease trajectory.

Autoantibodies increase the risk of dying from COVID-19

The results show that slightly more men than women have autoantibodies in their blood.

In addition, the proportion of people with autoantibodies against interferons increases with age, from less than 1% among people up to 30 years of age to up to 4% among 80-year-olds.

Further, 20% of those who died from COVID-19 had autoantibodies in their blood versus less than 1% among the survivors.

Finally, the relative risk of dying was significantly higher for individuals with autoantibodies in their blood.

The researchers investigated autoantibodies against several types of type I interferon, and the more types of interferon the autoantibodies targeted, the greater the risk of death.

“The results are interesting because they show that autoantibodies are associated with the severity of the disease course but also because of the differences between men and women and between younger and older people. This may help to explain the observed sex and age differences in the risk of a severe disease course,” says Trine Mogensen.

She also indicates that the autoantibodies are not created in response to COVID-19 but are already present before people develop the disease.

“This presumably has a genetic component, since more men than women have autoantibodies and they are more prevalent in certain genetic diseases,” adds Trine Mogensen.

Discovery has several perspectives

In further experiments, the researchers investigated how autoantibodies affect cells and found that the presence of the autoantibodies neutralises the effect of interferon in the cells, resulting in unhindered multiplication of SARS-CoV-2.

This can clearly lead to a more severe disease course.

Trine Mogensen says, however, that why and how some people develop autoantibodies against type I interferons are still unknown. A possible explanation is differences in genetics, which future research needs to investigate further.

For now, however, the research results can still be useful clinically.

Trine Mogensen envisions two ways to use or translate the results to help people with COVID-19.

· Testing for COVID-19 could include testing for autoantibodies against type I interferons. Testing positive for both should alert doctors to carefully monitor these people, who should perhaps start early antiviral therapy before becoming severely ill, since they have a significantly increased risk of a severe disease trajectory.

“Perhaps antiviral therapy should be started early, and they should receive even more extensive therapy to prevent illness from developing,” says Trine Mogensen.

· The other possible clinical application is for treating people with COVID-19. The autoantibodies can be removed from the blood using plasma exchange, by filtering the blood and separating out the unwanted autoantibodies.

“We will use these results to test new approaches to treating people with COVID-19. In France, researchers are currently investigating in a clinical trial whether testing for autoantibodies among people hospitalised with COVID-19 and using the results to guide treatment are worthwhile. The next step will also be to investigate whether plasma exchange is a cost-effective therapy and whether this can reduce the risk of dying from COVID-19,” concludes Trine Mogensen.