A new autoantibody adds fuel to the “fire storm” of inflammation of COVID-19, blood clots

Michigan Medicine researchers have discovered another functional autoantibody in patients with COVID-19 that contributes to the development of the disease and the “fire storm” of blood clots and the inflammation it induces.

A growing group of studies suggests that COVID-19 emulates many aspects of systemic autoimmune disorders, including the release of a rain of hyperactive immune cells that produce toxic networks of proteins and DNA called extracellular neutrophil traps or NETs

For this study, the team analyzed the serum of more than 300 hospitalized COVID patients, looking for a new antibody that would protect toxic NETs from being destroyed and produce a lasting harmful effect on the patient’s body.

The results, published in JCI Insight, reveal markedly high levels of anti-NET antibodies in many of the participants. Those with higher levels of autoantibodies were more likely to develop severe COVID-19 symptoms.

“We see a lot of different antibodies produced in patients with COVID-19 and we have now discovered another clinically significant one that probably contributes to severe COVID,” said Yu (Ray) Zuo, MD, lead author and rheumatologist at Michigan Medicine. “They feed on the inflammatory storm we see in the most severe cases of viral infection.”

The researchers generated NET networks in the laboratory and incubated them with COVID patient serum. They found that the serum of patients with higher levels of anti-NET antibodies struggled to degrade toxic traps.

The team also obtained a healthy serum with purified anti-NET from infected patients. Although a healthy person’s serum should completely disintegrate extracellular traps, purified anti-NET antibodies significantly hampered the process.

“We knew that people with severe forms of COVID have higher amounts of these extracellular neutrophil traps, which amplify inflammation and promote blood clot formation,” said Jason Knight, MD, corresponding author of the article and associate professor of rheumatology at Michigan Medicine. “We have now discovered that this process is aggravated by anti-NET antibodies, which alter our body’s immune homeostasis during COVID-19 infection.”

Similarities with another autoimmune disease

Zuo and the Michigan Medicine team previously reported the presence of anti-NET in patients with antiphospholipid syndrome, a systemic autoimmune condition characterized by severe blood clots and recurrent pregnancy loss.

Anti-NET antibodies, which are likely to be associated with the development of recurrent blood clots and more serious diseases in antiphospholipid syndrome, showed a remarkably similar function in this study of patients with COVID-19, said the corresponding author. , Yogen Kanthi, MD, cardiologist specializing in medicine at the National Heart, Lung and Blood Institute and Lasker researcher at the National Institutes of Health.

“In both diseases, anti-NET antibodies coat the surface of neutrophil extracellular traps, making it much more difficult for the body to eliminate this network that causes inflammation and clotting,” Kanthi said. “Knowing its function is likely to help doctors design more specific COVID-19 treatments and also for other inflammatory diseases.”

It is unknown how COVID-19 manages to trigger the production of various autoantibodies, including anti-NETs. Zuo noted that a more detailed study of the autoimmune aspects of the virus will not only lead to a better understanding of the disease, but will also shed light on the origins of autoimmune diseases.

Future research and “long COVID”

The document’s findings may also unravel other mysteries of COVID, including the persistence of symptoms in some people months after the virus clears up, a phenomenon known as long COVID, Zuo said.

The team is currently conducting a follow-up study and called on patients who had previously been hospitalized to repeat testing for anti-NET and other autoantibodies that were formed during hospitalizations.

Previously, they found persistent anti-NET antibodies that persisted antiphospholipid syndrome patients up to four years. The team will investigate whether and how autoantibodies influence long-term COVID, the post-acute sequelae of the virus marked by symptoms such as brain fog, fatigue, and shortness of breath.

While vaccination does its job to limit serious infections and hospitalizations, millions of people still feel the effects of long-term COVID, which is why this research is so important, Zuo said.

“The more we understand these COVID-induced autoantibodies, like anti-NET antibodies, the better equipped we will be to fight COVID-19 at all stages of viral infection,” Zuo said. “The study of these antibodies will also teach us about the mechanisms of autoimmunity in general, especially in the field of rheumatology.”