Researchers discover novel autoantibody, potential target for future COVID-19 therapies

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A team of researchers at Michigan Medicine, formerly he University of Michigan Health System, discovered a functional autoantibody in novel coronavirus (COVID-19) patients that contributes to the disease's development and the "firestorm" of blood clots and inflammation it induces, according to findings published in the Journal of Clinical Investigation.

A growing body of studies suggests COVID-19 emulates many aspects of systemic autoimmune disorders, including the release of a flurry of overactive immune cells that produce toxic webs of proteins and DNA called neutrophil extracellular traps (NETs).

For this study, researchers analyzed serum from over 300 hospitalized COVID-19 patients, searching for a novel autoantibody that shields the toxic NETs from being destroyed and produces a lasting noxious effect in a patient's body. The researchers found markedly elevated levels of the anti-NET antibodies in many of the participants. Those with higher levels of the autoantibodies were more likely to develop severe COVID-19 symptoms.

Researchers generated NETs in the lab and incubated them with COVID patient serum. They found the serum from patients with higher levels of anti-NET antibodies struggled to degrade the toxic traps.

The team also spiked healthy serum with anti-NETs purified from the infected patients. While a healthy person's serum should completely disintegrate the extracellular traps, the purified anti-NET antibodies significantly hindered the process.

Researchers have previously reported the presence of anti-NETs in patients with antiphospholipid syndrome, a systemic autoimmune condition characterized by severe blood clots and recurring pregnancy loss. The anti-NET antibodies, which are likely associated with the development of recurrent blood clots and more severe disease in antiphospholipid syndrome, showed remarkably similar function in this study of COVID-19 patients, the researchers said.

How COVID-19 manages to trigger the production of a variety of autoantibodies, including anti-NETs, remains unknown. Further study of the virus' autoimmune aspects will not only lead to better understanding of the disease but will also likely shed light onto the origins of autoimmune diseases, the researchers said.

The paper's findings may help researchers better understand COVID-19, including the persistence of symptoms in some people months after clearing the virus, a phenomenon known as long COVID, according to Yu Zuo, MD, lead author and a rheumatologist at Michigan Medicine. The team is currently conducting a follow-up study, calling back patients who were previously hospitalized to repeat testing for the anti-NETs and other autoantibodies that formed during their hospitalizations.

Previously, they found durable anti-NET antibodies that persisted in antiphospholipid syndrome patients for up to four years. The team will investigate if and how the autoantibodies influence long COVID, the post-acute sequalae of the virus marked by symptoms like brain fog, fatigue, and shortness of breath.

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

"The better we understand these COVID-induced autoantibodies such as anti-NET antibodies, the more equipped we will be to fight COVID-19 at every stage of viral infection," Zuo said in a statement. "Studying these antibodies will also teach us about the mechanisms of autoimmunity in general, especially in the field of rheumatology."

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