The coronavirus disease (COVID-19) pandemic may lead to severe illness in some people, particularly those belonging to high-risk groups. However, the exact disease mechanism is still unclear. It is widely thought that the individual's immune system determines the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whether it be severe, mild, or even asymptomatic.
Now, a new study by an international team of health experts shows that some life-threatening cases of COVID-19 can be traced to specific weak spots in the patients' immune system.
The study, published in the journal Science, may explain the erratic effects of the illness to people across the globe.
Global effort
The research team started gathering data and enrolling patients with COVID-19 in the study in February. During that time, the researchers looked for young people with severe COVID-19 to determine whether these patients might have underlying weaknesses in their immune systems that made them susceptible to the viral infection.
At first, the team planned to scan the genomes of the patients, and 13 sets of genes that are linked in interferon immunity against the flu virus. Interferon molecules work as a security system in the body of healthy people, detecting invading bacteria and viruses, sending an alarm to call other immune defenders to the area.
The team has previously found that genetic mutations impede interferon production and function, making the person with mutations more susceptible to certain pathogens, including flu. The team believed that finding similar mutations in COVID-19 may provide a better understanding of why some people may develop severe COVID-19, while others do not. Also, knowing these mutations can help doctors identify patients who are at a high risk of developing severe forms of the illness.
Auto-antibodies
Now, aside from these mutations that hinder interferon activity, the researchers thought that there could be something in the body of these severe COVID-19 patients harming the interferon molecules. Auto-antibodies, just like those seen in auto-immune illnesses, such as type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus (SLE) were considered.
The researchers found that at least 10 percent of patients with severe illness produce "auto-antibodies" that attack the immune system, instead of the virus.
The team noted that other infections are driven by monogenic inborn errors of interferon-gamma (IFN-y), Interleukin 6 (IL-6), and Interleukin 17A, which are cytokines, or by their genetically driven auto-immune phenocopies, with the production of neutralizing auto-antibodies against these cytokines.
Previous studies have shown that auto-antibodies have been found in some patients with viral diseases, such as severe chickenpox and viral pneumonia. The researchers also noted three patients with Auto-immune polyglandular syndrome type 1 (APS-1) and pre-existing anti-type I IFN auto-antibodies and life-threatening COVID-19 pneumonia. They wanted to determine if the presence of auto-antibodies against type I IFNs might also trigger severe COVID-19 pneumonia.
To arrive at the study findings, the team looked for the presence of auto-antibodies in 987 patients admitted to hospitals due to severe COVID-19 pneumonia. As well as these, they examined 663 people infected with SARS-CoV-2, who had an asymptomatic or mild infection, and more than 1,200 people who were healthy and whose samples were collected before the pandemic.
The researchers collected plasma or serum samples from COVID-19 patients who are critical during the acute phase of the disease. The team has found high fluorescence intensity for IgG auto-antibodies against IFN-α2 or IFN-ω in 135 patients with severe COVID-19. From these, 49 patients tested positive for auto-antibodies against both IFN-α2 and IFN-ω, while 45 tested positive only for antibodies against IFN-α2, and 41 were positive only for IFN-ω.
At least 101 of the patients also had auto-antibodies against an assortment of interferon proteins. These antibodies blocked interferon action and were not present in patients with mild COVID-19 patients.
"It's an unprecedented finding. You can almost predict who will become severely ill," Isabelle Meyts, a pediatrician at the University Hospitals KU Leuven, in Belgium, and a study co-author, said.
The team also found that most patients, 94 percent, with harmful antibodies were men, who are more likely to develop severe COVID-19. The study may have the answer as to why men are more vulnerable to severe disease when they contract SARS-CoV-2.
The team is now planning to look for the genetic driver behind the auto-antibodies, which could be tied to mutations on the X chromosome. These mutations may not affect women because they have a second X chromosome to compensate for any defects in the first. However, in men, who only have a single X chromosome, even a small genetic error could have negative effects.
The study findings provide insight on auto-antibodies and how they can wreak havoc in a patient with COVID-19, attacking interferons and antibodies, instead of the virus itself.
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