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Autoantibodies Contribute to Severe COVID-19 by Impairing Immune Responses

A SARS-CoV-2 virion, with surface proteins shown in red and orange.
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Recently, scientists found that some people who suffered from COVID-19 had auto-antibodies targeting their own type 1 interferons, which are important immune signaling proteins. Now, researchers conducted an in-depth study on 123 Japanese COVID-19 patients to clarify just how common these auto-antibodies are among severe cases and how they affect the immune system. Their findings could shed light on the role of auto-antibodies in exacerbating COVID-19 severity.

Even though COVID-19 manifests as a mild and short-lived disease in most people, some suffer extremely severe symptoms; in the worst cases, these patients die due to complications such as respiratory failure or thromboembolism. It is well-known that factors such as age and underlying medical conditions like diabetes or immunodeficiencies increase vulnerability to severe COVID-19. However, some patients still experience severe COVID-19 without any apparent reason.

One possible explanation may lie in auto-antibodies, which are antibodies that erroneously target specific proteins produced by one’s own body. In normal circumstances, type I interferons (or ‘t1-IFNs’) play a crucial role in the body’s defense against viral infections; they interfere with viral replication and help mobilize the immune system. However, auto-antibodies against t1-IFNs can neutralize their activity, compromising the body’s defense mechanisms. While detecting these auto-antibodies was uncommon before COVID-19, there have been multiple reports of severe COVID-19 patients bearing them since the pandemic started. Could auto-antibodies targeting t1-IFNs be more common than previously thought?

To answer this question, a research team, including Lecturer Chiaki Iwamura from Chiba University, Japan, investigated whether and how auto-antibodies targeting t1-IFNs are related to COVID-19 severity by analyzing blood samples from 123 Japanese patients. Their findings were published in Volume 44 of the Journal of Clinical Immunology on April 22, 2024. This research was co-authored by Dr. Kiyoshi Hirahara and Dr. Koutaro Yokote from Chiba University, as well as Dr. Ami Aoki from Niigata University.

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The researchers first conducted an enzyme immunoassay to detect auto-antibodies to t1-IFNs in the blood samples, and then confirmed whether these antibodies could effectively neutralize t1-IFNs in cell cultures. “We found that three out of 19 severe and four out of 42 critical COVID-19 patients had neutralizing auto-antibodies to t1-IFNs. Interestingly, there were no characteristic clinical features among patients with auto-antibodies to t1-IFNs,” comments Dr. Iwamura. In other words, there were no pointers in the data as to why some COVID-19 patients developed these auto-antibodies, even when considering previous infections, treatments received, and underlying immune disorders. “Based on these findings, it is difficult to estimate the presence of auto-antibodies to t1-IFNs from the usual blood tests and clinical background,” remarks Dr. Iwamura.

To shed some light on how auto-antibodies to t1-IFNs affected COVID-19 patients, the researchers then conducted RNA sequencing and B cell receptor analyses. These experiments showed that conventional dendritic cells and canonical monocytes, two types of white blood cells, exhibited attenuated IFN signaling for patients in which auto-antibodies were present. Moreover, B cells (yet another type of immune cell) in these patients had fewer SARS-CoV-2-specific receptors, implying reduced effectiveness in combating an infection.

Overall, these findings highlight the importance of looking at auto-antibodies to t1-IFNs in more detail when facing viral epidemics. “People with auto-antibodies to t1-IFNs are more susceptible not only to SARS-CoV-2 but also to common viruses such as influenza and to unknown viruses that may emerge in the future,” warns Dr. Iwamura, “Thus, we hope to collaborate with companies to develop a system to detect auto-antibodies to t1-IFNs in the blood. Ideally, we would develop a test to examine the presence of these auto-antibodies in regular health checkups so that people will be able to know whether they have them with little burden.

Reference: Aoki A, Iwamura C, Kiuchi M, et al. Suppression of type I interferon signaling in myeloid cells by autoantibodies in severe COVID-19 patients. J Clin Immunol. 2024;44(4):104. doi: 10.1007/s10875-024-01708-7

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