12.04.2023
Severely ill COVID-19 patients often have antibodies in their blood that bind to endogenous structures, so-called autoantibodies. Scientists from the BIH in the Charité and the Max Delbrück Center have now discovered that these autoantibodies often bind not just to one target, but to several.
This surprising finding calls into question the importance of autoantibodies for the course of the disease: In most cases, they are probably not to blame if the patient is doing particularly badly.
In the summer of 2020, a discovery by a French working group led by the immunologist Jean-Laurent Casanova caused a stir: His team had found antibodies in the blood of seriously ill COVID-19 patients that are directed against the messenger substance type 1 interferon. The body makes interferon to protect itself from the virus, and when the autoantibodies bind to interferon, they render it ineffective – and patients vulnerable.
Few COVID-19 samples show autoreactivity to a single target
“As a result, many immunologists started looking for other autoantibodies in the blood of COVID-19 patients,” says Dr. Kathrin de la Rosa, who holds a Johanna Quandt Professorship for Immune Mechanisms in Translation at the Berlin Institute of Health in the Charité (BIH). The immunologist also conducts research at the Max Delbrück Center. “And they also found what they were looking for: a total of 17 antibodies against endogenous structures have been discovered so far, including against the ACE2 protein, which serves as a receptor for the virus.”
Kathrin de la Rosa and her team also examined the blood of COVID-19 patients who were treated at the Charité. They also found autoantibodies against the ACE2 protein, against interferon alpha and other body proteins. “Interestingly, the connection between soluble ACE2 and ACE2-binding autoantibodies was not clear. The temporal occurrence of the autoantibodies also spoke against an ACE2-directed immune reaction,” reports Mikhail Lebedin, PhD student with Kathrin de la Rosa and first author of the current work. “But we found a connection between the amounts of different autoantibodies, which made us suspicious.”
“Auto” antibodies recognize a wide range of targets
The antibody specialists wondered why the infection with COVID-19 could cause the same amounts of different antibodies. Could it be one and the same antibody that can bind to different body proteins? So to speak, multi-specific antibodies?
The scientists then tested the reactivity of the antibodies from the COVID patient’s blood. The vast majority of the samples showed undirected autoimmunity, as the antibodies recognized a wide variety of proteins with similar strength. In only a few samples were the autoantibodies directed to a specific target. Kathrin de la Rosa comments: “For COVID-19, the question now arose as to whether multi-specific antibodies can have an impact on the course of the disease, or whether this is only the case for directed autoantibodies. Undirected antibodies are also found in other infectious diseases such as the glandular fever or HIV.”
Undirected autoantibodies have no effect on the interferon signaling pathway
The scientists then tested the antibodies found for their functionality: in the culture dish, they brought healthy blood cells together with the patient’s autoantibodies and observed whether this had an impact on the growth or behavior of the cells. “The cells did not react at all to the presence of the multi-reactive antibodies. Only when we added targeted mono-specific antibodies to the cells did their behavior change,” reports Mikhail Lebedin.
Kathrin de la Rosa does not want to question the importance of autoantibodies in general. “It is precisely the autoantibodies against type 1 interferon that certainly contribute to the severe course of the disease. With regard to diagnostics and therapeutic measures, however, one should check again whether antibodies are actually present that specifically recognize a certain body protein. Action may be taken it is just a more or less harmless representative of the multi-specific autoantibodies.”
» Originalpublikation
