Overactivation of the immune response by the complement system can result in severe COVID-19

Breaking new ground 25. dec 2021 2 min Clinical Professor Peter Garred Written by Morten Busch

Why do some people barely notice that they are infected with SARS-CoV-2 whereas others become terminally ill? Research shows that the reason is not related to the virus but to each individual’s immune system. Some people’s immune responses are effective, but for other people, the response is so strong that overactivation of the complement system, an important arm of the immune system, may become lethal. New research shows the importance of refining treatment to control complement activation.

People defend themselves against external microbes through the immune system, but if it becomes overactive, it can be lethal for patients with COVID-19. This may seem surprising but is true. SARS-CoV-2, which causes COVID-19, flies under the radar of many people’s immune systems for some time and then appears in such large amounts that it may trigger a cytokine storm, causing the lungs to draw in so much fluid that the disease may be lethal.

“Our immune system is like a double-edged sword when SARS-CoV-2 attacks the body. Viruses stimulate antibody production – immunoglobulins – that turn on the complement system, which is supposed to fight the viruses. Some people’s complement system is activated in such a way that the immune system overreacts and can threaten life. We have now measured exactly which types of immunoglobulins are produced in response to the infection, and we hope to understand why the immune response in some patients becomes overactivated and why most patients can neutralise and combat the virus without too much harm,” explains Peter Garred, Chief Physician and Professor at the Laboratory of Molecular Medicine, Department of Clinical Immunology at Rigshospitalet and University of Copenhagen.

Exacerbates COVID-19 symptoms

The study included 180 people who had had COVID-19, ranging from mild to very severe, but everyone had recovered. Using enzyme-linked immunosorbent assay (ELISA), the researchers determined the types of immunoglobulins and complement factors the immune response created because of the infection.

“During natural infection, immunoglobulins IgG1 and IgG3 activate the classical complement pathway, which can then eliminate external microbes, in this case, SARS-CoV-2. These are the two IgG subtypes we can measure in serum from people with COVID-19, whereas we can barely measure IgG2 and IgG4, so this shows which part of the immune system – the complement system – is activated,” explains Peter Garred.

Severely ill people had a large excess of IgG3. This excess IgG3 may lead to excessive activation of the complement system and thus excess tissue inflammation, rather than repairing the tissue, which exacerbates the COVID-19 symptoms among people with severe illness.

“Activating the complement system usually contributes effectively to controlling infection, but overactivation can cause acute respiratory distress syndrome, which can lead to lung failure and has a high mortality rate, up to 40–50% – and this is exactly what happens to people with severe COVID-19,” says Peter Garred.

The complement system, antibodies and uncontrolled activation

The complement system is an integral part of the immune system. Together with antibodies, it helps to remove invading microbes, including viruses, bacteria and fungi, by covering microbes with particular proteins, enabling phagocytosis and attracting inflammatory cells to sites of inflammation. Furthermore, under some circumstances, the complement system can punch holes in the microbes’ cell membrane and lyse them. This system is very effective, since it acts as an enzymatic reaction cascade. One protein activates the next, amplifying the system, which creates a strong inflammatory reaction. However, “overheating” can lead to uncontrolled activation that may be dangerous for the host.

“This suggests a link between complement activation and severe disease. We also confirmed that the antibodies induced the production of and increased the quantity of the inflammation-creating cytokine tumour necrosis factor-alpha,” says Peter Garred.

The caregivers of people with COVID-19 are very aware of the cytokine storms, because an overwhelming inflammatory reaction can be life-threatening. Since uncontrolled activation of the complement system may lead to cytokine storms and undesired inflammation, developing effective methods to control and balance the system is important.

“Our results suggest that the antibodies created in response to SARS-CoV-2 – and especially IgG3 – help to build a marked inflammatory response in severe COVID-19. Developing future new treatments is therefore important so that we can slow down the complement reaction and prevent people with COVID-19 from ending up being harmed by their own immune system,” concludes Peter Garred.

SARS-CoV-2 antibodies mediate complement and cellular driven inflammation” has been published in Frontiers of Immunology. The Novo Nordisk Foundation awarded a grant of DKK 4,803,750 to Peter Garred for The Copenhagen SARS-CoV-2 Antibody Testing Initiative.

Peter Garred leads a research group at Rigshospitalet and the University of Copenhagen. He tries to understand the structure, molecular genetics and c...

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