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WHETHER or not a person with COVID-19 develops severe disease depends a lot on how their immune system reacts to the coronavi- rus. But scientists still don't know why some people develop severe disease while others suffer only mild symptoms – or no symptoms at all. Now, a new study from Yale University sheds some light on the issue. The research, which has yet to be peer re- viewed and published in a journal, suggests that in patients with severe COVID, the body produces "autoantibodies". These are antibodies that – instead of attacking the in- vading virus – attack the patient's own im- mune system and organs. The researchers found that people with severe COVID had autoantibodies that latched onto crucial proteins involved in recognising, alerting and clearing cells in- fected with the coronavi- rus. These proteins include cytokines and chemokines – important messengers in the immune system. This interfered with the normal immune system function, blocking antiviral defenc- es, potentially making the disease more severe. Links with autoimmune disorders For many years, autoan- tibodies have been known to be involved in autoim- mune diseases, such as rheumatoid arthritis and lupus. It is not known why some people develop these antibodies, but it is likely to be a combination of genet- ics and environment. Viral infections have also been linked to the onset of some autoimmune diseases. Earlier this year, scientists reported that patients with no history of autoimmune dis- ease developed autoantibodies after getting COVID. In these studies, the autoantibodies were found to recognise similar targets to those found in other well-known autoim- mune diseases, such as proteins normally found in the nucleus of cells. Later studies discovered that people with severe COVID can also develop autoantibodies to interfer- ons, immune proteins that play a major role in fighting viral infections. The Yale scientists who carried out the latest study, used a new technique that screened for autoantibodies that work against thousands of the body's proteins. They searched for autoantibodies in 170 hospitalised patients and compared them with autoantibodies found in people who suffered mild illness or asymptomatic in- fection, as well as people who had not been infected with the virus. In the blood of the hospitalised patients, they found autoantibodies that could attack interferons, as well as autoantibodies that could interfere with other critical cells of the immune system such as natural killer cells and T cells. The findings showed that au- toantibodies were a very common feature of severely ill COVID patients. The Yale researchers conducted further tests in mice, which showed that the pres- ence of these autoantibodies could make the disease worse, suggesting that these autoan- tibodies could contribute to the severity of COVID in humans. Not the whole story Though COVID patients had many autoantibod- ies that targeted immune system proteins, the re- searchers didn't find any COVID-specific autoanti- bodies that could be used to distinguish severely ill COVID patients. What determines if a person is going to suffer from severe COVID depends on many things, and autoantibodies are not the whole story. But the research suggests that people with existing autoantibodies may be at higher risk of getting severe COVID. These people may have deficiencies in their im- mune response during early coronavirus infection or be predisposed to making new autoantibodies that could hinder their immune response to the virus. Researchers are increasingly focusing on the link between severe COVID and mis- directed immune responses that target healthy tissues and proteins in the body. The presence of autoantibodies suggests that, for some patients, COVID could be an autoim- mune disease triggered by the coronavirus. Understanding what drives the production of autoantibodies will help scientists to de- velop new treatments for this disease. Scientists don't know how long these au- toantibodies last for after the infection has cleared. An important unanswered question is whether long-term damage caused by au- toantibodies could explain some symptoms of long COVID. The particular deletions identi- fied in the spike protein of B.1.1.7 have appeared in multiple other lineages of the virus at increasing frequency and are also observed in chronic infections where they may alter antigenicity - recogni- tion by immune antibodies. These deletions may also be as- sociated with other mutations in the binding region of the coro- navirus spike protein, includ- ing those observed in infections among farmed mink and a muta- tion shown to play a role in the vi- rus's ability to evade the immune system in humans. B.1.1.7 also harbours a truncated ORF8 gene, with deletions in this region pre- viously associated with decreased disease severity. The functional effect of these mutations and deletions, particu- larly when in the combination reported in B.1.1.7, are still to be determined. The high number of mutations and the recent in- crease in prevalence of this par- ticular variant, together with the biological relevance of some of the mutation candidates, empha- sises the need for in-depth study. What does this mean for the vaccine? At the moment we don't know. Though we should be reassured that vaccines stimulate a broad antibody response to the entire spike protein, so it is anticipat- ed that their efficacy will not be significantly hampered by muta- tions. This is already being tested. However, there is an increasing body of evidence that other spe- cies of seasonal coronaviruses exhibit some ability to escape im- munity over longer time periods. It is therefore conceivable that we may reach a point where we are required to update our COV- ID-19 vaccines, as we do for in- fluenza, to reflect the variants in circulation at the time. It's too early to say if this will be the case now, but extensive genome sequencing, data shar- ing, and standardised reporting of variants will be vital to inform these efforts. 13 maltatoday | SUNDAY • 10 JANUARY 2021 Rebecca Aicheler is Senior Lecturer in Immunology, Cardiff Metropolitan University OPINION The variant carries 14 defining mutations including seven in the spike protein, the protein that mediates entry of the virus into human cells. This is a relatively large number of changes compared to the many variants we have in circulation globally Scientists still don't know why some people develop severe disease while others suffer only mild symptoms – or no symptoms at all Rebecca Aicheler Severe COVID may be caused by 'autoantibodies'