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Autoantibodies may cause severe COVID-19 infection diseases
Autoantibodies may cause severe COVID-19 infection diseases. There is growing evidence that “autoantibodies” that attack the body may be the key to some of the most serious SARS-CoV-2 infections.
In a Czech hospital, doctors are treating a COVID-19 patient in the intensive care unit.
It has been more than a year since COVID-19 appeared, but there are still many unsolved mysteries about this disease: Why are some people sicker than others? Why does lung damage sometimes continue to worsen after the body seems to be cleared of the SARS-CoV-2 virus? What caused the “long-term COVID-19”-patients with multiple organ damage that lasted for several months? More and more studies have shown that some of these problems may be caused by the immune system mistakenly attacking itself-a phenomenon called autoimmunity.
Aaron Ring, an immunologist at the Yale School of Medicine in New Haven, Connecticut, points out that this is a rapidly evolving field, but all the evidence points to one factor.
Researchers said that in the early stages of the pandemic, some patients had an overactive immune response to the new coronavirus infection. Immune system signaling proteins called cytokines rise to dangerous levels, causing a “cytokine storm” and damaging the body’s own cells. Some clinical trials have also shown that some drugs that broadly suppress immune activity, if used at the right time, seem to reduce the mortality of critically ill patients.
But scientists studying COVID-19 are increasingly emphasizing the role of autoantibodies. Autoantibodies are “rogue” antibodies that attack elements of the body’s immune defense system or specific proteins in organs such as the heart. Ring’s Yale University immunologist Akiko Iwasaki said that cytokine storms tend to cause systemic, short-lasting problems. In contrast, autoantibodies are thought to cause targeted, long-term damage.
Even healthy people produce autoantibodies, but they are usually not large in number, and these molecules usually do not cause damage or attack the immune system.
However, researchers also have evidence that harmful autoantibodies do play an important role in many infectious diseases.
There are several theories that explain how the new coronavirus and other infections produce autoimmunity. One theory is that some people may be inclined to produce autoantibodies, and these antibodies can cause severe damage during infection. Another theory is that infection may trigger the production of autoantibodies. If researchers can clarify the relationship between infection and autoantibodies, they may be able to find some widely used antiviral therapies that can deal with COVID-19 as well as diseases caused by other viruses.
Looking for autoantibodies
In late September 2020, a team led by Jean-Laurent Casanova of Rockefeller University in New York reported that among 987 patients with severe COVID-19, 10% of them attacked and blocked interleukin 1 (interleukin 1 usually Antibodies that enhance the immune system’s response to foreign pathogens. The researchers pointed out that this is an alarming ratio, because people’s antibody reserves are usually very different, and no one in the control group has these antibodies. Researchers also found that some people had this antibody before they were infected with COVID-19, so Casanova believes that some people may have a genetic predisposition to produce this antibody. And this kind of autoantibody is more common in men than women, which may be a factor that male patients with COVID-19 disease are more likely to get severe illness.
Casanova reminded that there is evidence for the first time that autoantibodies against interferon may increase the risk of individuals suffering from infectious diseases. This evidence was published in 1984, and since then, relevant evidence has continued to accumulate. But now, COVID-19 has attracted more attention to this connection. Now that people understand this problem, they suddenly realize that what Casanova’s laboratory has done for 25 years is actually quite meaningful.
Casanova is now screening 40,000 people to see how many people already have autoantibodies, and based on age, ancestry, and gender to determine whether their distribution matches severe COVID-19.
Other research groups also support Casanova’s theory. Iwasaki, Ring and others conducted extensive autoantibody tests on 194 COVID-19 patients and hospital staff of varying severity. Their research was published online in December last year and has not yet received peer review. The study found that compared with uninfected people, the proportion of autoimmune antibodies in infected people is higher. They also found autoantibodies that attack B cells and some antibodies that attack interferon in these patients.
But this study also shows that SARS-CoV-2 may cause the body to produce autoantibodies that attack its own tissues. Some infected people have antibodies against their own proteins in their blood vessels, heart, and brain. This is particularly interesting because many of the symptoms seen in a pandemic affect these organs. What remains unclear is whether the COVID-19 caused the body to produce these antibodies or whether these antibodies existed before the infection. Iwasaki said that they hope to study other cases to determine whether there is a causal relationship, which requires more blood samples to be collected before people are infected.
Michel Goldman, an immunologist at the Free University of Brussels and former director of the European’s Innovative Medicines Initiative, added that the researchers also discovered autoantibodies against phospholipid molecules. One of the largest such studies published in November last year found that 52% of 172 patients hospitalized with COVID-19 carried these autoantibodies. This worries researchers because some phospholipids are known to play a role in controlling blood clotting, and the COVID-19 can cause abnormal blood clotting.
Another study that has not been peer-reviewed reported that autoantibodies that may be stimulated by COVID-19 have been discovered. David Lee, Ph.D., Emergency Medicine, Langone Health, New York University, and New York University microbiologist Ana Rodriguez, and others analyzed the serum samples of 86 patients hospitalized with COVID-19. They are looking for autoantibodies against proteins such as annexin A2 (annexin A2), because annexin A2 helps keep cell membranes stable and ensures the integrity of small blood vessels in the lungs. Researchers found that the average level of anti-Annexin A2 antibodies in dead patients was significantly higher than in patients with non-critical illnesses. Like other studies, these studies have not clarified whether these autoantibodies existed before the coronavirus.
The autoantibody theory may explain the delayed appearance of severe COVID-19 symptoms to a certain extent. If, as Lee et al. believed, inflammation caused by cell damage and viral infection would trigger the production of autoantibodies, which would take several weeks to accumulate in the body. Lee reminded that this may be why the lungs and other tissues are damaged long after a person has fever and other symptoms. In this way, autoimmunity may be the real culprit that continues to cause fatal damage after the coronavirus is eliminated. Clinicians may be thinking that this virus is too deadly and must be eliminated. But when you talk to a pathologist, they think, yes, they saw all the damage, but not many viruses.
An MRI scan taken in a Paris clinic shows how COVID-19 damages the lungs of patients.
Cause an infection?
Over the years, scientists have found many examples of infections that trigger autoimmunity. Some reports indicate that infection with the malaria parasite causes the body to begin attacking red blood cells, leading to anemia. The Epstein-Barr virus that causes glandular fever (also known as mononucleosis) is related to dozens of autoimmune diseases, including lupus. As Anish Suri, president of Cue Biopharma, a company that studies autoimmune therapy, puts it, it is very difficult to find an absolutely reliable association because it is difficult to determine whether it is autoimmune caused by infection or other reasons.
Strep throat is a good example. This disease caused by Streptococcus pyogenes, if left untreated, will trigger an autoimmune response, the so-called rheumatic fever, which attacks organs and may cause permanent heart damage. Other bacteria may also cause autoimmunity: the stomach bacterium Helicobacter pylori (H. pylori) is thought to cause a disease called immune thrombocytopenic purpura (ITP). In this disease, the body begins to destroy platelets in the blood. In some patients with ITP, treatment with anti- Helicobacter pylori antibiotics can improve platelet counts, indicating that these antibacterial drugs help reverse autoimmune diseases.
Yehuda Shoenfeld, director of the Zabludowicz Center for immunology in Tel-Hasomo, Israel, suspects that COVID-19 may cause autoimmune diseases. In June 2020, he published an article on COVID-19 and autoimmunity and cited the case report of a 65-year-old female patient with COVID-19 in April 2020. The patient’s platelet count dropped sharply and required blood transfusion. Although there is not enough evidence to prove that this is an ITP, there are dozens of ITP cases related to COVID-19 in the literature.
Some people may be genetically susceptible to an autoimmune response to infection. For example, some people carry the gene encoding the immune system protein HLA-DRB1, and Shoenfeld pointed out that this protein is “notorious” for its link to autoimmunity. It is strongly suspected that a related protein called HLA-DQB1 may cause narcolepsy in people who have received the H1N1 “swine flu” vaccine (this vaccine is currently discontinued). It is generally believed that narcolepsy is caused by autoimmune attacks on brain neurons.
Another way pathogens trigger autoimmunity is that some part of them is very similar to some part of human cells. For example, S. pyogenes has an “M” protein, which is very similar to certain proteins in the human heart. This is the so-called molecular mimicry. In their June 2020 article, Shoenfeld and others found similarities between many short sequences of the SARS-CoV-2 spike protein (the molecular machine used by the new coronavirus to enter cells) and human proteins. However, others cautioned that this may not have a meaningful impact. Brian Wasik, a virologist at Cornell University in Ithaca, New York, points out that this does not completely deny the existence of the new coronavirus molecular mimicry. But most molecular mimicry is determined by testing the actual response of pathogen proteins to antibodies in the laboratory.
Leona Gilbert, a consultant and molecular biologist at the Dutch diagnostic company Te? ted Oy (which developed and sold a method to detect SARS-CoV-2 antibodies), pointed out that inflammation caused by infection can mislead the immune system and cause it to be The contents released by destroying cells are regarded as pathogens, and autoantibodies are produced to attack these cell debris. Gilbert said that the tissue damage that accompanies inflammation gives the body an instruction to attack itself, which is a trigger for the development of autoimmune diseases.
Lee, a researcher who focuses on Annexin A2, pointed out that the evidence that infection can cause autoimmunity has not received enough attention. This theory can change our understanding of dozens or even hundreds of diseases. What he wonders is, why don’t others realize this?
If autoimmune factors make individuals more susceptible to COVID-19, or make them produce autoantibodies after being infected with tCOVID-19, then this is of great significance to the treatment of COVID-19. Casanova pointed out that if pre-existing autoimmunity against interferon increases the risk of an individual being infected with COVID-19, then tests that detect these autoantibodies can help screen out these susceptible individuals. Fortunately, these tests are becoming more common in research laboratories and university hospitals.
Casanova suggested that if these people are infected with SARS-CoV-2, they can supplement with interferon-β as soon as possible. This interferon is not as vulnerable to the immune system as other interferons. In November last year, a preliminary study found that an inhaled form of interferon-beta seemed to improve the clinical condition of patients with COVID-19 pneumonia, prompting people to conduct larger trials of this treatment.
Interferon replacements are designed to enhance the activity of the weakened immune system. But if autoantibodies attack organs, such as the lungs and brain, a simple strategy against them might be to suppress the immune system.
In fact, before autoantibodies became the focus, there was already a view that the cytokine storm might be the culprit, so researchers tested immunosuppressive steroids (such as dexamethasone) or arthritis drugs (such as touzumab and saalilumab). Whether to stabilize immune system abnormalities caused by COVID-19. The World Health Organization now “strongly recommends” the use of dexamethasone in severe cases. A clinical trial on January 7, 2021 showed that these immunosuppressants can significantly reduce the mortality of patients in the intensive care unit, and the United Kingdom is also using arthritis drugs for COVID-19 patients.
The doctor emphasized that whether it is used to calm the cytokine storm or try to solve the autoimmunity, the use of drugs must be carefully chosen to avoid interference with the human body against SARS-CoV-2. Suri pointed out that broad-spectrum immunosuppressants make the body more susceptible to infections. His company is one of the few companies engaged in pre-clinical work, aiming to develop engineered molecules that target specific immune pathways, rather than suppress immunity across the board.
At the same time, Lee said that if autoantibodies against Annexin A2 and other proteins are proved to be induced by COVID-19, then the study uses a certain procedure to remove these antibodies from the patient’s plasma before returning them to the patient’s body. , May be of great significance.
Scientists are very interested in understanding whether autoimmunity is also related to long-term COVID-19. Ring pointed out that, first of all, they don’t know whether these autoantibodies are driving the long-term COVID-19. But if so, what is the lifespan of these antibodies? How long will they last? How long will the body continue to produce these antibodies? The work involved in answering these questions is very complicated, because humans naturally produce many different kinds of antibodies, including autoantibodies.
Ring hopes that research on viruses and autoimmunity will eventually provide much-needed answers for autoimmune patients (possibly including COVID-19 patients) after viral infection. These patients were so upset that the doctors did not believe some of the symptoms they described and referred them to the counseling department. If they can be diagnosed with the disease and tell the cause-it will be very meaningful.
(source:internet, reference only)