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A dose of science | nature: Rogue antibodies may be the culprit leading to neocrown critical illness

2022-05-07 20:27:01Popular science China

The intensive care unit of a hospital in the Czech Republic is receiving a new crown patient

More than a year after the emergence of COVID-19 , Many mysteries about the disease remain : Why are some people so much worse off than others ? Why sometimes after the body has cleared novel coronavirus , Lung injury will continue to worsen ? What are the reasons behind the multiple organ sequelae of patients with new crown lasting for several months ? More and more studies show that , Some of these problems may be explained by the wrong turn of the immune system to the body —— This phenomenon is called autoimmunity .

“ This is a fast-growing area , But all the evidence is converging ,” Aaron, an immunologist at Yale Medical School (Aaron Ring) say .

At the beginning of the pandemic , The researchers suggest , Some people have an overactive immune response to novel coronavirus infection . Immune system signaling proteins called cytokines can rise to dangerous levels , Lead to “ Cytokine storm ” And damage to the body's own cells . Clinical trials now show that , If given at the right time , Some immunosuppressants seem to reduce mortality in critically ill patients .

Studies have shown that , Cytokine storm is the main clinical feature of the deterioration of patients with new crown

But scientists studying novel coronavirus are also increasingly emphasizing autoantibodies —— A rogue antibody that attacks specific proteins in the body's immune defense elements or organs such as the heart . Yale immunologist Iwasaki (Akiko Iwasaki) say , Cytokine storms often lead to systemic 、 Short term problems , Autoantibodies are thought to cause targeted long-term damage .

Even healthy people produce autoantibodies , But it usually produces less , And these molecules usually don't seem to cause damage or attack the immune system . However , Researchers also have evidence that , Evil autoantibodies actually play a role in many infectious diseases .

There are several theories that explain how autoimmunity emerges from novel coronavirus and other infections . Some people may tend to produce autoantibodies , Then cause serious damage during infection . perhaps , Infection may directly trigger the production of autoantibodies . If researchers can establish this connection , They may be able to propose a treatment , It can not only aim at the impact of novel coronavirus , Also for other diseases caused by viruses .

01: Look for autoantibodies

9 late , By Rockefeller University Casanova (Jean-Laurent Casanova) Led a group report , stay 987 Of the patients with severe new crown , exceed 10% Antibodies can attack and block 1 The role of type I interferon molecules , and 1 Interferon type I molecules usually help to strengthen the immune response to foreign pathogens . Researchers say , This is an amazing proportion , Because people's antibody libraries are usually very different , And no one in the control group in this study had these antibodies . The researchers also detected these antibodies before people became infected with COVID-19 , So Casanova believes that some people may be genetically predisposed to produce them . And autoantibodies are more common in men than in women —— This may be a factor that COVID-19 has a greater impact on men .

A male patient who developed fatigue after recovering from COVID-19 was examined by ultrasound in a hospital

The first related paper was published in 1984 year , For the first time “ Autoantibodies against interferon may increase the risk of infectious diseases ”, Since then, evidence has accumulated . And now , Novel coronavirus is drawing more attention to this connection .

Casanova is now screening 40000 people , See how many people already have autoantibodies , And determine their age 、 Whether the lineage and sex distribution match the distribution of severe novel coronavirus .

Other research groups supported Casanova's autoantibody research . Iwasaki 、 Aaron et al 194 Patients with different severity of novel coronavirus and hospital staff were extensively screened for autoantibodies , It was found that the prevalence of autoantibodies against the immune system in infected individuals was higher than that in uninfected individuals . They found the attack B Cell autoantibodies , And some autoantibodies that attack interferon .

This study also shows that , Novel coronavirus may cause the body to produce autoantibodies that attack its own tissues . The blood vessels of some infected people 、 There are autoantibodies against proteins in the heart and brain . It's very important , Because many of the symptoms seen in the new coronavirus pandemic are related to these organs . It is not clear whether infection with COVID-19 causes the body to start producing these autoantibodies , Or whether the infected person already has these autoantibodies . Iwasaki said , They want research to determine whether there is a causal relationship , And this will require more blood samples before people get infected .

Want to confirm whether autoantibodies are produced due to infection with the new crown , Blood samples need to be collected before the patient is infected

Immunologist at the Free University of Brussels 、 Michelle Goldman, former director of the European innovative drugs initiative, added , The researchers also found autoantibodies against phospholipid molecules . On 11 The largest such study published in may found , stay 172 Of the hospitalized patients with COVID-19 , Yes 52% Of people have these autoantibodies .“ It's a real problem ,” He said , Because some phospholipids play a role in controlling blood coagulation ,( Produce antibodies against them ) It will cause the body to make mistakes in resisting COVID-19 .

This month, , Another study reported the discovery of autoantibodies that may be triggered by COVID-19 . David, an emergency doctor at New York University (David Lee) With New York University microbiologist Rodriguez (Ana Rodriguez) Et al. Analyzed 86 Serum samples from hospitalized patients with COVID-19 . They look for targets such as annexin A2 Autoantibodies to proteins such as , This is particularly interesting , Because it helps to keep the cell membrane stable and ensure the integrity of small blood vessels in the lung . The researchers found that , Compared with non critical patients , Anti annexin in dead patients A2 The average antibody level increased significantly . Like other studies , It is unclear whether these autoantibodies existed before coronavirus infection .

At a clinic in Paris MRI The scan showed how COVID-19 damaged the patient's lungs

Autoantibody theory may explain some of the delays in the emergence of critical symptoms of COVID-19 . If it is caused by cell damage and inflammation caused by virus infection , Autoantibodies will take weeks to accumulate in the body . This may be why most of the damage to tissues such as lungs occurs long after a person has symptoms such as fever . In this way , Autoimmunity may be the real culprit for the continued deadly destruction after the virus is cleared .

02: One has 「 appeal 」 Ideas

these years , Scientists have identified many examples of infections that produce autoimmunity . Some reports show that , Infection with malaria parasites causes the body to start attacking red blood cells , Cause anemia . Cause glandular fever ( Also known as mononucleosis ) Of EB The virus is associated with dozens of autoimmune diseases, including lupus . Immunologist anish (Anish Suri) say , Finding a solid connection can be difficult , Because it is difficult to prove that infection is the cause of autoimmune diseases , Or other reasons why they suddenly appear in the body .

Streptococcal laryngitis is a recognized example . If not treated in time , This disease caused by Streptococcus pyogenes triggers an autoimmune response called rheumatic fever , This reaction can attack organs and cause permanent heart damage . Other bacteria can also cause autoimmunity : Helicobacter pylori is thought to cause a form of purpura called immune thrombocytopenic purpura (ITP) Disease , The patient's immune cells begin to destroy platelets in the blood .

When the body lacks platelets , All bleeding sites will be difficult to stop bleeding , Bruises can also occur under the skin due to a slight collision or without obvious cause , Hemophilia like symptoms . Related links :“ Pass men, not women ” Of “ Noble disease ”—— hemophilia

Shaun field, head of the Israeli Center for autoimmune diseases (Yehuda Shoenfeld) It is suspected that COVID-19 may lead to autoimmune diseases . last year 6 month , He published an article on COVID-19 and autoimmunity , And quoted 2020 year 4 One month 65 A case report of a - year-old woman with COVID-19 , The woman's platelet count fell sharply , Need platelet transfusion . Although there is not enough evidence to prove that this is ITP, However, there are still dozens of cases related to COVID-19 in the literature ITP Case .

Some people may have a genetic predisposition to develop an autoimmune response to infection . for example , Some individuals have proteins that encode the immune system HLA-DRB1 Of DNA, Seanfeld said the protein has been implicated in autoimmunity “ notorious ”. He strongly suspected a related protein HLA-DQB1 Inoculate the now discontinued H1N1“ Swine flu ” Vaccinated people increase the risk of narcolepsy , This narcolepsy is thought to be caused by autoimmune attacks on brain neurons .

Another theory is , Inflammation caused by infection may cause the immune system to mistakenly treat the contents ejected by damaged cells as “ Foreign matter ”, And produce autoantibodies against these cell fragments . Tissue damage associated with inflammation is an important reason why the body begins to attack itself , Molecular biologist Gilbert (Leona Gilbert) say :“ This will accelerate the development of autoimmune diseases .”

03: Rethink the treatment

If there are autoimmune factors in the causes that make people susceptible to COVID-19 or other viruses , It may have an impact on the treatment . Casanova said , If pre-existing autoimmunity against interferon may put people at greater risk , Then blood tests of autoantibodies in laboratories and hospitals may help to identify them .

The discovery of autoantibodies in COVID-19 may promote the progress of personalized precision medicine

If these people are infected with novel coronavirus , Casanova suggested , They can receive interferon as soon as possible -β A supplement to , This interferon is not as vulnerable to attack by the immune system as other interferons . last year 11 month , A preliminary study found that , An inhaled form of interferon -β It seems to improve the clinical condition of patients with novel coronavirus , This has led to larger trials of the treatment .

Interferon substitutes are designed to enhance the activity of the immune system . however , If autoantibodies attack organs such as the lungs and brain , The strategy against them may be to suppress the immune system directly .

Even before autoantibodies became the focus of attention ,“ Cytokine storm may be the culprit ” The conjecture led people to try immunosuppressive steroids ( Such as dexamethasone ) Or the arthritis drugs tozumab and Kevzara. The World Health Organization is now “ Strongly recommended ” Dexamethasone is used in severe cases , In Britain 2010 year 1 month 7 Clinical trials showed that these arthritis drugs can reduce the mortality of intensive care patients , This arthritis drug is being used in patients with severe new crowns .

The immunosuppressive steroid dexamethasone is used to treat patients with COVID-19 in a critical state

The doctor emphasized , Whether it's used to calm the cytokine storm or try to solve the problem of autoimmunity , The administration time of drugs needs to be careful , So as not to interfere with the immune system's fight against the new crown . Anish pointed out , Broad spectrum immunosuppressants make the body more susceptible to infection .

Scientists are very interested in understanding whether autoimmunity is also associated with long-term COVID-19 infection .“ First , We don't know whether these autoantibodies will lead to long-term new coronal infection , If so , So how long will they last ? How long does the body continue to produce these antibodies ?” Aaron said . But answering these questions is a complex task , Because people usually produce many different kinds of antibodies , Including autoantibodies .

Aaron wants , The study of virus and autoimmunity can eventually provide patients with autoimmunity after infection with virus ( May include COVID-19 ) Provide urgently needed answers , Help doctors make correct judgments .

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