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A dose of science | nature: Rogue antibodies may be the culprit leading to neocrown critical illness
2022-05-07 20:27:01【Popular 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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