An ‘uncontrolled’ immune response may explain why COVID-19 attacks some of the more difficult, especially the elderly. Science


The timing of antibody and T cell responses to the immune system of the new coronovirus cannot occur in unison, explaining why many elderly and some others receive severe cases of COVID-19.

Stanislav Krasilnikov / TAS / Newscom

By John Cohen

ScienceThere is COVID-19 reporting supported by Pulwitter Center and Haising-Simmons Foundation.

Even a world-class orchestra will produce a cacophony if its strings, woodwind, brass, and percussion sections do not play in harmony. Likewise, the sophisticated human immune system may fail to repel a pathogen if many of its players do not hit the right note at the right time. A new study now finds that those who suffer the most from COVID-19 have an immune response that is out of sync.

The results clarify how the disease progresses and may possibly explain how to design the best and most effective vaccines to use different treatments. “We need to know how the immune response to the virus is,” says Columbia University immunologist Donna Farber. “This is perhaps the most comprehensive analysis of virus-specific immunity in people who either had COVID or are severely infected.”

New study, published online today CellFocuses on the three most powerful weapons of the adaptive immune response, the immune system watchdog first protects the body after detecting infection. “It appears to be a virus [against which] All three weapons can work together and to some extent compensate for each other, ”says immunologist Shane Crotti of the La Jolla Institute for Immunology, who led the study with co-worker Alessandro Sette. “In general, if you react with all three, you will do well. People got into trouble when they did not have a coordinated adaptive immune response. ”

When the body detects a novel virus, “innate” defensive cells – which immediately attack any pathogen. They also release chemical messengers called cytokines to alert other immune cells. The adaptive response, which targets a specific invader in the case of COVID-19, coronovirus dubbed SARS-CoV-2 — then forms in the following days. An adaptive arm contains antibodies that aim to attach and “neutralize” the virus. If antibodies fail, killer T cells serve as a backup to identify and destroy any infected cells. The third arm, helper T cells, are conductors that coordinate the production of antibodies, killer T cells, and the rest of the immune orchestra.

Kratty, Sette and their colleagues analyzed the blood of 24 people whose COVID-19 cases ranged from mild to ultimately fatal. The researchers compared their immune response with 26 others who had recovered from the disease and with a control group, 65 people who were not infected with the virus. The participants of the study were aged between 20 and 86 years. Crotti called the study “exploratory” because he wants to conduct a similar analysis among hundreds of people who are ill or recovered from COVID-19. Nevertheless, the team made several discoveries. Due to the non-change in immunity levels, they found, and in the worst cases of COVID-19, patients had lower levels of helper and killer T cells. “It seems that T cells play a more important role than antibodies during natural infection,” Kratty says.

Blood samples from 10 study participants with active infections who were over 65 years of age and showed that they were more likely to have “uncoordinated” reactions between the antibodies and the two T cells arms – higher antibodies than younger infected ones. Can grow up to While one of the cellular responses remained weak, for example. This older group had a smaller population of “naïve” T cells that could recognize new invaders and then develop into mature killer and helper cells capable of increasing coordinated attack against SARS-COV-2.

Scientists are still debating the mechanics of the “storm” of cytokines released by innate immune cells that contribute to the severity of COVID-19, but the new study may explain how this occurs, at least in some cases. it happens. “If you kick an innate and adaptive immune response too quickly, you’re going to be fine,” Kratty says. But if the adaptive arm lacks T cells, the antibody response and cytokines by themselves are often disturbed by SARS-CoV-2, causing the virus to grow to higher levels. The innate system still reacts by pumping more cytokines. “Perhaps the virus gets so far ahead of them that it is too late for the adaptive immune system to take hold,” he says.

Studies have clearly shown that corticosteroids such as dexamethasone, which largely reduces the immune response, may protect some people from serious illness. Kratty warns that if physicians give steroids too early, “you could actually shoot yourself in the foot because it could be someone whose adaptive immune response is just happening.”

In theory, the analyzes conducted in this study may help doctors better determine when to use these drugs. “You can assess patients based on their adaptive immune profile,” Farber says. “This is really important.” But she also warns that blood may not reflect immune responses in tissues such as the lungs, which is an important site of attack by the virus. “I don’t know if blood monitoring is going to tell us what’s going on to prevent a mild case from getting serious,” says Farber, who studies lung and airway immunity.

Julie McElrath, head of the Vaccine and Infectious Diseases Division of the Fred Hutchinson Cancer Research Center, says these “interesting findings” may help COVID-19 vaccineers to focus more on T cell responses. Most COVID-19 vaccines have different versions of the surface protein spike of SARS-CoV-2. Researchers hope that these vaccines will teach the body to eliminate infection by creating neutralizing antibodies against it. But it is a tall order for vaccines to prevent infection altogether; In fact, most vaccine efficacy trials are primarily evaluating protection against disease rather than infection.

If viruses slip by antibodies, T cells will be needed to remove them from above. “Obtaining both antibody and T cell responses with vaccines is an important step to achieve efficacy against potential COVID-19,” says McElrath. But she notes that some of the T efficacy tests are not designed to analyze levels of T cells. And training an immune system to have a strong T cell response against SARS-CoV-2 may eventually require the use of more parts of the virus in a vaccine than a spike protein.

Kratty notes that there are practical challenges to measuring T cell responses, which are more difficult than antibody levels. But if the vaccine being tested may not work well, expect more intensive efforts to measure and promote T cell responses. “If you could have a vaccine that has superb neutralizing antibodies and can maintain them, it would be a really big winner,” he says. “But if the virus does slip through, our data indicates that these T cell responses are indeed important — and perhaps even more important — that are older.”