COVID-19 confounds immune response

With autoantibo­dies, body may attack itself

- Liz Szabo

There’s a reason soldiers go through basic training before heading into combat: Without careful instructio­n, green recruits armed with powerful weapons could be as dangerous to one another as to the enemy.

The immune system works much the same way. Immune cells, which protect the body from infections, need to be “educated” to recognize bad guys — and to hold their fire around civilians.

In some COVID-19 patients, this education may be cut short. Scientists say unprepared immune cells appear to be responding to the coronaviru­s with a devastatin­g release of chemicals, inflicting damage that may endure long after the threat has been eliminated.

“The body may say, ‘Who cares. Give me all you’ve got.’ ” Dr. Nina Luning Prak Co-author of a January study on COVID-19 and the immune system

“If you have a brand-new virus and the virus is winning, the immune system may go into an ‘all hands on deck’ response,” said Dr. Nina Luning Prak, co-author of a January study on COVID-19 and the immune system. “Things that are normally kept in close check are relaxed. The body may say, ‘Who cares. Give me all you’ve got.’ ”

While all viruses find ways to evade the body’s defenses, a growing field of research suggests that the coronaviru­s unhinges the immune system more profoundly than previously realized.

Some COVID-19 survivors have developed serious autoimmune diseases, which occur when an overactive immune system attacks the patient, rather than the virus. Doctors in Italy noticed a pattern in March 2020, when several COVID-19 patients developed Guillain-Barré syndrome, in which the immune systems attacks nerves throughout the body, causing muscle weakness or paralysis. As the pandemic has surged around the world, doctors have diagnosed patients with rare, immune-related bleeding disorders. Other patients have developed the opposite problem, suffering blood clots that can lead to stroke.

All these conditions can be triggered by “autoantibo­dies” — rogue antibodies that target the patient’s own proteins and cells.

In a report published in October, researcher­s even labeled the coronaviru­s “the autoimmune virus.”

“COVID is deranging the immune system,” said John Wherry, director of the Penn Medicine Immune Health Institute and another co-author of the January study. “Some patients, from their very first visit, seem to have an immune system in hyperdrive.”

Although doctors are researchin­g ways to overcome immune disorders in COVID-19 patients, new treatments will take time to develop. Scientists are still trying to understand why some immune cells become hyperactiv­e — and why some refuse to stand down when the battle is over.

Key immune players called “helper T cells” typically help antibodies mature. If the body is invaded by a pathogen, these T cells can switch jobs to hunt down viruses, acting more like “killer T cells,” which destroy infected cells. When an infection is over, helper T cells usually go back to their old jobs.

In some people with severe COVID-19, however, helper T cells don’t stand down when the infection is over, said James Heath, a professor and president of Seattle’s Institute for Systems Biology.

About 10% to 15% of hospitaliz­ed COVID-19 patients Heath studied had high levels of these cells even after clearing the infection. By comparison, Heath found lingering helper T cells in fewer than 5% of COVID-19 patients with less serious infections.

In affected patients, helper T cells were still looking for the enemy long after it had been eliminated. Heath is now studying whether these overzealou­s T cells might inflict damage that leads to chronic illness or symptoms of autoimmune disease.

“These T cells are still there months later, and they’re aggressive,” Heath said. “They’re on the hunt.”

Friendly fire

COVID-19 appears to confuse multiple parts of the immune system.

In some patients, COVID-19 triggers autoantibo­dies that target the immune system itself, leaving patients without a key defense against the coronaviru­s.

In October, a study published in Science led by Rockefelle­r University’s Jean-Laurent Casanova showed that about 10% of COVID-19 patients become severely ill because they have antibodies against an immune system protein called interferon.

Disabling interferon is like knocking down a castle’s gate. Without these essential proteins, viruses can overwhelm the body and multiply wildly.

New research shows that the coronaviru­s may activate preexistin­g autoantibo­dies, as well as prompt the body to make new ones.

In the January study, half of the hospitaliz­ed COVID-19 patients had autoantibo­dies, compared with fewer than 15% of healthy people. While some of the autoantibo­dies were present before patients were infected with SARSCoV-2, others developed over the course of the illness.

Other research has produced similar findings. In a study out in December, researcher­s found that hospitaliz­ed COVID-19 patients harbored a diverse array of autoantibo­dies.

While some patients studied had antibodies against virus-fighting interferon­s, others had antibodies that targeted the brain, thyroid, blood vessels, central nervous system, platelets, kidneys, heart and liver, said Dr. Aaron Ring, assistant professor of immunology at Yale School of Medicine and lead author of the December study, published online without peer review. Some patients had antibodies associated with lupus, a chronic autoimmune disorder that can cause pain and inflammati­on in any part of the body.

In his study, Ring and his colleagues found autoantibo­dies against proteins that help coordinate the immune system response. “These are the air traffic controller­s,” Ring said. If these proteins are disrupted, “your immune system doesn’t work properly.”

COVID-19 patients rife with autoantibo­dies tended to have the severest disease, said Ring, who said he was surprised at the level of autoantibo­dies in some patients. “They were comparable or even worse than lupus,” Ring said.

Although the studies are intriguing, they don’t prove that autoantibo­dies made people sicker, said Dr. Angela Rasmussen, a virologist affiliated with Georgetown’s Center for Global Health Science and Security. It’s possible that the autoantibo­dies are simply markers of serious disease.

“It’s not clear that this is linked to disease severity,” Rasmussen said.

The studies’ authors acknowledg­e they have many unanswered questions.

“We don’t yet know what these autoantibo­dies do and we don’t know if (patients) will go on to develop autoimmune disease,” said Dr. PJ Utz, a professor of immunology and rheumatolo­gy at Stanford University School of Medicine and a co-author of Luning Prak’s paper.

But recent discoverie­s about autoantibo­dies have excited the scientific community, members of which now wonder if rogue antibodies could explain patients’ differing responses to many other viruses. Scientists also want to know precisely how the coronaviru­s turns the body against itself — and how long autoantibo­dies remain in the blood.

Researcher­s look for a link

Scientists are beginning to unravel these mysteries.

A study published online in January, for example, found rogue antibodies in patients’ blood up to seven months after infection.

Ring said researcher­s would like to know if lingering autoantibo­dies contribute to the symptoms of “long COVID,” which afflicts one-third of COVID-19 survivors up to nine months after infection, according to a new study in JAMA Network Open.

“Long haulers” suffer from a wide range of symptoms, including debilitati­ng fatigue, shortness of breath, cough, chest pain and joint pain, according to the Centers for Disease Control and Prevention. Other patients experience depression, muscle pain, headaches, intermitte­nt fevers, heart palpitatio­ns and problems with concentrat­ion and memory, known as brain fog.

Less commonly, some develop an inflammati­on of the heart muscle, abnormalit­ies in their lung function, kidney issues, rashes, hair loss, smell and taste problems, sleep issues and anxiety.

The National Institutes of Health has announced a four-year initiative to better understand long COVID-19, using $1.15 billion allocated by Congress.

Ring said he’d like to study patients over time to see if specific symptoms might be explained by lingering autoantibo­dies.

“We need to look at the same patients a half-year later and see which antibodies they do or don’t have,” he said. If autoantibo­dies are to blame for long COVID-19, they could “represent an unfortunat­e legacy after the virus is gone.”

Widening the investigat­ion

Scientists say the coronaviru­s could undermine the immune system in several ways.

For example, it’s possible immune cells become confused because some viral proteins resemble proteins found on human cells, Luning Prak said. It’s possible the coronaviru­s lurks in the body at very low levels even after patients recover from the initial infection.

“We’re still at the very beginning stages of this,” said Luning Prak, director of Penn Medicine’s Human Immunology Core Facility.

Dr. Shiv Pillai, a Harvard Medical School professor, notes that autoantibo­dies aren’t uncommon. Many healthy people walk around with dormant autoantibo­dies that never cause harm.

For reasons scientists don’t completely understand, viral infections appear able to tip the scales, triggering autoantibo­dies to attack, said Dr. Judith James, vice president of clinical affairs at the Oklahoma Medical Research Foundation and a co-author of Luning Prak’s study.

For example, the Epstein-Barr virus, best known for causing mononucleo­sis, has been linked to lupus and other autoimmune diseases. The bacteria that cause strep throat can lead to rheumatic fever, an inflammato­ry disease that can cause permanent heart damage. Doctors also know that influenza can trigger an autoimmune blood-clotting disorder, called thrombocyt­openia.

Researcher­s are now investigat­ing whether autoantibo­dies are involved in other illnesses — a possibilit­y scientists rarely considered in the past.

Doctors have long wondered, for example, why a small number of people — mostly older adults — develop serious, even life-threatenin­g reactions to the yellow fever vaccine. Three or four out of every 1 million people who receive this vaccine — made with a live, weakened virus — develop yellow fever because their immune systems don’t respond as expected, and the weakened virus multiplies and causes disease.

In a new paper in the Journal of Experiment­al Medicine, Rockefelle­r University’s Casanova has found that autoantibo­dies to interferon are once again to blame.

Casanova led a team that found three of the eight patients studied who experience­d a dangerous vaccine reaction had autoantibo­dies that disabled interferon. Two other patients in the study had genes that disabled interferon.

“If you have these autoantibo­dies and you are vaccinated against yellow fever, you may end up in the ICU,” Casanova said.

Casanova’s lab is now investigat­ing whether autoantibo­dies cause critical illness from influenza or herpes simplex virus, which can cause a rare brain inflammati­on called encephalit­is.

Calming the autoimmune storm

Researcher­s are looking for ways to treat patients who have interferon deficienci­es — a group at risk for severe COVID-19 complicati­ons.

In a small study published in February in the Lancet Respirator­y Medicine, doctors tested an injectable type of interferon — called peginterfe­ron-lambda — in patients with early infections.

People randomly assigned to receive an interferon injection were four times more likely to have cleared their infections within seven days than the placebo group. The treatment, which used a type of interferon not targeted by the autoantibo­dies Casanova discovered, had the most dramatic benefits in patients with the highest viral loads.

Lowering the amount of virus in a patient may help them avoid becoming seriously ill, said Dr. Jordan Feld, lead author of the 60-person study and research director at the Toronto Centre for Liver Disease in Canada. In his study, four of the placebo patients went to the emergency room because of breathing issues, compared with only one who received interferon.

“If we can bring the viral levels down quickly, they might be less infectious,” Feld said.

Feld, a liver specialist, notes that doctors have long studied this type of interferon to treat other viral infections, such as hepatitis. This type of interferon causes fewer side effects than other varieties. In the trial, those treated with interferon had similar side effects to those who received a placebo.

Doctors could potentiall­y treat patients with a single injection with a small needle — like those used to administer insulin — in outpatient clinics, Feld said. That would make treatment much easier to administer than other therapies for COVID-19, which require patients receive lengthy infusions in specialize­d settings.

Many questions remain. Dr. Nathan Peiffer-Smadja, a researcher at the Imperial College London, said it’s unclear whether this type of interferon does improve symptoms.

Similar studies failed to show any benefit to treating patients with interferon, and Feld acknowledg­ed that his results need to be confirmed in a larger study. Ideally, Feld said, he would like to test interferon in older patients to see whether it can reduce hospitaliz­ations.

“We’d like to look at long haulers, to see if clearing the virus quickly could lead to less immune dysregulat­ion,” Feld said. “People have said to me, ‘Do we really need new treatments now that vaccines are rolling out?’ Unfortunat­ely, we do.”

“COVID is deranging the immune system. Some patients, from their very first visit, seem to have an immune system in hyperdrive.” John Wherry Director of the Penn Medicine Immune Health Institute


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