Post by Nadica (She/Her) on Jun 24, 2024 9:00:50 GMT
Antibodies from Long Covid patients prompt symptoms in mice - Published June 21, 2024
In the quest to explain the symptoms of Long Covid, one suspect—antibodies in the blood that target a patient’s own tissues—is getting extra scrutiny from two teams of scientists an ocean apart. Both groups injected mice with antibodies from the blood of people with Long Covid, the constellation of symptoms that sometimes persist for months or years after a SARS-CoV-2 infection. And in certain cases, they say, the rodents developed symptoms seemingly mirroring those of their human donors, in particular a heightened sensitivity to pain.
Some scientists say these studies, one posted earlier this week, bolster the case for a dysfunctional immune system, triggered by a coronavirus infection, directly fueling Long Covid symptoms—and open the door to potential new treatment trials. “This is strong evidence” for Long Covid being an immune-mediated disorder, and likely applies to other post-viral syndromes too, says Danilo Buonsenso, a pediatric infectious disease doctor who studies and treats Long Covid in children at Gemelli University Hospital, and was not involved in the work.
But while other researchers said the studies were elegantly done, and may offer novel mouse models of Long Covid, they are less certain about the bottom line. “There’s no uniform autoantibodies” in these groups of patients, says Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke. This makes it tricky to say that certain autoantibodies are causing certain symptoms—in mice or in people.
“If you think of a [typical] autoimmune disease, you have antibodies against a target and it’s the same target in all patients,” says Petter Brodin, an immunologist at the Karolinska Institute. “What’s clear is that this is not such a disease.”
Autoantibodies have long been eyed in Long Covid, with various studies finding them enduring in patients’ blood. But their role has been ambiguous in the syndrome, partly because so many different types show up in patients. Autoantibodies are also common in healthy people. And they can surface and then fade away after infections. “Anytime you stimulate your immune system,” autoantibodies can result, says Brodin. But some autoantibodies cause clear harm: in certain autoimmune diseases, they target a specific tissue and are key to triggering illness.
So far, it hasn’t been clear whether antibodies found in Long Covid patients’ blood directly cause illness—and thus are a good target for treatment. So two Long Covid research teams recently decided to dig into the question—one led by immunologist Akiko Iwasaki at Yale University, the other by immunologist Jeroen den Dunnen at Amsterdam UMC and neuroimmunologist Niels Eijklekamp at UMC Utrecht. Both teams first isolated antibodies from the blood of Long Covid patients and then transferred the mixture into healthy mice to see if that would prompt symptoms that mirrored those of the patients, or the abnormalities in their immune system.
The researchers were mindful of an ongoing challenge in Long Covid research: huge variation in the type and intensity of symptoms, which can include brain fog, headaches, and crushing fatigue after exertion. Increasingly, scientists and doctors believe that there are probably multiple causes of the syndrome, maybe even multiple drivers of different symptoms in the same person. Studies that cluster together patients with similarities and study each group separately may have the best shot at understanding the syndrome’s biology, says Iwasaki. “You can’t generally look at everybody with Long Covid and hope to see a signal.”
Both Iwasaki’s team and the Dutch scientists were especially interested in Long Covid’s neurological symptoms. A 2021 study had found that mice receiving autoantibodies from people with a different chronic illness, fibromyalgia, showed signs of pain similar to what those patients experienced. That left the scientists behind this new research wondering whether pain from Long Covid could also be recapitulated. “That was the inspiration,” says Iwasaki.
The Dutch team analyzed blood from 31 Long Covid patients; all had had initial mild cases of the virus and symptoms that had persisted for at least six months. Based on different immune abnormalities in their blood, the researchers divvied the patients into three groups: those with markers of neuroinflammation; those with immune signaling proteins called interferons that often turn up after a viral illness; and a third group that had neither of these signatures. From all these blood samples, researchers extracted immunoglobulin G (IgG), a common class of antibody that includes autoantibodies.
Mice that got an injection of IgG from the neuroinflammation and interferon subgroups showed a heightened sensitivity to pain—which set in especially quickly for the interferon group, the Dutch team reported 31 May in a preprint on bioRxiv. Mice who got IgG from the third group showed reduced walking distance a day after the injection, which researchers proposed could be related to high levels of muscle-related proteins in these patients’ blood. Those who received IgG from healthy control participants had no changes to behavior.
“At this stage we don’t know” exactly how the IgG is causing these effects, says Eijkelkamp, but he is intrigued that the differences between the mouse cohorts matched some immune signatures in patients.
He’s also heartened that another team reported something very similar just three weeks later. Iwasaki and her group studied Long Covid patients with significant neurological symptoms, including brain fog, headache, memory loss, and dizziness. Many also reported chronic pain. Mice given IgG from these patients, as well as healthy controls, then underwent a battery of tests. Tests for anxiety, motor coordination, blood pressure and heart rate revealed no differences between the two groups. But on a test of pain sensitivity that exposed animals to a hot plate, mice that got autoantibodies from Long Covid patients reacted after an average of 7 seconds, compared to 10 seconds for animals whose injection was from a healthy control, they reported in a medRxiv preprint on 19 June.
Even though the human participants in both studies had various symptoms, pain was the most vivid symptom in the mice. Whether other symptoms don’t readily transfer via IgG antibodies, or they’re simply hard to detect in the rodents, the researchers can’t say. “We can’t exclude” that the mice are experiencing something like brain fog too, says Eijkelkamp.
Still unknown is whether autoantibodies are the initial trigger of Long Covid in people. Nath suspects the wide mix of autoantibodies seen in patients points to some earlier chain reaction in the immune system, perhaps from fragments of lingering virus.
A direct line between autoantibodies and illness, Nath says, would be strengthened by showing that specific autoantibodies are binding to certain sites, and in turn triggering specific symptoms. Iwasaki agrees, and is aiming to push forward with such work.
A crucial question is whether wiping out autoantibodies in Long Covid patients could ease symptoms. A recent trial found that efgartigimod, a drug that depletes autoantibodies and is approved for the autoimmune disease myasthenia gravis, did not help Long Covid patients who had a circulation disorder called postural orthostatic tachycardia syndrome. And Nath notes that rituximab, a drug that depletes antibody-producing B cells, wasn’t effective in a study of myalgic encephalitis-chronic fatigue syndrome – another chronic illness thought to arise after an infection. (Others point out that rituximab may not quickly erase all autoantibodies.) Nath is currently running a Long Covid trial of intravenous immunoglobulin, which broadly modulates the immune system, including neutralizing autoantibodies.
Both groups say that further clinical trials of autoantibody depletion are worth trying. “We need these kinds of studies,” says Eijkelkamp, and “that’s going to be our proof” of whether autoantibodies are driving Long Covid. Den Dunnen notes that the team is considering a trial that would remove IgG from the blood of someone with Long Covid. But to increase the odds this treatment will be effective, the team might search for patients whose aberrant immunity appears to trigger symptoms – with help from mice like the ones in the recent studies. Scientists could first inject a patient’s IgG into a mouse. “If the mouse gets sick,” he says, “then yes, you’re in a trial.”
In the quest to explain the symptoms of Long Covid, one suspect—antibodies in the blood that target a patient’s own tissues—is getting extra scrutiny from two teams of scientists an ocean apart. Both groups injected mice with antibodies from the blood of people with Long Covid, the constellation of symptoms that sometimes persist for months or years after a SARS-CoV-2 infection. And in certain cases, they say, the rodents developed symptoms seemingly mirroring those of their human donors, in particular a heightened sensitivity to pain.
Some scientists say these studies, one posted earlier this week, bolster the case for a dysfunctional immune system, triggered by a coronavirus infection, directly fueling Long Covid symptoms—and open the door to potential new treatment trials. “This is strong evidence” for Long Covid being an immune-mediated disorder, and likely applies to other post-viral syndromes too, says Danilo Buonsenso, a pediatric infectious disease doctor who studies and treats Long Covid in children at Gemelli University Hospital, and was not involved in the work.
But while other researchers said the studies were elegantly done, and may offer novel mouse models of Long Covid, they are less certain about the bottom line. “There’s no uniform autoantibodies” in these groups of patients, says Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke. This makes it tricky to say that certain autoantibodies are causing certain symptoms—in mice or in people.
“If you think of a [typical] autoimmune disease, you have antibodies against a target and it’s the same target in all patients,” says Petter Brodin, an immunologist at the Karolinska Institute. “What’s clear is that this is not such a disease.”
Autoantibodies have long been eyed in Long Covid, with various studies finding them enduring in patients’ blood. But their role has been ambiguous in the syndrome, partly because so many different types show up in patients. Autoantibodies are also common in healthy people. And they can surface and then fade away after infections. “Anytime you stimulate your immune system,” autoantibodies can result, says Brodin. But some autoantibodies cause clear harm: in certain autoimmune diseases, they target a specific tissue and are key to triggering illness.
So far, it hasn’t been clear whether antibodies found in Long Covid patients’ blood directly cause illness—and thus are a good target for treatment. So two Long Covid research teams recently decided to dig into the question—one led by immunologist Akiko Iwasaki at Yale University, the other by immunologist Jeroen den Dunnen at Amsterdam UMC and neuroimmunologist Niels Eijklekamp at UMC Utrecht. Both teams first isolated antibodies from the blood of Long Covid patients and then transferred the mixture into healthy mice to see if that would prompt symptoms that mirrored those of the patients, or the abnormalities in their immune system.
The researchers were mindful of an ongoing challenge in Long Covid research: huge variation in the type and intensity of symptoms, which can include brain fog, headaches, and crushing fatigue after exertion. Increasingly, scientists and doctors believe that there are probably multiple causes of the syndrome, maybe even multiple drivers of different symptoms in the same person. Studies that cluster together patients with similarities and study each group separately may have the best shot at understanding the syndrome’s biology, says Iwasaki. “You can’t generally look at everybody with Long Covid and hope to see a signal.”
Both Iwasaki’s team and the Dutch scientists were especially interested in Long Covid’s neurological symptoms. A 2021 study had found that mice receiving autoantibodies from people with a different chronic illness, fibromyalgia, showed signs of pain similar to what those patients experienced. That left the scientists behind this new research wondering whether pain from Long Covid could also be recapitulated. “That was the inspiration,” says Iwasaki.
The Dutch team analyzed blood from 31 Long Covid patients; all had had initial mild cases of the virus and symptoms that had persisted for at least six months. Based on different immune abnormalities in their blood, the researchers divvied the patients into three groups: those with markers of neuroinflammation; those with immune signaling proteins called interferons that often turn up after a viral illness; and a third group that had neither of these signatures. From all these blood samples, researchers extracted immunoglobulin G (IgG), a common class of antibody that includes autoantibodies.
Mice that got an injection of IgG from the neuroinflammation and interferon subgroups showed a heightened sensitivity to pain—which set in especially quickly for the interferon group, the Dutch team reported 31 May in a preprint on bioRxiv. Mice who got IgG from the third group showed reduced walking distance a day after the injection, which researchers proposed could be related to high levels of muscle-related proteins in these patients’ blood. Those who received IgG from healthy control participants had no changes to behavior.
“At this stage we don’t know” exactly how the IgG is causing these effects, says Eijkelkamp, but he is intrigued that the differences between the mouse cohorts matched some immune signatures in patients.
He’s also heartened that another team reported something very similar just three weeks later. Iwasaki and her group studied Long Covid patients with significant neurological symptoms, including brain fog, headache, memory loss, and dizziness. Many also reported chronic pain. Mice given IgG from these patients, as well as healthy controls, then underwent a battery of tests. Tests for anxiety, motor coordination, blood pressure and heart rate revealed no differences between the two groups. But on a test of pain sensitivity that exposed animals to a hot plate, mice that got autoantibodies from Long Covid patients reacted after an average of 7 seconds, compared to 10 seconds for animals whose injection was from a healthy control, they reported in a medRxiv preprint on 19 June.
Even though the human participants in both studies had various symptoms, pain was the most vivid symptom in the mice. Whether other symptoms don’t readily transfer via IgG antibodies, or they’re simply hard to detect in the rodents, the researchers can’t say. “We can’t exclude” that the mice are experiencing something like brain fog too, says Eijkelkamp.
Still unknown is whether autoantibodies are the initial trigger of Long Covid in people. Nath suspects the wide mix of autoantibodies seen in patients points to some earlier chain reaction in the immune system, perhaps from fragments of lingering virus.
A direct line between autoantibodies and illness, Nath says, would be strengthened by showing that specific autoantibodies are binding to certain sites, and in turn triggering specific symptoms. Iwasaki agrees, and is aiming to push forward with such work.
A crucial question is whether wiping out autoantibodies in Long Covid patients could ease symptoms. A recent trial found that efgartigimod, a drug that depletes autoantibodies and is approved for the autoimmune disease myasthenia gravis, did not help Long Covid patients who had a circulation disorder called postural orthostatic tachycardia syndrome. And Nath notes that rituximab, a drug that depletes antibody-producing B cells, wasn’t effective in a study of myalgic encephalitis-chronic fatigue syndrome – another chronic illness thought to arise after an infection. (Others point out that rituximab may not quickly erase all autoantibodies.) Nath is currently running a Long Covid trial of intravenous immunoglobulin, which broadly modulates the immune system, including neutralizing autoantibodies.
Both groups say that further clinical trials of autoantibody depletion are worth trying. “We need these kinds of studies,” says Eijkelkamp, and “that’s going to be our proof” of whether autoantibodies are driving Long Covid. Den Dunnen notes that the team is considering a trial that would remove IgG from the blood of someone with Long Covid. But to increase the odds this treatment will be effective, the team might search for patients whose aberrant immunity appears to trigger symptoms – with help from mice like the ones in the recent studies. Scientists could first inject a patient’s IgG into a mouse. “If the mouse gets sick,” he says, “then yes, you’re in a trial.”