People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Have an “Exhausted” Immune System

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder from which adults rarely recover. Researchers have struggled to find changes in the body that underlie the illness, which often appears following an infection, partly because it may arise in different forms. Now scientists at the National Institutes of Health (NIH) have completed perhaps the most comprehensive study of ME/CFS to date by examining a carefully selected group of participants. In the study, which was published today in Nature Communications, the researchers observed changes that reveal how the disease disrupts the immune and nervous systems.

In addition to having overwhelming fatigue, people with ME/CFS experience a range of other symptoms such as brain fog, hypersensitivity to light and short-term memory loss. Medical professionals have historically dismissed the condition as a psychosomatic disorder by implying the disease lacks a physiological basis.

These dismissive views have held back ME/CFS research, and scientists have made little progress toward developing diagnostics and therapies and understanding the mechanism behind the condition. In recent years some progress has been made in accepting ME/CFS as a real physiological condition, in part because of the emergence of long COVID (a condition that, according to some studies, qualifies for an ME/CFS diagnosis about half of the time). But doubt over its legitimacy lingers. Alison Sbrana, a person with ME/CFS who was a participant in the new study, says that she would be shocked to meet someone with ME/CFS who hasn’t had their concerns brushed aside at some point.

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Avindra Nath, a neurologist at NIH, set out to unravel the condition’s inner workings. First, his team had to carefully select a cohort of ME/CFS participants for the study because the condition has numerous forms that might not share the same physiological manifestations. The researchers focused on a subset of people with ME/CFS who had developed the condition following an infection (before the COVID pandemic). They homed in on this group by pursuing a rigorous selection process, and they only included participants whom a panel of five clinicians unanimously agreed met the criteria. Only 17 ME/CFS participants remained after the selection process, alongside 21 healthy volunteers. With its carefully selected cohort, Nath’s team employed a slew of tests to study several body systems.

The researchers saw signs that the immune system had become “worn out” in ME/CFS participants. In the blood of this group, they found that killer T cells, which normally target infected cells for destruction, had reduced levels of a protein called CD226 that would otherwise boost their proliferation and activity. In the cerebrospinal fluid, killer T cells had elevated levels of programmed cell death protein 1 (PD1). This protein is considered an “exhaustion” marker, and its presence can indicate that an overstimulated T cell has shut down. “The immune system in effect burns out, becomes exhausted and can no longer respond to infectious triggers,” says Katharine Seton, an immunologist researching ME/CFS at the Quadram Institute, who was not involved with this study.

Nath speculates that such exhaustion might occur if remnants of an infection persist long after it’s over and continue to stimulate immune cells long-term, but further evidence is needed to confirm this. Seton hypothesizes that a “leaky gut” could be another trigger. If inflammatory microbes that live in the gut leak into the bloodstream, they might perpetually stimulate immune cells, leading to exhaustion, she says.

But not all of the immune system’s defenses decline in ME/CFS. Past studies have also pointed to an overactive immune response: a condition called autoimmunity, whereby other immune cells mistakenly attack healthy tissue, often by producing autoantibodies that target the body’s proteins. Nath’s team found low levels of autoantibodies in only one person with ME/CFS. But the researchers might not have spotted more because they excluded participants who had underlying autoimmune conditions. Maureen Hanson, a cell and molecular biologist at Cornell University who works on ME/CFS but was not involved with this study, adds that “it’s very difficult to examine every possible antibody,” making it hard to rule out the presence of other autoantibodies.

Nath found some indirect evidence for autoimmunity. His team observed overactive B-cell genes in female ME/CFS participants. B cells are the source of autoantibodies, so it’s possible that this change could predispose women to autoimmunity, he suggests. This and other sex differences that popped up show that “there are potentially two different mechanisms that are occurring in males versus females,” Seton says, which might partly account for why ME/CFS is three times more common in women.

Beyond the immune system, Nath’s team searched for changes in the brain. When participants were asked to grip an object, those with ME/CFS had decreased activity in their right temporal-parietal junction, a brain region involved in self-agency, whereby the brain predicts an action before one becomes consciously aware of it. Though other brain differences in people with ME/CFS have been known for some time, “this particular finding of that particular region is new,” Hanson says. Nath hypothesizes that this dip in activity suggests the brain is cautioning people with ME/CFS against exerting force during the grip test, which he says makes sense because ME/CFS symptoms often intensify if people with the condition overwork themselves. The finding is preliminary, however, and further experiments are needed to corroborate it.

The study was “one of the first of its kind,” Seton says, but it had a few limitations. Given the small number of participants, the researchers might have missed subtle differences between people with ME/CFS and healthy controls, she says. Nath explains that the pandemic stalled recruitment. “We were hoping to recruit at least 10 if not 20 more [people with the condition],” he says. His team enrolled people with moderate to severe ME/CFS in the study, but bedbound people with extreme ME/CFS couldn’t participate because of their physical limitations. Despite these caveats, Seton says comprehensive studies like this are “the way forward in [ME/CFS] research.”

Next Nath plans to study long COVID. “I think that’s how I can benefit the ME/CFS patients a lot faster than I could otherwise,” he says. It’s easier to recruit a larger cohort given the escalating numbers of people with long COVID and because their condition began after the same viral trigger, which could help standardize the analysis, Nath says. He has already begun clinical trials of intravenous immunoglobulin, a common treatment for autoimmune disorders or infections, in people with long COVID. “I think if it shows a benefit, it’ll benefit [other ME/CFS] patients, too.”

In the meantime, Sbrana hopes this study will raise awareness of her illness. Before the study, many people—even medical professionals—didn’t believe her condition was real. “I was being gaslit left and right whenever I tried to receive care,” she says. “Once I returned from NIH, my experience of getting care in my local community changed drastically.” Nobody questioned her condition once the NIH put it in writing. “But there were only 17 of us that [took part], and I wish that all patients with ME/CFS could be taken seriously the way that I was,” she says.