Jennifer Brea, who has Chronic fatigue syndrome/myalgic encephalomyelitis, reveals her story in her film, Unrest. 

More clues link immune system imbalance with chronic fatigue syndrome

After a 5-month road trip across Asia in 2010, 22-year-old college graduate Matthew Lazell-Fairman started feeling constantly tired, his muscles sore and head aching. A doctor recommended getting a gym membership, but after the first training session, Lazell-Fairman’s body crashed: He was so exhausted he couldn’t go to work as a paralegal for the Federal Trade Commission in Washington, D.C., for days. Lazell-Fairman has never fully recovered. He can now do a few hours of light activity—cooking, for example—per day but has to spend the rest of his time lying flat in bed.

Lazell-Fairman is among the estimated 17 million people worldwide with chronic fatigue syndrome (CFS), a disease whose trigger is unknown and for which there are neither standard diagnostic tools nor effective treatments. In the largest study of its kind, researchers have now found that the blood levels of immune molecules that cause flulike symptoms such as fever and fatigue track the severity of symptoms in people who have received a diagnosis of CFS. The results may provide insight into the cause of the mysterious illness, or at least provide a way of gauging its progress and evaluating treatments.

“This work is another strong piece of evidence that there is a biologic dysfunction at the root of the disease,” says Mady Hornig, a physician scientist at Columbia University whose research has also identified potential biomarkers for CFS.

People with CFS—many patients and advocates prefer to call the condition myalgic encephalomyelitis (ME) because of the complex set of symptoms that are not limited to fatigue—experience prolonged, extreme exhaustion that doesn’t improve with rest. The fatigue may worsen with physical or mental activity and often comes with “brain fog,” a feeling of mental clouding, and sensitivity to noise, light, or other stimuli like taste and smell. Patients may also have memory impairment, muscle pain, and gut problems such as diarrhea, bloating, and nausea.

For years, CFS had been dismissed as a psychological disorder, and some physicians advocated treating it primarily with psychotherapy or a gradual increase in physical activity. But many researchers, and funding agencies such as the National Institutes of Health, increasingly view it as a physiological problem. “It’s a medical mystery,” says Mark Davis, an immunologist at Stanford University in Palo Alto, California.

For this reason, Davis, together with Stanford immunologist Jose Montoya and their teams, recently evaluated whether an imbalance of the immune system may trigger CFS/ME, as previous studies have suggested. By analyzing the blood of 192 people who had met one of the established criteria for CFS/ME diagnosis and 392 healthy individuals, the team found that the levels of 17 cytokines, substances produced by immune cells in response to infection, correlated with disease severity. They were higher in patients with the severest symptoms than in patients with milder symptoms or healthy people. In patients with the mildest symptoms, the levels of those same cytokines were lower than in healthy people, and in patients with moderate symptoms they were comparable to individuals with no disease. Of these 17 immune molecules, the vast majority is known to stimulate inflammation and produce flulike symptoms, the researchers report today in the Proceedings of the National Academy of Sciences.

“I found surprising that so many cytokines are altered in the patients,” Davis says. “It seems like the disease is leaving no cytokine untouched.” The work “adds to our understanding that there are complex alterations of the immune system,” Hornig says.

A few immune molecules drew particular attention because their levels didn’t correlate with disease severity. The researchers have found that the blood level of TGF-β, a cytokine that is involved in myriad biological processes, such as inflammation and cancer, was higher in CFS/ME patients, regardless of the severity of their symptoms, than in healthy people. And the blood levels of resistin, a hormone produced by immune cells, were lower in patients compared with individuals with no disease.

These molecules might drive the disorder, scientists speculate, but they could also simply reflect the patients’ immune system fighting back against an inflammation of different origin. “These are deliberately agnostic assays,” Davis says. “First you look for correlation and then you try to understand why these things correlate with the disease.”

Nonetheless, the new study is a “tremendous step forward,” says Gordon Broderick, a systems biologist at Rochester General Hospital in New York. Being able to examine so many CFS/ME patients and identify which immune molecules are associated with more intense symptoms is “a big deal,” he says.

Although it is important to rule out that altered levels of cytokines aren’t linked to factors such as allergies or sex hormones, which can also influence the immune system, the large number of patients showing an imbalance in these immune molecules suggests that it is either a cause or result of CFS/ME, Broderick says.

In the future, the scientists hope to use these immune molecules as diagnostic tools for the puzzling condition, and also figure out the role of cytokines and the immune system in the disease. “I hope to see more research along those lines,” Hornig says. “There’s a lot of patients waiting for some answers.”