Distinct changes in the immune systems of patients with ME or chronic fatigue syndrome have been found, say scientists.
Increased levels of immune molecules called cytokines were found in people during the early stages of the disease, a Columbia University study reported.
It said the findings could help improve diagnosis and treatments.
UK experts said further refined research was now needed to confirm the results.
People with ME (myalgic encephalopathy) or CFS (chronic fatigue syndrome) suffer from exhaustion that affects everyday life and does not go away with sleep or rest.
They can also have muscle pain and difficulty concentrating.
ME can also cause long-term illness and disability, although many people improve over time.
It is estimated that around 250,000 people in the UK have the disease.
The US research team, who published their findings in the journal Science Advances, tested blood samples from nearly 300 ME patients and around 350 healthy people.
They found specific patterns of immune molecules in patients who had the disease for up to three years.
These patients had higher levels of of cytokines, particularly one called interferon gamma, which has been linked to the fatigue that follows many viral infections.
Healthy patients and those who had the disease for longer than three years did not show the same pattern.
Lead author Dr Mady Hornig said this was down to the way viral infections could disrupt the immune system.
"It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop."
This shows there are distinct stages to the disease, she said. When the cytokine response starts to settle down, the disease also appears to quieten down.
Peter White, professor of psychological medicine at Queen Mary University of London, said it was premature to draw any conclusions from the study.
"Only one out of the 51 immune proteins studied was elevated in all cases compared with controls, something that could happen by chance alone.
"I hope the authors will go on to re-examine their data after stratifying their samples by other factors that determine the different sub-groups that most scientists now accept make up this illness.
"Finally, as the authors themselves suggest, we need to see these results replicated independently."
Dr Charles Shepherd, medical adviser to the ME Association, said the research was interesting and useful, and added more support to what is already known about the abnormal immune response in people with chronic fatigue syndrome.
"If distinctive patterns of cytokine abnormality can be linked to both stage and severity of disease, this is a finding which could be used to aid diagnosis and open the door to the use of anti-inflammatory drug treatments that would dampen down the abnormal immune system response."
But he indicated that this was still some way off.
He added: "Although some doctors do still mistakenly believe that ME/CFS is a psychological illness, there is now very robust evidence being produced to show that we are dealing with a physical disease process that includes significant abnormalities involving the brain, muscle and the immune system."