Dr. Akiko Iwasaki, Sterling Professor of Immunology at Yale University and winner of the 2025 Solve Catalyst Award, recently published a study on distinguishing groups of people with ME/CFS based on blood-plasma and cerebrospinal fluid proteins. For this work, Dr. Iwasaki collaborated with two other Solve-funded researchers, Dr. Michael VanElzakker and Dr. Amy Proal.
Comparing questionnaire answers from 39 patients with ME/CFS and 40 healthy participants, the research team found that people with ME/CFS reported having more pain, brain fog, and fatigue, and poorer walking speed, memory, sleep, concentration, and quality of life. However, the blood-plasma and cerebrospinal fluid samples from people with ME/CFS were much like those from healthy participants. Both groups had been exposed to the same parasites, viruses, and bacteria. Both groups had the same levels of autoantibodies (with a few modest differences). And both groups had the same plasma levels of immune-related proteins and hormones.
But there were some differences. For example, while levels of eotaxin (a chemokine that attracts eosinophil immune cells) and fractalkine (a chemokine that attracts other immune cells, like T cells and monocytes) correlated significantly with distinct cytokines, hormones, and matrix metalloproteinases in healthy participants, they correlated much less in patients with ME/CFS. Also, cerebrospinal fluid levels of several matrix metalloproteinases (which break down proteins outside of cells and which affect neuroinflammation and blood–brain barrier permeability) were higher in some patients with ME/CFS than in other patients with ME/CFS or in healthy participants.
The patients with higher metalloproteinase levels also had higher levels of cerebrospinal fluid proinflammatory cytokines. Patients with these higher levels may have had craniocervical structural problems that affected how cerebrospinal fluid was made and how it flowed; thus, changing levels of metalloproteinases and cytokines in the fluid.
Patients with higher cerebrospinal fluid levels of metalloproteinases and cytokines were also significantly more likely to have antibodies against cytomegalovirus. In contrast, patients with lower levels of these proteins were more likely to have antibodies against SARS-CoV-2 or parvovirus B19. Otherwise, symptoms and medical histories of patients with higher matrix metalloproteinase and cytokine levels were much like those of patients with lower levels.
These results are interesting because they suggest that distinct mechanisms underlying ME/CFS—for example, different cerebrospinal fluid levels of key metalloproteinases and proinflammatory cytokines, reflecting distinct central nervous system changes—can lead to the same symptoms.
These results also inform strategies to treat people with ME/CFS. For example, the fact that autoantibody levels in people with ME/CFS were like those in healthy participants is consistent with the failure of rituximab (a drug that reduces autoantibody levels) in a phase 3 clinical trial for ME/CFS.
Also, treatments targeting metalloproteinases and proinflammatory cytokines may be better for those patients with elevated levels of these proteins in their cerebrospinal fluid.
The researchers suggested that future studies should compare levels of other matrix metalloproteinases and autoantibodies in people with ME/CFS with those in healthy participants; examine other tissues and fluids (beyond blood plasma and cerebrospinal fluid); and assess more symptoms by using more objective measures.
Why This Study Matters to the Patient Community:
- Suggests candidate proteins that may contribute to neuroinflammation in ME/CFS: Finds specific matrix metalloproteinases (which can dysregulate neuronal functions and disrupt the blood–brain barrier) and proinflammatory cytokines overexpressed in some patients with ME/CFS.
- Lays the Groundwork for Targeted Treatments: Uncovers distinct subgroups of patients with ME/CFS and suggests targeted treatments (like anti-neuroinflammatory drugs or metalloproteinase inhibitors) may help one subgroup.
- Advances Diagnostic Tools: Finds cerebrospinal proteins that correlate with distinct histories of viral infection and distinct cerebrospinal fluid protein levels.
- Validates key symptoms of ME/CFS: Finds people with ME/CFS have significantly worse quality of life (like more pain, fatigue, and neurological issues) than healthy participants.
- Centers Patient Experience: Shows how symptoms of ME/CFS can be the same regardless of viral infection history.
This work was published in the Journal of Immunology.