This study for the first time found 2 distinct immunotypes of ME/CFS patients based on CSF marker analysis. Our findings shed light on ME/CFS immune phenotypes and generate hypotheses for future research in disease pathogenesis and treatment development by exploring disease subgroups.
Bastos et al 2025, Journal of Immunology
Summary
- ME/CFS (Myalgic encephalomyelitis/chronic fatigue syndrome) is a complex, multisystem disease with significant quality-of-life impact.
- Symptoms include postexertional malaise, persistent fatigue, sleep dysfunction, pain, and autonomic issues.
- ME/CFS may not have a single pathophysiological mechanism, contributing to heterogeneity in research findings.
- Study Design and Methods:
- Enrolled 40 ME/CFS patients and 41 matched healthy controls at Bragée Clinic, Sweden.
- Collected plasma from all participants and CSF from ME/CFS participants.
- Key Findings:
- Altered interaction patterns in plasma biological factors in ME/CFS cases.
- Identified two patient clusters based on CSF MMP profiles.
- Similar clinical symptoms, but distinct inflammatory and pathogen exposure profiles.
- Immune Findings and Pathophysiology:
- Plasma analysis showed increased correlations among cytokines in ME/CFS.
- Disrupted interactions in fractalkine–CX3CR1 signaling, potentially affecting CNS inflammation.
- Lower IgM autoantibody reactivity in ME/CFS; anti-factor P IgM slightly reduced.
- No significant differences in IgG autoantibodies.
- Immune profiling supports chronic antigenic stimulation theory.
- Subtle immune alterations may result from persistent pathogen antigens.
- Importance of Subtyping
- Two distinct immunotypes identified in CSF, despite similar clinical symptoms.
- Suggests importance of biological subtyping for targeted therapy development.
- Highlights the need for biomarkers and standardised phenotyping.
- Implications:
- Study supports ME/CFS heterogeneity and the existence of distinct biological subgroups.
- Emphasises the need for immunomodulatory treatment exploration.
- Findings provide a foundation for future biomarker research and pathophysiological understanding
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex heterogeneous multiorgan disease that can have severe impact on individuals' quality of life. Diagnosis of ME/CFS is based on symptom presentation, and a significant goal for the field is to establish meaningful subtypes. The heterogeneity in the literature suggests that individuals living with ME/CFS may suffer from overlapping but different underlying pathophysiological mechanisms.
We enrolled 40 participants with ME/CFS and 41 matched healthy control subjects at the Bragée Clinic in Sweden. We assessed plasma samples from both ME/CFS cases and control groups and cerebrospinal fluid (CSF) samples from individuals with ME/CFS. We investigated dysregulated pathways and disease profiles through clinical questionnaires; multiplex analyses of cytokines, hormones, and matrix metalloproteinases; pathogen seroreactivity through peptide display bacteria libraries; and high-throughput microarray for autoantibodies.
All samples used were from humans. We show altered interaction patterns between circulating biological factors in plasma of ME/CFS participants. Our analysis of CSF from individuals with ME/CFS revealed different immunotypes of disease. We found 2 patient clusters based on matrix metalloproteinases profiles. The subgroups had similar clinical presentation but distinct pathogen exposure and CSF inflammatory profiles. Our findings shed light on ME/CFS immune phenotypes and generate hypotheses for future research in disease pathogenesis and treatment development by exploring disease subgroups.
MEA Comment
This is a fairly small but well designed and rather unusual research study from Sweden.
It used both blood (plasma) and cerebrospinal fluid (CSF) samples to look for evidence of biomarker abnormalities in people with ME/CFS. The plasma results were compared to healthy controls. The spinal fluid samples were not.
Not surprisingly, there has been very little research involving spinal fluid samples in ME/CFS. This is because obtaining a small amount of spinal fluid is a rather unpleasant invasive procedure which can cause side-effects. So many thanks to everyone with ME/CFS who agreed to provide a spinal fluid sample.
The results suggest that that there are sub groups of people with ME/CFS who have different immunological profiles. The research also adds further weight to a model of ME/CFS disease causation that involves the production of immune system chemicals called cytokines – which may then result in some form of low level inflammation involving the brain.
It would be interesting to see if these results could now be validated by another independent research group.
Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association,
Member of the 2018-2021 NICE guideline on ME/CFS committee,
Member of the 2002 Chief Medical Officer's Working Group on ME/CFS
