Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome

• Published in: The Journal of immunology (1950) Vol. 214; no. 7; pp. 1539 - 1551
• Main Authors: Bastos, Victoria C, Greene, Kerrie A, Tabachnikova, Alexandra, Bhattacharjee, Bornali, Sjögren, Per, Bertilson, Bo, Reifert, Jack, Zhang, Minlu, Kamath, Kathy, Shon, John, Gehlhausen, Jeff R, Guan, Leying, VanElzakker, Michael, Proal, Amy, Bragée, Björn, Iwasaki, Akiko
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2025
• Subjects: Adult; Autoantibodies - blood; Autoantibodies - cerebrospinal fluid; Autoantibodies - immunology; Biomarkers - cerebrospinal fluid; Clinical and Human Immunology; Cytokines - blood; Cytokines - cerebrospinal fluid; Fatigue Syndrome, Chronic - cerebrospinal fluid; Fatigue Syndrome, Chronic - diagnosis; Fatigue Syndrome, Chronic - immunology; Female; Humans; Immunophenotyping; Male; Matrix Metalloproteinases - cerebrospinal fluid; Middle Aged; Phenotype; Sweden; Sweden; neuroimmunology; immune phenotypes; matrix metalloproteinases; ME/CFS; cerebrospinal fluid
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.1093/jimmun/vkaf087

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.