Blood and Immune System Convergence in ME/CFS

1 Seifert2026 — Extracellular Vesicle Signatures

  • Full Citation: Seifert M et al. (2026). Extracellular Vesicle Protein and MiRNA Signatures as Biomarkers for Post-Infectious ME/CFS Patients. Int J Mol Sci, 27(5).

  • DOI: 10.3390/ijms27052314

  • PMID: 41828537

  • Status: NEW — not yet in bib/

  • Key Findings:

    • Altered EV cargo proteins: hemoglobin subunit alpha, IGFBP acid labile subunit
    • hsa-let-7b-5p downregulated in post-COVID ME/CFS EVs
    • Reduced hsa-let-7b-5p correlates with impaired physical functioning, fatigue, pain

  • Conclusion: EV cargo and miRNA signatures are promising biomarker candidates for diagnosis and stratification

  • Limitations: Very small n (≤10 per cohort); female-only; no replication

2 Bragée2026 — CSF Proteomics

  • Full Citation: Bragée B et al. (2026). Proteomic signatures in CSF and their clinical associations in ME/CFS. Sci Rep.

  • DOI: 10.1038/s41598-026-46965-1

  • PMID: 41932997

  • Status: NEW — not yet in bib/

  • Key Findings:

    • 902 CSF proteins quantified in 31 ME/CFS patients
    • Neutrophil degranulation, platelet activation enriched in POTS+ patients
    • Complement cascade, coagulation, IGFBP-mediated IGF transport enriched in severe cases
    • Four severity-associated protein ratios identified

  • Conclusion: CSF proteomics reveals biological processes associated with clinical heterogeneity

  • Limitations: No control group; n=31; single-center; needs validation

3 Yu2026 — White Matter Neuroinflammation

  • Full Citation: Yu Q et al. (2026). Evidence of White Matter Neuroinflammation in ME/CFS: A Diffusion-Based Neuroinflammation Imaging Study. Hum Brain Mapp, 47(4):e70505.

  • DOI: 10.1002/hbm.70505

  • PMID: 41834684

  • Status: NEW — not yet in bib/

  • Key Findings:

    • 67 ME/CFS vs 67 matched HC: widespread white matter abnormalities on NII metrics
    • Reduced NII-HR (cerebral edema), reduced NII-RF (cellular infiltration), increased NII-FF (axonal reorganisation)
    • Conventional DTI showed minimal differences — NII far more sensitive
    • NII metrics correlated with mental health, disability, disease severity

  • Conclusion: First in vivo evidence of white matter neuroinflammation in ME/CFS using advanced NII model

  • Limitations: Cross-sectional; single-center; NII model needs further validation

4 Shahbaz2026 — Single-Cell Immune Remodeling

  • Full Citation: Shahbaz S et al. (2026). Single-cell analysis reveals immune remodeling in Long COVID with ME/CFS. Front Immunol, 17:1745933.

  • DOI: 10.3389/fimmu.2026.1745933

  • PMID: 41822518

  • Status: NEW — not yet in bib/

  • Key Findings:

    • LC-ME/CFS: reduced naïve T cells, Tregs, MAIT, gamma-delta T cells; expanded effector T cells
    • NK cells reduced with altered activation; monocytes: reduced phagocytosis, increased pro-inflammatory genes
    • Galectin-9–TIM-3 identified as driver of gamma-delta and MAIT cell depletion
    • Idiopathic ME/CFS: less pronounced changes, no MAIT/NK reduction, no T cell exhaustion

  • Conclusion: Extensive peripheral immune remodeling in LC-ME/CFS, distinct from idiopathic ME/CFS

  • Limitations: Female-only; cross-dataset comparison introduces batch effects

5 Maya2026 — Complement Genetics

  • Full Citation: Maya J et al. (2026). Genetic Insights into Circulating Complement Proteins in ME/CFS: A Potential Inflammatory Subgroup. Int J Mol Sci, 27(3).

  • DOI: 10.3390/ijms27031574

  • PMID: 41683992

  • Status: NEW — not yet in bib/

  • Key Findings:

    • pQTL analysis: 50 ME/CFS vs 121 non-fatigued
    • Alternative complement pathway dysregulation in ME/CFS subset (high C3/low Bb)
    • 6 pQTLs associated with fatigue in UK Biobank (4 complement-related)

  • Conclusion: Genetic basis for complement dysregulation in ME/CFS inflammatory subgroup

  • Limitations: Small discovery cohort; general population controls; pQTL is indirect

6 Germain2025 — Plasma Proteome Post-Exertion

  • Full Citation: Germain A et al. (2025). Temporal Dynamics of the Plasma Proteomic Landscape Reveals Maladaptation in ME/CFS Following Exertion. Mol Cell Proteomics, 24(12):101467.

  • DOI: 10.1016/j.mcpro.2025.101467

  • PMID: 41237904

  • Status: NEW — not yet in bib/

  • Key Findings:

    • 132 individuals (79 ME/CFS, 53 sedentary controls); SomaScan 7K; pre/post maximal exercise
    • ME/CFS: persistent dysregulation during recovery (PEM onset) — immune, metabolic, neuromuscular
    • T/B cell signaling suppressed; IL-17 and cell-cell communication downregulated
    • Glycolysis/gluconeogenesis upregulated — mitochondrial stress
    • Sex-stratified: distinct molecular responses females vs males

  • Conclusion: Dynamic proteomics captures PEM maladaptation; sedentary controls distinguish disease from deconditioning

  • Limitations: Single-center; 24h recovery may miss later PEM dynamics

7 Hoel2026 — Circulating Proteome

  • Full Citation: Hoel A et al. (2026). Charting the circulating proteome in ME/CFS using cross-system profiling. Cell Rep Med, 7(3):102647.

  • DOI: 10.1016/j.xcrm.2026.102647

  • PMID: 41785863

  • Status: ALREADY CITED as Hoel2026proteome

  • Key Findings:

    • 50 ME/CFS vs 29 HC; 7326 protein targets; 1823 significant (845 FDR-corrected)
    • Broad increase in secreted proteins; intracellular/skeletal muscle proteins reduced
    • Immune reprogramming: reduced activated-neutrophil secreted proteins
    • Secretome: intensified immune, inflammation, vasculature, metabolism interactions

  • Conclusion: Serum proteome reveals immune reprogramming and multi-system dysregulation

  • Limitations: Single-center (Bergen); n=50/29; cross-sectional

8 Faro2024 — 7T fMRI Cognitive Fatigue

  • Full Citation: Inderyas M et al. (2026). Distinct functional connectivity patterns in ME/CFS and Long COVID during cognitive fatigue: 7T task-fMRI. J Transl Med, 24(1):236.

  • DOI: 10.1186/s12967-026-07708-y

  • PMID: 41559785

  • Status: ALREADY CITED as Faro2024connectivity

  • Key Findings:

    • 32 ME/CFS, 19 LC, 27 HC; Stroop paradigm at 7T
    • HC increased subcortical FC with engagement; patients showed reduced/dysregulated FC
    • Reduced dopaminergic hippocampal–nucleus accumbens connectivity
    • Core network FC to cerebellum, amygdala, caudate correlated with cognition scores

  • Conclusion: Brain network dyscoordination during cognitive fatigue as candidate biomarker

  • Limitations: Cross-sectional; single-center; 7T limits reproducibility

9 Lipidaccumulation2025 — Lipids in Cell Lines

  • Full Citation: Missailidis D et al. (2026). Multi-omics identifies lipid accumulation in ME/CFS cell lines. J Transl Med, 24(1):145.

  • DOI: 10.1186/s12967-025-07620-x

  • PMID: 41508032

  • Status: ALREADY CITED as Lipidaccumulation2025

  • Key Findings:

    • 15 ME/CFS vs 17 HC B-cell LCLs; multi-omics integration
    • PC(O-38:4) almost entirely discriminative of ME/CFS status
    • Triglycerides, DGs, fatty acids elevated; PTDSS1 elevated (proteomics + transcriptomics)
    • ME/CFS LCLs: more saturated lipid content

  • Conclusion: Lipid accumulation in immune cell lines points to immunometabolic dysfunction

  • Limitations: Cell line model; all female; small n; transformed cells

10 Heng2025 — Multi-omics Energy/Immune/Vascular

  • Full Citation: Heng B et al. (2025). Mapping the complexity of ME/CFS: abnormal energy metabolism, altered immune profile, vascular dysfunction. Cell Rep Med, 6(12):102514.

  • DOI: 10.1016/j.xcrm.2025.102514

  • PMID: 41406947

  • Status: ALREADY CITED as heng2025mecfs

  • Key Findings:

    • Multimodal: AMP/ADP elevated, ATP/ADP reduced in immune cells
    • Immune skewing: less mature T cell subsets, reduced terminal NK cells, reduced cDC2
    • Plasma proteins for thrombus formation and vascular reactivity elevated
    • CART modeling identified strong predictive variables

  • Conclusion: Concurrent energy stress, immune skewing, and endothelial dysfunction

  • Limitations: Exact sample size not in abstract; single-center; cross-sectional

11 Che2025 — Lipkin Multi-Omics

  • Full Citation: Che X et al. (2025). Heightened innate immunity may trigger chronic inflammation, fatigue and PEM in ME/CFS. npj Metab Health Dis, 3(1):34.

  • DOI: 10.1038/s44324-025-00079-w

  • PMID: 40903540

  • Status: ALREADY CITED as Che2025

  • Key Findings:

    • Multi-site; metabolomics + proteomics + immune stimulation; pre/post exercise
    • Exaggerated innate immune response to microbial antigens
    • Impaired TCA cycle, beta-oxidation, urea cycle; lipid abnormalities
    • ECM disruption, complement activation, redox imbalance, tryptophan pathway dysregulation
    • Many abnormalities worsened post-exercise

  • Conclusion: Broad multi-system dysfunction with innate immune hyperactivation as trigger

  • Limitations: Cross-sectional exercise challenge; multi-site variability; heterogeneous cohort

12 Sasso2026 — TRPM3 NK Cell

  • Full Citation: Sasso EM et al. (2025). Large-scale investigation confirms TRPM3 ion channel dysfunction in ME/CFS. Front Med, 12:1703924.

  • DOI: 10.3389/fmed.2025.1703924

  • PMID: 41585253

  • Status: ALREADY CITED as Sasso2026trpm3

  • Key Findings:

    • 36 ME/CFS vs 42 HC; multi-site (2 labs); whole-cell patch-clamp on NK cells
    • Significant TRPM3 function reduction across all parameters
    • No laboratory site effect — consistent biomarker

  • Conclusion: TRPM3 confirmed as consistent potential biomarker; multi-site replication

  • Limitations: Same research group; no independent external replication; NK cells only

13 Petrov2026 — Monocyte/DC Immunophenotyping: ME/CFS vs Long COVID

  • Full Citation: Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Dudova D, Todorova Y, Dimitrova R, Murdjeva M, Taskov H, Nikolova M, Maes M. Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID. Int J Mol Sci. 2026;27(10):4488.

  • DOI: 10.3390/ijms27104488

  • Status: NEW — added 2026-05-20

  • Study Design: Cross-sectional; multiparameter flow cytometry (12-parameter)

  • Sample Size: n=207 (103 ME/CFS, 63 long COVID, 41 HC) — largest comparative monocyte/DC study

  • Key Findings:

    • Long COVID: ↑ M2-like monocyte polarization (CD206-high), ↑ CD80 across monocyte subsets, ↑ DC frequency, ↓ HLA-DR on DCs → persistent immune activation + exhaustion
    • ME/CFS: ↓ CD80 on M1-like monocytes, ↓ CCR7 on monocytes and DCs, ↓ DC frequency → immune suppression with impaired trafficking
    • Inverse correlation: higher monocyte HLA-DR → lower depression/anxiety scores in ME/CFS (protective association)
    • PCA/PLS-DA: moderate discrimination between ME/CFS and long COVID using composite immune markers
    • VIP discriminators: CD80 on monocytes, CCR7 on DCs, M2-like polarization

  • Conclusion: ME/CFS and long COVID exhibit divergent immune architecture despite clinical overlap — immune suppression (ME/CFS) vs activation + exhaustion (long COVID). Supports distinct therapeutic approaches.

  • Limitations: Cross-sectional; no functional assays; vaccination status not analyzed; single-center; no replication cohort; excluded common ME/CFS medications (LDN, antihistamines, beta-blockers); healthy controls significantly younger than patient groups (age-adjusted ANCOVA applied).

  • Certainty: 0.70 — Largest comparative immunophenotyping study to date; well-validated methodology; FDR correction; post-hoc power ≥0.80; but cross-sectional and unreplicated.