Tag: immune dysfunction

Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with undefined mechanisms, no diagnostic tools and treatments. To investigate concurrent system dysfunctions, we recruited age- and sex-matched ME/CFS patients and healthy controls for a multimodal analysis of energy metabolism, immune profiles, and plasma proteomics.

Immune cells from ME/CFS patients show elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) with a reduced ATP/ADP ratio, indicating decreased ATP generation and cellular energy stress. Immune profiling reveals skewing toward less mature effector subsets of CD4+, CD8+, and γδ T cells, with reduced CD1c+CD141– conventional DC type 2 and CD56lowCD16+ terminal natural killer cells.

Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Classification and regression tree modeling identifies variables with strong predictive potential for ME/CFS. Together, this study provides insights into the somatic symptoms and underlying biology of ME/CFS.

Source: Heng B, Gunasegaran B, Krishnamurthy S, Bustamante S, Pires AS, Chow S, Ahn SB, Paul-Heng M, Maciver Y, Smith K, Tran DP, Howley PP, Bilgin AA, Sharland A, Schloeffel R, Guillemin GJ. Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction. Cell Rep Med. 2025 Dec 16;6(12):102514. doi: 10.1016/j.xcrm.2025.102514. PMID: 41406947. https://www.sciencedirect.com/science/article/pii/S2666379125005877 (Full text)

Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion

Abstract:

The overarching symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM), an exacerbation of symptoms following physical or mental exertion. To investigate the molecular underpinnings of PEM, we performed longitudinal plasma proteomics using the Somascan® 7K aptamer-based assay to monitor 6,361 unique plasma proteins in 132 individuals (96 females and 36 males) subjected to two maximal cardiopulmonary exercise tests separated by a 24-hour recovery period.

The cohort included 79 ME/CFS cases compared to 53 age- and BMI-matched sedentary controls, allowing us to distinguish disease-specific molecular alterations from those due to physical deconditioning. Longitudinal profiling revealed widespread proteomic changes following exertion, with the most pronounced alterations observed in ME/CFS participants during the recovery phase, coinciding with the onset of PEM.

Compared to controls, ME/CFS subjects showed persistent dysregulation of immune, metabolic, and neuromuscular pathways. Key findings included suppression of T and B cell signaling, downregulation of IL-17 and cell-cell communication pathways, and upregulation of glycolysis/gluconeogenesis, suggestive of mitochondrial stress and impaired immune recovery from exercise. Proteomic associations with physiological performance (VO2max, anaerobic threshold) revealed disruptions between protein abundance and exercise capacity in ME/CFS versus controls.

Correlations with symptom severity linked changes in immune-related proteins and ME/CFS symptoms including muscle pain, recurrent sore throat, and lymph node tenderness. Sex-stratified analyses revealed distinct molecular responses between females and males, emphasizing the importance of considering sex as a biological variable in ME/CFS research.

Finally, our analysis of sedentary controls contributes new data of molecular responses to acute exertion in a predominantly female sedentary cohort, a population historically underrepresented in exercise physiology studies. Together, these findings underscore the value of dynamic, proteomic profiling over time for characterizing maladaptive responses to exertion in ME/CFS and provide a foundation for deeper mechanistic investigation into PEM.

Source: Germain A, Glass KA, Eckert MA, Giloteaux L, Hanson MR. Temporal dynamics of the plasma proteomic landscape reveals maladaptation in ME/CFS following exertion. Mol Cell Proteomics. 2025 Nov 12:101467. doi: 10.1016/j.mcpro.2025.101467. Epub ahead of print. PMID: 41237904. https://www.mcponline.org/article/S1535-9476(25)00566-3/fulltext (Full text)

The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers

Abstract:

Chronic fatigue syndrome (CFS) is a complex disease involving multiple systems throughout the body with unknown pathogenesis and is characterized by chronic fatigue. To date, no effective treatment for CFS has been found, as well as biomarkers for early identification of diagnosis. However, exosomes, a subpopulation of extracellular vesicles (EVs), are membranous vesicles secreted by cells into the surrounding environment, and long noncoding RNAs (LncRNAs) in EVs can mediate inter-organ and inter-cellular communication, which maybe associate with CFS.

Therefore, this study aims to review the association between EV-LncRNAs and CFS, and to explore whether LncRNAs can be used as potential biomarkers for early identification and diagnosis of CFS, which put forward new ideas and a theoretical basis for the pathogenesis of CFS, as well as the identification of novel targeted therapies.

Source: Wang Lei , Xu Yujia , Zhong Xiang , Wang Guiping , Shi Zijun , Mei Can , Chen Linwanyue , Zhan Jianbo , Cheng Jing. The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers. Frontiers in Molecular Biosciences. Volume 12 – 2025 https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1653627/full (Full text)

Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

People living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience heterogeneous and debilitating symptoms that lack sufficient biological explanation, compounded by the absence of accurate, noninvasive diagnostic tools. To address these challenges, we explored circulating cell-free RNA (cfRNA) as a blood-borne bioanalyte to monitor ME/CFS. cfRNA is released into the bloodstream during cellular turnover and reflects dynamic changes in gene expression, cellular signaling, and tissue-specific processes.

We profiled cfRNA in plasma by RNA sequencing for 93 ME/CFS cases and 75 healthy sedentary controls, then applied machine learning to develop diagnostic models and advance our understanding of ME/CFS pathobiology. A generalized linear model with least absolute shrinkage selector operator regression trained on condition-specific signatures achieved a test-set AUC of 0.81 and an accuracy of 77%.

Immune cfRNA deconvolution revealed differences in platelet-derived cfRNA between cases and controls, as well as elevated levels of plasmacytoid dendritic, monocyte, and T cell-derived cfRNA in ME/CFS. Biological network analysis further implicated immune dysfunction in ME/CFS, with signatures of cytokine signaling and T cell exhaustion. These findings demonstrate the utility of RNA liquid biopsy as a minimally invasive tool for unraveling the complex biology behind chronic illnesses.

Source: Gardella AE, Eweis-LaBolle D, Loy CJ, Belcher ED, Lenz JS, Franconi CJ, Scofield SY, Grimson A, Hanson MR, De Vlaminck I. Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2025 Aug 19;122(33):e2507345122. doi: 10.1073/pnas.2507345122. Epub 2025 Aug 11. PMID: 40789036. https://pubmed.ncbi.nlm.nih.gov/40789036/

A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID

Abstract:
The underlying pathologies driving post-acute infectious syndromes (e.g. myalgic encephalomyelitis / chronic fatigue syndrome, long COVID, etc) remain poorly understood. Given the extreme burden these illnesses impose on suffers, and the dramatic increase in cases following the COVID-19 pandemic, it is important to establish a deeper understanding of these pathologies.
We propose a model of how ME/CFS (and related illnesses), might emerge following a viral insult. Central to this hypothesis is the recognition that the core diagnostic features of ME/CFS involve bodily systems known to be governed by the brainstem. This is consistent with the growing literature suggesting that spinal and craniocervical pathologies are over-represented in people with ME/CFS and other post-infectious disorders.
We hypothesize that a non-trivial number of cases of ME/CFS and Long Covid (LC) may have a “mechanical basis.” We propose that an infectious insult may trigger an initial loss of connective tissue integrity in susceptible individuals (e.g. those with pre-existing hypermobility spectrum disorders), which in turn leads to instability at the craniocervical junction, and ultimately mechanical deformation of the brainstem. This ultimately causes widespread autonomic nervous system and immune system dysfunction due to aberrant signaling from the deformed nuclei.
This causal chain may also lead to a vicious cycle: if the dysregulation produced by the initial brainstem deformation leads to a deranged immune response or state of chronic hyper-inflammation, further expression of connective tissue degrading and remodeling factors such as MMPs and mast cells may be triggered. This could further degrade the connective tissues of the craniocervical junction and, in turn, increase mechanical deformation of the brainstem, leading to symptom exacerbation over time and leading to the chronic, lifelong presentation typical of ME/CFS.
Source: Wood, J., Varley, T., Hartman, J., Melia, N., Kaufman, D., & Falor, T. (2025). A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID. Preprints. https://doi.org/10.20944/preprints202506.0874.v1 https://www.preprints.org/manuscript/202506.0874/v1 (Full text)

Evaluating the Causal Role of Genetically Inferred Immune Cells and Inflammatory Cytokines on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background/Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted and diverse disorder with an ambiguous etiology. Recent evidence indicates that immune system impairment and inflammatory mechanisms are pivotal to the initiation and advancement of ME/CFS. Nonetheless, the causal relationships among these factors remain inadequately comprehended.

Methods: This study investigated the causative contributions of immunological dysfunction and inflammatory variables in ME/CFS utilizing genome-wide association study (GWAS) data. We employed Mendelian randomization (MR) to investigate associations between 91 inflammatory cytokines, 731 immune cell characteristics, and the risk of ME/CFS. Summary statistics for immune cell traits and inflammatory cytokines were sourced from European GWAS cohorts (n = 3757 and n = 14,824, respectively), while ME/CFS data were obtained from the UK Biobank (n = 462,933, including 2076 cases). We predominantly employed the inverse variance weighted (IVW) approach, complemented by MR-Egger, weighted median, BWMR, and MR-RAPS tests to guarantee robust and precise outcomes.

Results: The study revealed significant causal links between various inflammatory factors, immune cell characteristics, and the risk of ME/CFS. Increased CXCL5 and CCL20 levels were significantly linked to a higher risk of ME/CFS, while elevated TNF levels were inversely related to ME/CFS risk. Furthermore, 13 immune cell characteristics were identified as having substantial causal associations with the likelihood of ME/CFS. These data are supportive of the causality that immune system dysfunction and inflammatory variables play a pivotal role in the development of ME/CFS.

Conclusions: This study provides new insights into the causal role of immune system dysfunction in the development of ME/CFS, contributing to a deeper understanding of its underlying mechanisms. These results offer a foundation for identifying diagnostic biomarkers and developing targeted therapeutic strategies. Future research should validate these findings using multi-center cohort studies and further investigate the mechanisms behind key factors to enable the development of personalized treatment approaches.

Source: Duan L, Yang J, Zhao J, Chen Z, Yang H, Cai D. Evaluating the Causal Role of Genetically Inferred Immune Cells and Inflammatory Cytokines on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomedicines. 2025 May 15;13(5):1200. doi: 10.3390/biomedicines13051200. PMID: 40427027; PMCID: PMC12109099. https://pmc.ncbi.nlm.nih.gov/articles/PMC12109099/ (Full text)

Prevalence of EBV, HHV6, HCMV, HAdV, SARS-CoV-2, and Autoantibodies to Type I Interferon in Sputum from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

An exhausted antiviral immune response is observed in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-SARS-CoV-2 syndrome, also termed long COVID. In this study, potential mechanisms behind this exhaustion were investigated.

First, the viral load of Epstein-Barr virus (EBV), human adenovirus (HAdV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV6), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was determined in sputum samples (n = 29) derived from ME/CFS patients (n = 13), healthy controls (n = 10), elderly healthy controls (n = 4), and immunosuppressed controls (n = 2). Secondly, autoantibodies (autoAbs) to type I interferon (IFN-I) in sputum were analyzed to possibly explain impaired viral immunity.

We found that ME/CFS patients released EBV at a significantly higher level compared to controls (p = 0.0256). HHV6 was present in ~50% of all participants at the same level. HAdV was detected in two cases with immunosuppression and severe ME/CFS, respectively. HCMV and SARS-CoV-2 were found only in immunosuppressed controls. Notably, anti-IFN-I autoAbs in ME/CFS and controls did not differ, except in a severe ME/CFS case showing an increased level.

We conclude that ME/CFS patients, compared to controls, have a significantly higher load of EBV. IFN-I autoAbs cannot explain IFN-I dysfunction, with the possible exception of severe cases, also reported in severe SARS-CoV-2. We forward that additional mechanisms, such as the viral evasion of IFN-I effect via the degradation of IFN-receptors, may be present in ME/CFS, which demands further studies.

Source: Hannestad U, Allard A, Nilsson K, Rosén A. Prevalence of EBV, HHV6, HCMV, HAdV, SARS-CoV-2, and Autoantibodies to Type I Interferon in Sputum from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Viruses. 2025 Mar 14;17(3):422. doi: 10.3390/v17030422. PMID: 40143349; PMCID: PMC11946815. https://pmc.ncbi.nlm.nih.gov/articles/PMC11946815/ (Full text)

An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by serious physical and cognitive impairments. Recent research underscores the role of immune dysfunction, including the role of autoantibodies, in ME/CFS pathophysiology.

Expanding on previous studies, we analyzed 7542 antibody-antigen interactions in ME/CFS patients using two advanced platforms: a 1134 autoantibody Luminex panel from Oncimmune and Augmenta Bioworks, along with Rapid Extracellular Antigen Profiling (REAP), a validated high-throughput method that measures autoantibody reactivity against 6183 extracellular human proteins and 225 human viral pathogen proteins.

Unlike earlier reports, our analysis of 172 participants revealed no significant differences in autoantibody reactivities between ME/CFS patients and controls, including against GPCRs such as β-adrenergic receptors. However, subtle trends in autoantibody ratios between male and female ME/CFS subgroups, along with patterns of herpesvirus reactivation, suggest the need for broader and more detailed exploration.

Source: Germain A, Jaycox JR, Emig CJ, Ring AM, Hanson MR. An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques. Int J Mol Sci. 2025 Mar 20;26(6):2799. doi: 10.3390/ijms26062799. PMID: 40141440; PMCID: PMC11943395. https://pmc.ncbi.nlm.nih.gov/articles/PMC11943395/ (Full text)

Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Post-COVID syndrome (PCS) has emerged as a significant health concern with persisting symptoms. A subset of PCS patients develops severe myalgic encephalomyelitis/chronic fatigue syndrome (pcME/CFS). Dysregulated autoantibodies (AABs) have been implicated in PCS, contributing to immune dysregulation, impairment of autonomous nerve and vascular function. As recently shown in autoimmune diseases, IgG fractions translate disease-specific pathways into various cells. Therefore, we asked whether IgG fractions from PCS patients could be applied in vitro to identify specific cytokine rersponses for PCS patients without (nPCS) and with pcME/CSF.

To assess this, we have stimulated monocyte cell lines with IgG fractions from PCS patients. Our findings reveal distinct patterns of immune regulation by AABs in vascular and immune dysfunction. In contrast to nPCS, pcME/CSF AABs induced enhanced neurotrophic responses, characterized by significant cytokine correlations involving brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and LIGHT. AAB-induced cytokine levels correlate with clinical symptoms. Further, this study emphasizes a contribution of AAB in PCS, in mitigating long-term immune dysregulation, and a need for therapies modulating IgG-induced pathways.

Source: Alexander Hackel, Franziska Sotzny, Elise Mennenga, Harald Heidecke, Kai Schulze-Foster,  Kontantinos Fourlakis,  Susanne Lueders, Hanna Grasshoff, Kerstin Rubarth, Frank Konietschke, Tanja Lange, Carmen Scheibenbogen, Reza Akbarzade, Gabriela Riemekasten. Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv 2025.01.09.25320264; doi: https://doi.org/10.1101/2025.01.09.25320264 https://www.medrxiv.org/content/10.1101/2025.01.09.25320264v1.full.pdf+html (Full text available as PDF file)

Meta-analysis of natural killer cell cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Reduced natural killer (NK) cell cytotoxicity is the most consistent immune finding in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Meta-analysis of the published literature determined the effect size of the decrement in ME/CFS. Databases were screened for papers comparing NK cell cytotoxicity in ME/CFS and healthy controls. A total of 28 papers and 55 effector:target cell ratio (E:T) data points were collected.

Cytotoxicity in ME/CFS was significantly reduced to about half of healthy control levels, with an overall Hedges’ g of 0.96 (0.75-1.18). Heterogeneity was high but was explained by the range of E:T ratios, different methods, and potential outliers. The outcomes confirm reproducible NK cell dysfunction in ME/CFS and will guide studies using the NK cell model system for pathomechanistic investigations.

Source: Baraniuk JN, Eaton-Fitch N, Marshall-Gradisnik S. Meta-analysis of natural killer cell cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome. Front Immunol. 2024 Oct 17;15:1440643. doi: 10.3389/fimmu.2024.1440643. PMID: 39483457; PMCID: PMC11524851. https://pmc.ncbi.nlm.nih.gov/articles/PMC11524851/ (Full text)