Tag: immune dysfunction

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)

Immune exhaustion in ME/CFS and long COVID

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating multisystemic conditions sharing similarities in immune dysregulation and cellular signaling pathways contributing to the pathophysiology. In this study, immune exhaustion gene expression was investigated in participants with ME/CFS or long COVID concurrently.

RNA was extracted from peripheral blood mononuclear cells isolated from participants with ME/CFS (n = 14), participants with long COVID (n = 15), and healthy controls (n = 18). Participants with ME/CFS were included according to Canadian Consensus Criteria. Participants with long COVID were eligible according to the case definition for “Post COVID-19 Condition” published by the World Health Organization. RNA was analyzed using the NanoString nCounter Immune Exhaustion gene expression panel.

Differential gene expression analysis in ME/CFS revealed downregulated IFN signaling and immunoglobulin genes, and this suggested a state of immune suppression. Pathway analysis implicated dysregulated macrophage activation, cytokine production, and immunodeficiency signaling.

Long COVID samples exhibited dysregulated expression of genes regarding antigen presentation, cytokine signaling, and immune activation. Differentially expressed genes were associated with antigen presentation, B cell development, macrophage activation, and cytokine signaling.

This investigation elucidates the intricate role of both adaptive and innate immune dysregulation underlying ME/CFS and long COVID, emphasizing the potential importance of immune exhaustion in disease progression.

Source: Natalie Eaton-Fitch, Penny Rudd, Teagan Er, Livia Hool, Lara Herrero, and Sonya Marshall-Gradisnik. Immune exhaustion in ME/CFS and long COVID. JCI Insight. 2024;9(20):e183810. https://doi.org/10.1172/jci.insight.183810. https://insight.jci.org/articles/view/183810 (Full text)

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing

Abstract:

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls.

We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.

CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular.

Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms.

The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only.

These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Source: Sun Y, Zhang Z, Qiao Q, Zou Y, Wang L, Wang T, Lou B, Li G, Xu M, Wang Y, Zhang Z, Hou X, Chen L, Zhao R. Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing. J Transl Med. 2024 Oct 11;22(1):925. doi: 10.1186/s12967-024-05710-w. PMID: 39394558. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05710-w (Full text)

Over-Representation of Torque Teno Mini Virus 9 in a Subgroup of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disorder classified by the WHO as postviral fatigue syndrome (ICD-11 8E49 code). Diagnosing ME/CFS, often overlapping with fibromyalgia (FM), is challenging due to nonspecific symptoms and lack of biomarkers. The etiology of ME/CFS and FM is poorly understood, but evidence suggests viral infections play a critical role. This study employs microarray technology to quantitate viral RNA levels in immune cells from ME/CFS, FM, or co-diagnosed cases, and healthy controls.

The results show significant overexpression of the Torque Teno Mini Virus 9 (TTMV9) in a subgroup of ME/CFS patients which correlate with abnormal HERV and immunological profiles. Increased levels of TTMV9 transcripts accurately discriminate this subgroup of ME/CFS patients from the other study groups, showcasing its potential as biomarker for patient stratification and the need for further research into its role in the disease. Validation of the findings seems granted in extended cohorts by continuation studies.

Source: Giménez-Orenga K, Martín-Martínez E, Oltra E. Over-Representation of Torque Teno Mini Virus 9 in a Subgroup of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study. Pathogens. 2024 Sep 1;13(9):751. doi: 10.3390/pathogens13090751. PMID: 39338942; PMCID: PMC11435283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11435283/ (Full text)

Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex illness characterized by severe and often disabling physical and mental fatigue. So far, scientists have not been able to fully pinpoint the biological cause of the illness and yet it affects millions of people worldwide.

To gain a better understanding of ME/CFS, we compared the metabolic networks in the plasma of 38 ME/CFS patients to those of 24 healthy control participants. This involved an untargeted metabolomics approach in addition to the measurement of targeted substances including tryptophan and its metabolites, as well as tyrosine, phenylalanine, B vitamins, and hypoxanthine using liquid chromatography coupled to mass spectrometry.

mass

Source: Abujrais S, Vallianatou T, Bergquist J. Untargeted Metabolomics and Quantitative Analysis of Tryptophan Metabolites in Myalgic Encephalomyelitis Patients and Healthy Volunteers: A Comparative Study Using High-Resolution Mass Spectrometry. ACS Chem Neurosci. 2024 Sep 20. doi: 10.1021/acschemneuro.4c00444. Epub ahead of print. PMID: 39302151. https://pubs.acs.org/doi/10.1021/acschemneuro.4c00444 (Full text)

Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition that is characterized by unresolved fatigue, post-exertion symptom exacerbation (PESE), cognitive dysfunction, orthostatic intolerance, and other symptoms. ME/CFS lacks established clinical biomarkers and requires further elucidation of disease mechanisms.

A growing number of studies demonstrate signs of hematological and cardiovascular pathology in ME/CFS cohorts, including hyperactivated platelets, endothelial dysfunction, vascular dysregulation, and anomalous clotting processes. To build on these findings, and to identify potential biomarkers that can be related to pathophysiology, we measured differences in protein expression in platelet-poor plasma (PPP) samples from 15 ME/CFS study participants and 10 controls not previously infected with SARS-CoV-2, using DIA LC-MS/MS.

We identified 24 proteins that are significantly increased in the ME/CFS group compared to the controls, and 21 proteins that are significantly downregulated. Proteins related to clotting processes – thrombospondin-1 (important in platelet activation), platelet factor 4, and protein S – were differentially expressed in the ME/CFS group, suggestive of a dysregulated coagulation system and abnormal endothelial function. Complement machinery was also significantly downregulated, including C9 which forms part of the membrane attack complex. Additionally, we identified a significant upregulation of lactotransferrin, protein S100-A9, and an immunoglobulin variant.

The findings from this experiment further implicate the coagulation and immune system in ME/CFS, and bring to attention the pathology of or imposed on the endothelium. This study highlights potential systems and proteins that require further research with regards to their contribution to the pathogenesis of ME/CFS, symptom manifestation, and biomarker potential, and also gives insight into the hematological and cardiovascular risk for ME/CFS individuals affected by diabetes mellitus.

Source: Nunes, M., Vlok, M., Proal, A. et al. Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery. Cardiovasc Diabetol 23, 254 (2024). https://doi.org/10.1186/s12933-024-02315-x https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02315-x (Full text)

Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract;
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic and incapacitating multisystem condition with unknown etiology, no cure, and no FDA- approved treatments, all of which can be attributed to historical underfunding, widespread misinformation, and the complexity of the disease. Many patients encounter several immune-related symptoms, extreme fatigue, post-exertional malaise, and a flu-like onset. Studies have documented changes in ME/CFS immune cell populations and decreased natural killer (NK) cell performance, along with aberrant cytokine production, reduced glycolysis in T cells, and altered metabolites relevant to fatty acid oxidation, implicating potential intracellular metabolic dysregulation.
This knowledge prompted me to investigate fatty acid oxidation and immune cell functional states in isolated ME/CFS lymphocytes. Using extracellular flux analysis and flow cytometry, I observed elevated fatty acid oxidation levels in ME/CFS immune cells, including NK cells, CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells compared to healthy controls, particularly during high energy demands and activation. My findings suggest a metabolic dysfunction in ME/CFS immune cells, consistent with T cell exhaustion – a state that hinders immune cell proliferation, survival, and cytokine production following persistent antigen stimulation.
Building upon these results, I further investigated immune cell exhaustion and dysfunction in isolated CD8+ and CD4+ T cells from ME/CFS and healthy samples. I analyzed T cell sub-populations, including naïve, effector, memory, regulatory, and helper T cells, for frequencies of inhibitory receptors and transcription factors associated with dysfunctional immune cell states.
I detected distinct transcription factor dynamics and elevated exhausted T cell phenotype proportions in ME/CFS CD8+ T cell populations compared to healthy controls. In ME/CFS CD4+ T cells, I also observed altered inhibitory receptor population frequencies compared to healthy control samples. Moreover, dysfunctional T cell features correlated with ME/CFS health status and symptom presentation.
Overall, my findings detect dysfunctional T cell states in specific ME/CFS cell populations, which can lead to reduced effector function that may contribute to ME/CFS symptom presentation. This work highlights the significance of assessing both metabolic components and immune cell dysfunction-associated targets in the development of potential therapeutic interventions for individuals with ME/CFS.
Source: Maya, Jessica. Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome. Cornell Theses and Dissertations. 2024. https://ecommons.cornell.edu/items/242f8723-6f87-47cc-b36d-bf51a21f4255