Tag: immune dysfunction

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

Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by profound fatigue, post-exertional malaise (PEM), and neurocognitive dysfunction. Immune dysregulation and gastrointestinal symptoms are commonly observed in ME/CFS patients. Despite affecting approximately 0.89% of the general population, the underlying pathophysiological mechanisms remain poorly understood. This study aimed to elucidate the relationship between immunological characteristics and intestinal barrier function in ME/CFS patients.

ME/CFS patients were stratified into two groups based on their immune competence. After documentation of detailed medical records, serum and plasma samples were collected for assessment of inflammatory immune mediators and biomarkers for intestinal barrier integrity by ELISA. We found reduced complement protein C4a levels in immunodeficient ME/CFS patients suggesting a sub-group specific innate immune dysregulation. ME/CFS patients without immunodeficiencies exhibit a mucosal barrier leakage, as indicated by elevated levels of Lipopolysaccharide-binding protein (LBP).

Stratifying ME/CFS patients based on immune competence enabled the distinction of two subgroups with different pathophysiological patterns. The study highlights the importance of emphasizing precise patient stratification in ME/CFS, particularly in the context of defining suitable treatment strategies. Given the substantial health and socioeconomic burden associated with ME/CFS, urgent attention and research efforts are needed to define causative treatment approaches.

Source: Rohrhofer, J.; Hauser, L.; Lettenmaier, L.; Lutz, L.; Koidl, L.; Gentile, S.A.; Ret, D.; Stingl, M.; Untersmayr, E. Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2023, 2023112007. https://doi.org/10.20944/preprints202311.2007.v1 https://www.preprints.org/manuscript/202311.2007/v1 (Full text available as PDF file)

Unraveling Post-COVID-19 Immune Dysregulation Using Machine Learning-based Immunophenotyping

Abstract:

The COVID-19 pandemic has left a significant mark on global healthcare, with many individuals experiencing lingering symptoms long after recovering from the acute phase of the disease, a condition often referred to as “long COVID.” This study delves into the intricate realm of immune dysregulation that ensues in 509 post-COVID-19 patients across multiple Iraqi regions during the years 2022 and 2023.

Utilizing advanced machine learning techniques for immunophenotyping, this research aims to shed light on the diverse immune dysregulation patterns present in long COVID patients. By analyzing a comprehensive dataset encompassing clinical, immunological, and demographic information, the study provides valuable insights into the complex interplay of immune responses following COVID-19 infection.

The findings reveal that long COVID is associated with a spectrum of immune dysregulation phenomena, including persistent inflammation, altered cytokine profiles, and abnormal immune cell subsets. These insights highlight the need for personalized interventions and tailored treatment strategies for individuals suffering from long COVID-19.

This research represents a significant step forward in our understanding of the post-COVID-19 immune landscape and opens new avenues for targeted therapies and clinical management of long COVID patients. As the world grapples with the long-term implications of the pandemic, these findings offer hope for improving the quality of life for those affected by this enigmatic condition.

Source: Maitham G. Yousif, Ghizal Fatima and Hector J. Castro et al. Unraveling Post-COVID-19 Immune Dysregulation Using Machine Learning-based Immunophenotyping. 2023. https://arxiv.org/ftp/arxiv/papers/2310/2310.01428.pdf (Full text)

L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!

Abstract:

COVID-19 pandemic is over now and we are in great peace of relief after three years. This pandemic has observed significant impact on quality of life globally and the put unforgettable imprints on history of mankind. Reason for more havoc in this pandemic was less studied virus by medical scientists regarding its pathophysiology, available treatment options and lack of effective vaccine to tackle this dragon. COVID-19 is the first observed and reported pandemic of corona virus related global disease apart from its previous SARS and MERS. Fast track developments in medical treatment options due to this ultrafast digital and artificial intelligence techniques have curtailed mortality on large scale globally.
Although mortality is significantly reduced, morbidity is documented on a large scale worldwide in this pandemic. Morbidity due to COVID-19 now called as ‘Long COVID’, which is underreported & half-heartedly evaluated globally. Long COVID is related to persistent immune dysregulation occurs during evolution of COVID-19 as natural trend of disease.
Immune dysregulation has documented during course of active viremia, during recovery of viral illness and after post viral phase. Immune dysregulation occurs in ‘selected group’ of cases irrespective of disease severity and vaccination status and observed in cases with negligible illness to advanced one mandates further research. Thus, Immune dysregulation in COVID-19 is predominant cause for long covid and leading to brainstorming effect on medical scientists and researchers as of today.
Globally, one third of recovered or affected cases of COVID-19 are facing long covid and needs prompt treatment options to tackle this dragon related long term effect on body. ‘Immunomodulatory’ or immunity modifying agents are the primary targets to curtail immune dysregulation and long covid. Some experts recommend ‘disease modifying agents’ to treat long covid cases. Still, many miles to go to reach to effective treatment options for long covid and we don’t have effective options for this ‘health issue of global concern’.
L-Arginine is amino acid with multiple beneficial effects such as immunomodulatory effects which will regulates immunological response in inhibit dysregulated immune system additional to its universally known antioxidant, vasodilatory and regenerative and cellular proliferation effects on immune cells. These Immunomodulatory and or diseases modifying effects of L-Arginine makes it the future candidate with ‘game changer’ role for management of Long covid resulting from immune dysregulation as a core pathophysiologic pathway of this Dragon Pandemic.
Source: Patil, Dr Shital, Patil, Swati, Gondhali, Gajanan. L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!  South Asian Journal of Life Sciences, 5(4):60-74. https://www.researchgate.net/publication/373217918_L-Arginine_in_Restoring_%27Immune_Dysregulation%27_in_Long_COVID_It%27s_the_Therapeutic_Role_Beyond_the_Routine_Dietary_Supplement (Full text)