Tag: immune dysfunction

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown.

Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

Source: Ariza ME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules. 2021 Jan 29;11(2):185. doi: 10.3390/biom11020185. PMID: 33572802; PMCID: PMC7912523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912523/ (Full text)

What Causes ME/CFS: The Role of the Dysfunctional Immune System and Viral Infections

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigmatic highly disabling and complex long-term condition with a wide range of aetiologies and symptoms.

A viral onset is commonly mentioned by patients and several bodily systems are ultimately disturbed. The parallel with long-covid is clear.

However, immune dysregulation with impaired NK cell dysfunction and tendency to novel autoimmunity have been frequently reported. These may contribute to reactivation of previous acquired viruses/retroviruses accompanied by impaired endocrine regulation and mitochondrial energy generation.

The unpredictable nature of seemingly unconnected and diverse symptoms that are poorly responsive to several allopathic and alternative therapies then contributes to an escalation of the illness with secondary dysfunction of multiple other systems. Treatment of established ME/CFS is therefore difficult and requires multi-specialty input addressing each of the areas affected by the illness.

Source: Amolak S Bansal, Aletta D Kraneveld, Elisa Oltra and Simon Carding. What Causes ME/CFS: The Role of the Dysfunctional Immune System and Viral Infections. Journal of Immunology and Allergy 2022;3(2):1-15. https://maplespub.co.in/assets/images/files/doc_1663924267.pdf (Full text)

Evaluation of Immune Dysregulation in an Austrian Patient Cohort Suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multi-systemic disease characterized by debilitating fatigue that is not relieved by rest. The causes of the disease are still largely unexplained, and no causative treatment is currently available. Changes in the immune response are considered as fundamental in the development of ME/CFS. Thus, we aimed to evaluate the immunological profile of ME/CFS patients in a retrospective data analysis.

As part of the routine workup for ME/CFS patients, a differential blood count, leukocyte subtyping, and quantification of immunoglobulins and IgG subclasses, as well as a complement analysis, was performed. Out of 262 ME/CFS patients, 64.9% had a reduction or deficiency in at least one of the listed immune parameters. In contrast, 26.3% showed signs of immune activation or inflammation. A total of 17.6% of the ME/CFS patients had an unclassified antibody deficiency, with IgG3 and IgG4 subclass deficiencies as the most common phenotypes. Reduced MBL (mannose-binding lectin) levels were found in 32% of ME/CFS patients, and MBL deficiency in 7%.

In summary, the present results confirmed the relevance of immune dysfunction in ME/CFS patients underlining the involvement of a dysfunctional immune response in the disease. Thus, immune parameters are relevant disease biomarkers, which might lead to targeted therapeutic approaches in the future.

Source: Lutz L, Rohrhofer J, Zehetmayer S, Stingl M, Untersmayr E. Evaluation of Immune Dysregulation in an Austrian Patient Cohort Suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomolecules. 2021 Sep 14;11(9):1359. doi: 10.3390/biom11091359. PMID: 34572574. https://pubmed.ncbi.nlm.nih.gov/34572574/

Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of unknown etiology lasting for a minimum of 6 months but usually for many years, with features including fatigue, cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Dysregulation of cytokine signaling could give rise to many of these symptoms. Cytokines are present in both plasma and extracellular vesicles, but little investigation of EVs in ME/CFS has been reported. Therefore, we aimed to characterize the content of extracellular vesicles (EVs) isolated from plasma (including circulating cytokine/chemokine profiling) from individuals with ME/CFS and healthy controls.

Methods: We included 35 ME/CFS patients and 35 controls matched for age, sex and BMI. EVs were enriched from plasma by using a polymer-based precipitation method and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and immunoblotting. A 45-plex immunoassay was used to determine cytokine levels in both plasma and isolated EVs from a subset of 19 patients and controls. Linear regression, principal component analysis and inter-cytokine correlations were analyzed.

Results: ME/CFS individuals had significantly higher levels of EVs that ranged from 30 to 130 nm in size as compared to controls, but the mean size for total extracellular vesicles did not differ between groups. The enrichment of typical EV markers CD63, CD81, TSG101 and HSP70 was confirmed by Western blot analysis and the morphology assessed by TEM showed a homogeneous population of vesicles in both groups. Comparison of cytokine concentrations in plasma and isolated EVs of cases and controls yielded no significant differences. Cytokine-cytokine correlations in plasma revealed a significant higher number of interactions in ME/CFS cases along with 13 inverse correlations that were mainly driven by the Interferon gamma-induced protein 10 (IP-10), whereas in the plasma of controls, no inverse relationships were found across any of the cytokines. Network analysis in EVs from controls showed 2.5 times more significant inter-cytokine interactions than in the ME/CFS group, and both groups presented a unique negative association.

Conclusions: Elevated levels of 30-130 nm EVs were found in plasma from ME/CFS patients and inter-cytokine correlations revealed unusual regulatory relationships among cytokines in the ME/CFS group that were different from the control group in both plasma and EVs. These disturbances in cytokine networks are further evidence of immune dysregulation in ME/CFS.

Source: Giloteaux L, O’Neal A, Castro-Marrero J, Levine SM, Hanson MR. Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study. J Transl Med. 2020 Oct 12;18(1):387. doi: 10.1186/s12967-020-02560-0. PMID: 33046133. https://pubmed.ncbi.nlm.nih.gov/33046133/

Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems.

Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30.

Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3-11 were significantly associated with ME/CFS without sr-IBS.

In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774-0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806-0.846) and ME/CFS without sr-IBS (AUC = 0.754-0.780).

Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.

Source: Milivojevic M, Che X, Bateman L, et al. Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS. PLoS One. 2020;15(7):e0236148. Published 2020 Jul 21. doi:10.1371/journal.pone.0236148 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236148 (Full text)

Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules

Abstract:

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.

METHODS: Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.

FINDINGS: The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.

IMPLICATIONS: The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies. (Clin Ther. 2019;41:XXX-XXX) © 2019 Elsevier Inc.

Copyright © 2019. Published by Elsevier Inc.

Source: Jeffrey MG, Nathanson L, Aenlle K, Barnes ZM, Baig M, Broderick G, Klimas NG, Fletcher MA, Craddock TJA. Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules. Clin Ther. 2019 Mar 6. pii: S0149-2918(19)30047-5. doi: 10.1016/j.clinthera.2019.01.011. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30851951

Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI). Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor-associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI.

METHODS: We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA.

RESULTS: Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance. Both enhanced IgE and diminished IgG3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI.

CONCLUSION: Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.

 

Source: Löbel M, Mooslechner AA, Bauer S, Günther S, Letsch A, Hanitsch LG, Grabowski P, Meisel C, Volk HD, Scheibenbogen C. Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome. J Transl Med. 2015 Aug 14;13:264. doi: 10.1186/s12967-015-0628-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536662/ (Full article)

 

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

BACKGROUND: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients.

METHODS: We included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8(+) T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4(+) T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56(bright) and CD56(dim)) and regulatory T cells expressing FoxP3 transcription factor.

RESULTS: Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10, IFN-γ, TNF-α, CD4(+)CD25(+) T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8(+) T cells and NK phenotypes, in particular the CD56(bright) NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients.

CONCLUSIONS: Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.

 

Source: Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J, Klimas NG, Marshall-Gradisnik SM. Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med. 2011 May 28;9:81. doi: 10.1186/1479-5876-9-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120691/ (Full article)

 

Chronic fatigue syndrome: exercise performance related to immune dysfunction

Abstract:

PURPOSE: To date, the exact cause of abnormal exercise response in chronic fatigue syndrome (CFS) remains to be revealed, but evidence addressing intracellular immune deregulation in CFS is growing. Therefore, the aim of this cross-sectional study was to examine the interactions between several intracellular immune variables and exercise performance in CFS patients.

METHODS: After venous blood sampling, subjects (16 CFS patients) performed a maximal exercise stress test on a bicycle ergometer with continuous monitoring of cardiorespiratory variables. The following immune variables were assessed: the ratio of 37 kDa Ribonuclease (RNase) L to the 83 kDa native RNase L (using a radiolabeled ligand/receptor assay), RNase L enzymatic activity (enzymatic assay), protein kinase R activity assay (comparison Western blot), elastase activity (enzymatic-colorimetric assay), the percent of monocytes, and nitric oxide determination (for monocytes and lymphocytes; flow cytometry, live cell assay).

RESULTS: Forward stepwise multiple regression analysis revealed 1) that elastase activity was the only factor related to the reduction in oxygen uptake at a respiratory exchange ratio (RER) of 1.0 (regression model: R = 0.53, F (1,14) = 15.5, P < 0.002; elastase activity P < 0.002); 2) that the protein kinase R activity was the principle factor related to the reduction in workload at RER = 1.0; and 3) that elastase activity was the principle factor related to the reduction in percent of target heart rate achieved.

CONCLUSION: These data provide evidence for an association between intracellular immune deregulation and exercise performance in patients with CFS. To establish a causal relationship, further study of these interactions using a prospective longitudinal design is required.

 

Source: Nijs J, Meeus M, McGregor NR, Meeusen R, de Schutter G, van Hoof E, de Meirleir K. Chronic fatigue syndrome: exercise performance related to immune dysfunction. Med Sci Sports Exerc. 2005 Oct;37(10):1647-54. http://www.ncbi.nlm.nih.gov/pubmed/16260962