Category: Immune System

Decreased Expression of the CD57 Molecule in T Lymphocytes of Patients with Chronic Fatigue Syndrome

Abstract:

The chronic fatigue syndrome (CFS) is characterized by a prolonged incapacitating fatigue, headaches, sleep disturbances, and decreases in cognition, besides alterations in other physiological functions. At present, no specific biological markers have been described in this pathology.

In the present study, we analyzed in lymphocytes the CD57 expression for the diagnosis of CFS, evaluating both the percentage of blood lymphocytes expressing CD57 and the average amount of the molecule expressed per cell. The study demonstrated a marked and significant decrease in the expression of CD57 in lymphocytes of CFS patients regarding healthy controls. In T lymphocytes, the decrease was significant both in the percentage of cells expressing CD57 (7.5 ± 1.2 vs 13.3 ± 1.6, p = 0.024) and in a more relevant way in the amount of CD57 molecule expressed per cell (331 ± 59 vs 1003 ± 104, p ≤ 0.0001). In non-T lymphocytes, the decrease was significant only in the amount of CD57 expressed per cell (379 ± 114 vs 691 ± 95, p = 0.007).

The study of CD57 antigen in blood lymphocytes is a useful marker that could cooperate in the diagnosis of CFS patients. Its decrease in T lymphocytes provides most valuable results than the results in other lymphocyte subpopulations.

Source: Espinosa P, Urra JM. Decreased Expression of the CD57 Molecule in T Lymphocytes of Patients with Chronic Fatigue Syndrome. Mol Neurobiol. 2019 Mar 21. doi: 10.1007/s12035-019-1549-7. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30895436 

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

Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood disease affecting 0.2%-2% of the global population. To gain insight into the pathophysiology of ME/CFS in New Zealand, we examined the transcriptomes of peripheral blood mononuclear cells by RNA-seq analysis in a small well-characterized patient group (10 patients), with age/gender-matched healthy controls (10 control subjects).

Twenty-seven gene transcripts were increased 1.5- to sixfold and six decreased three- to sixfold in the patient group ( P < 0.01). The top enhanced gene transcripts, IL8, NFΚBIA and TNFAIP3, are functionally related to inflammation, and significant changes were validated for IL8 and NFΚBIA by quantitative polymerase chain reaction (qPCR). Functional network analysis of the altered gene transcripts ( P < 0.01) detected interactions between the products related to inflammation, circadian clock function, metabolic dysregulation, cellular stress responses and mitochondrial function. Ingenuity pathway analysis ( P < 0.05) provided further insights into the dysfunctional physiology, highlighting stress and inflammation pathways.

This analysis provides novel insights into the molecular changes in ME/CFS and contributes to the understanding of the pathophysiological mechanisms of the disease.

Source: Sweetman E, Ryan M, Edgar C, MacKay A, Vallings R, Tate W. Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350121/ (Full article)

Stress, inflammation and natural treatments

Abstract:

Stress and inflammation have become the curses of our times and are the main pathogenetic factors in multiple diseases that are often comorbid and include allergies and asthma, eczema and psoriasis, fibromyalgia syndrome, mast cell activation syndrome, irritable bowel syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and autism spectrum disorder (ASD). Unfortunately, there are no effective drugs.

Cross-talk between mast cells and microglia in the hypothalamus and amygdala could explain stress-induced inflammation. We recently showed that the “alarmin” IL-33 could play a major role through its synergistic action with the neuropeptide substance P to stimulate human mast cell secretion of the pro-inflammatory molecules IL-1β, TNF and VEGF. A new formulation using pure luteolin with Ashwagandha has now been developed and could be of significant benefit to patients suffering from these diseases.

Source: Theoharides TC, Kavalioti M. Stress, inflammation and natural treatments. J Biol Regul Homeost Agents. 2018 Nov-Dec;32(6):1345-1347. https://www.ncbi.nlm.nih.gov/pubmed/30574737

Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome

Abstract:

The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present.

Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having ‘persistent fatigue’ (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered ‘resolved fatigue’.

Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p =  0.011 for IL-6 and p = 0.001 for IL-10).

There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

Source: Russell A, Hepgul N, Nikkheslat N, Borsini A, Zajkowska Z, Moll N, Forton D, Agarwal K, Chalder T, Mondelli V, Hotopf M, Cleare A, Murphy,  G, Foster G, Wong T, Schütze GA, Schwarz MJ, Harrison N, Zunszain PA, Pariante CM. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. 2018 Dec 14. pii: S0306-4530(18)30196-3.  doi: 10.1016/j.psyneuen.2018.11.032. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30567628

Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis

Abstract:

Background: Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue. Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME.

Methods: In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls.

Results: Correlations between the covariates ranged between [− 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10−7, 1 × 10−5, and 3 × 10−3, respectively.

Conclusions: Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease.

© The Author(s) 2018

Source: Kenny L. De Meirleir, Tatjana Mijatovic, Krishnamurthy Subramanian, Karen A. Schlauch and Vincent C. Lombardi. Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis. Journal of Translational Medicine201816:322
https://doi.org/10.1186/s12967-018-1696-z Received: 1 September 2018, Accepted: 14 November 2018, Published: 21 November 2018 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1696-z (Full article)

Antioxidant and immunomodulatory properties of Spilanthes oleracea with potential effect in chronic fatigue syndrome infirmity

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) holds a mystery for researchers due to its multifactorial nature; hence, its diagnosis is still based on symptoms and aetiology remains obscured. Number of scientific evidences regarding the role of oxidative stress, immune dysfunction in CFS and alleviation of symptoms with the help of nutritional supplements guided us to study effect of ethanolic extract of Spilanthes oleracea (SPE) in CFS.

OBJECTIVES: Present study was designed to evaluate antioxidant, immunomodulatory properties of S. oleracea flower to ameliorate CFS infirmity in mice.

MATERIALS AND METHOD: In order to induce fatigue, experimental animals were stressed by chronic water – immersion stress model. Meanwhile, parameters like immobility period and tail withdrawal latency were assessed. On the 21st day, mice blood was collected and they were immediately sacrificed for biochemical estimations.

RESULTS: Biochemical analysis results revealed that CFS elevates lipid peroxidation, nitrite level and diminishes the endogenous antioxidant enzyme like catalase level in stressed animal’s brain homogenate. Stressful condition developed muscle fatigue leading in alteration of lactate dehydrogenase level (LDH), Blood urea nitrogen (BUN) and Triglycerides (TG) levels. Concurrent and chronic treatment of SPE for 21 days restored all these behavioural despairs and associated biochemical adaptation in mice in dose-dependent manner.

CONCLUSION: The outcome of this study indicates ability of SPE in amelioration of CFS by mitigating the oxidative stress and thus provide a powerful combat against CFS which may be due to its antioxidant and immunomodulatory properties.

Source: Nipate SS, Tiwari AH. Antioxidant and immunomodulatory properties of Spilanthes oleracea with potential effect in chronic fatigue syndrome infirmity. J Ayurveda Integr Med. 2018 Nov 16. pii: S0975-9476(17)30116-X. doi: 10.1016/j.jaim.2017.08.008. [Epub ahead of print] https://www.sciencedirect.com/science/article/pii/S097594761730116X?via%3Dihub (Full article)

Tetramethoxyluteolin for the treatment of neurodegenerative diseases

Abstract:

Background: Most neurodegenerative and other brain disorders, especially Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and autism spectrum disorder (ASD) continue to elude objective biomarkers and effective treatments. Increasing evidence indicates that such diseases involve focal inflammation of the brain.

Objective: To review the role of cytokine-neuropeptide interactions in the pathogenesis of inflammation of the brain and the beneficial role of natural flavonoids.

Method: Medline search was conducted (2000-2017) for articles using the terms allergy, amygdala, atopy, autism, brain, chemokines, cytokines, hypothalamus, immunity, inflammation, mast cells, microglia, neurotensin, peptides, substance P, TNF.

Results: Neuropeptides and cytokine stimulation of mast cells and microglia can results in focal inflammation in the hypothalamus and amygdala, thus explaining most of the symptoms at least in ME/CFS and ASD. Some of the triggers may be corticotropin-releasing hormone (CRH), neurotensin (NT), and substance P (SP), which has synergistic action with IL-33. The natural flavonoids luteolin and tetramethoxyluteolin inhibit these processes and have neuroprotective actions. Tetramethoxyluteolin is also more metabolically stable and has greater oral absorption.

Conclusion: Inhibition of inflammatory processes unique to the brain with intranasal formulations of tetramethoxyluteolin could provide new possibilities for the understanding and treatment of neurodegenerative diseases.

Source: Theoharides TC, Tsilioni I. Tetramethoxyluteolin for the treatment of neurodegenerative diseases. Curr Top Med Chem. 2018 Nov 19. doi: 10.2174/1568026617666181119154247. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/30451113

CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation.

In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM).

In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p < 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naïve and memory B cell populations decreased. P < 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2 = 0.76; p < 0.01), which was subsequently lost over sequential cycles of proliferation.

There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naïve and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells.

In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood. CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets.

Source: Mensah FFK, Armstrong CW, Reddy V, Bansal AS, Berkovitz S, Leandro MJ, Cambridge G. CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Immunol. 2018 Oct 22;9:2421. doi: 10.3389/fimmu.2018.02421. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204382/ (Full article)