Immune System – Page 13 – American ME and CFS Society

MicroRNAs as biomarkers of pain intensity in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Numerous experimental models have shown that microRNAs play an important role in regulating pain-processing in clinical pain disorders. In this study, we evaluated a set of micro-RNAs as diagnostic biomarkers of pain intensity in adolescents with chronic fatigue syndrome (CFS). We then correlated the expression of these microRNAs with the levels of inflammatory markers and pain-related comorbidities in adolescents with CSF and healthy controls (HCs).

METHODS: A total of 150 adolescents, aged 12-18 years, participated in this study between April 2016 and April 2017. The participants were classified into two groups: adolescents with CFS (n=100) and HCs (n=50). RT-PCR was used to evaluate the expression of miR-558, miR-146a, miR-150, miR-124, and miR-143. Immunoassay analysis was used to assess the levels of immune inflammatory markers IL-6, TNF-α, and COX-2.

RESULTS: Adolescents with CFS showed significantly higher pain thresholds than comparable non-fatigued HCs. Also, enjoy of life and relation to others as the life domains, showed lower pain interference in CFS patients. Differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143 was significantly down regulated and notably interfered with pain intensity and frequency in patients with CFS. Also, the expression of these miRNAs was significantly correlated with that of IL-6, TNF-α, and COX-2, which have been shown to mediate pain intensity in patients with CFS.

Girls with CSF showed significantly decreased expression levels of these miRNAs compared with the levels of boys with CSF. Girls with CSF also showed increased expression of inflammatory pain-related markers IL-6, TNF-α, and COX-2, compared with the levels of boys with CSF

CONCLUSIONS: The intensity and consequences of pain were influenced by differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143, which was directly, associated with higher expression of immune inflammatory related genes TNFα, IL-6, and COX-2 in adolescences with CFS. Further studies of larger patient cohorts will help clarify the role of miRNAs in the pathogenesis of CFS.

Source: Al-Rawaf HA, Alghadir AH, Gabr SA. MicroRNAs as biomarkers of pain intensity in patients with chronic fatigue syndrome. Pain Pract. 2019 Jul 8. doi: 10.1111/papr.12817. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31282597

The clinical value of cytokines in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disorder with uncertain pathogenesis. Without effective therapy, CFS is characterized by disabling fatigue, depression, memory loss, and somatic discomfort. This comprehensive and impartial review aimed to assess the available evidence and examined the potential clinical value of using cytokines for the monitoring of CFS and as targets for the treatment of CFS.

Inflammatory reactions and immune modulation are considered to contribute to the pathophysiology of CFS, and it is well documented that cytokines present in both blood and cerebrospinal fluid (CSF) are closely associated with the progression and severity of CFS. However, pathophysiological and methodological limitations prevent using circulating cytokines as independent diagnostic indices. Moreover, there is no evidence to support the use of CSF cytokines as independent diagnostic indices.

Nevertheless, a comprehensive evaluation of changes in circulating and CSF cytokines may improve clinical understanding of the pathophysiology of patients with CFS, aiding in the establishment of an appropriate diagnosis. Importantly, the available evidence does not support the value of cytokines as therapeutic targets. We believe that an improved understanding of cytokine-related mechanisms will be helpful to explore new cytokine-related therapeutic targets.

Source: Yang T, Yang Y, Wang D, Li C, Qu Y, Guo J, Shi T, Bo W, Sun Z, Asakawa T. The clinical value of cytokines in chronic fatigue syndrome. J Transl Med. 2019 Jun 28;17(1):213. doi: 10.1186/s12967-019-1948-6 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1948-6 (Full article)

Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study

Abstract:

Introduction: Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness of unknown etiology with considerable social and economic impact. To investigate a putative genetic predisposition to ME/CFS we conducted genome-wide single-nucleotide polymorphism (SNP) analysis to identify possible variants.

Methods: 383 ME/CFS participants underwent DNA testing using the commercial company 23andMe. The deidentified genetic data was then filtered to include only non-synonymous and nonsense SNPs from exons and microRNAs, and SNPs close to splice sites. The frequencies of each SNP were calculated within our cohort and compared to frequencies from the Kaviar reference database. Functional annotation of pathway sets containing SNP genes with high frequency in ME/CFS was performed using over-representation analysis via ConsensusPathDB. Furthermore, these SNPs were also scored using the Combined Annotation Dependent Depletion (CADD) algorithm to gauge their deleteriousness.

Results: 5693 SNPs were found to have at least 10% frequency in at least one cohort (ME/CFS or reference) and at least two-fold absolute difference for ME/CFS. Functional analysis identified the majority of SNPs as related to immune system, hormone, metabolic, and extracellular matrix organization. CADD scoring identified 517 SNPs in these pathways that are among the 10% most deleteriousness substitutions to the human genome.

Source: Perez M, Jaundoo R, Hilton K, Del Alamo A, Gemayel K, Klimas NG, Craddock TJA, Nathanson L. Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study. Front Pediatr. 2019 May 24;7:206. doi: 10.3389/fped.2019.00206. eCollection 2019. https://www.ncbi.nlm.nih.gov/pubmed/31179255

Patients with fibromyalgia and chronic fatigue syndrome show increased hsCRP compared to healthy controls

Abstract:

Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are both chronic disorders that have a devastating effect on the lives of the affected patients and their families. Both conditions have overlapping clinical features that partly resemble those of inflammatory disorders. The etiology is still not understood, and it is suggested that the immune system might be a contributing factor. So far, the results are inconclusive. The purpose of this study was to compare the two conditions and investigate the level of the inflammatory marker high-sensitivity CRP (hsCRP) in CFS and FM patients compared to healthy controls.

Female participants aged 18-60 years were enrolled in this study. The group consisted of 49 CFS patients, 57 FM patients, and 54 healthy controls. hsCRP levels were significantly higher for both the CFS and the FM groups compared to healthy controls when adjusting for age, smoking, and BMI (p < .001).

There was no difference between the two patient groups. The level of hsCRP was affected by BMI but not by age and smoking. Patients with CFS and FM have higher concentrations of hsCRP compared to healthy controls. This remains significant even after adjusting for BMI. CFS and FM cannot be distinguished from each other on the basis of hsCRP in our study.

Source: Groven N, Fors EA, Klæbo Reitan S. Patients with fibromyalgia and chronic fatigue syndrome show increased hsCRP compared to healthy controls. Brain Behav Immun. 2019 Jun 6. pii: S0889-1591(19)30208-9. doi: 10.1016/j.bbi.2019.06.010. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31176728

Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study

Abstract:

Source: Melanie Perez, Rajeev Jaundoo, Kelly Hilton, Ana Del Alamo, Kristina Gemayel, Nancy G. Klimas, Travis J. A. Craddock and Lubov Nathanson. Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study. Front. Pediatr., 24 May 2019 | https://doi.org/10.3389/fped.2019.00206 (Full article)

Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities

Abstract:

In 2011, it was reviewed that a) there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS; and b) the comorbidity between both disorders may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear.

This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies, which are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicates that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue.

In conclusion, based on our review we may posit that shared immune-inflammatory pathways and especially activated microglia underpin comorbid depression and CFS. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

Source: Filho AJMC, Macedo DS, de Lucena DF, Maes M. Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities. Behav Brain Res. 2019 May 25:111975. doi: 10.1016/j.bbr.2019.111975. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31136774

Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial and poorly undersood disabling disease. We present epidemiological, clinical and experimental evidence that ME/CFS constitutes a major type of adverse effect of vaccines, especially those containing poorly degradable particulate aluminum adjuvants.

Evidence has emerged very slowly due to the multiplicity, lack of specificity, delayed onset, and frequent medical underestimation of ME/CFS symptoms. It was supported by an epidemiological study comparing vaccinated vs unvaccinated militaries that remained undeployed during Gulf War II.

Affected patients suffer from cognitive dysfunction affecting attention, memory and inter-hemispheric connexions, well correlated to brain perfusion defects and associated with a stereotyped and distinctive pattern of cerebral glucose hypometabolism. Deltoid muscle biopsy performed to investigate myalgia typically yields macrophagic myofasciitis (MMF), a histological biomarker assessing longstanding persistency of aluminum agglomerates within innate immune cells at site of previous immunization. MMF is seemingly linked to altered mineral particle detoxification by the xeno/autophagy machinery.

Comparing toxicology of different forms of aluminum and different types of exposure is misleading and inadequate and small animal experiments have turned old dogma upside down. Instead of being rapidly solubilized in the extracellular space, injected aluminum particles are quickly captured by immune cells and transported to distant organs and the brain where they elicit an inflammatory response and exert selective low dose long-term neurotoxicity. Clinical observations and experiments in sheep, a large animal like humans, confirmed both systemic diffusion and neurotoxic effects of aluminum adjuvants. Post-immunization ME/CFS represents the core manifestation of “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA).

Source: Gherardi RK, Crépeaux G, Authier FJ. Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system. Autoimmun Rev. 2019 May 3. pii: S1568-9972(19)30109-0. doi: 10.1016/j.autrev.2019.05.006. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31059838

Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome

Abstract:

PURPOSE: A role for the immune system in causing myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is long suspected, but few studies have looked for specific autoantibodies that might contribute to the symptoms. Our aim was to look for evidence of antibodies to neuronal proteins in patients with ME/CSF.

METHODS: Sera samples from 50 patients and 50 healthy individuals were sent coded to the Neuroimmunology Laboratory in Oxford. Screening for antibody binding to neuronal tissue was performed on brain tissue and neuronal cultures. Specific serum antibodies were assessed by antigen-specific cell-based assays and radioimmunoassays. After antibody testing, the associations between seropositive status and clinical data were investigated.

FINDINGS: Overall, 8 patients and 11 participants were found to have some serum immunoreactivity toward neuronal or neuromuscular junction proteins, but only 1 patient and 2 participants had specific serum antibodies. Nevertheless, seropositive status in patients with ME was associated with shorter duration since onset and a more severe disease.

IMPLICATIONS: The results indicate no overall increased frequency of antibodies to neuronal proteins in ME/CSF and no evidence of a specific antibody that might be causative or contribute to clinical features in patients. However, the association of seropositive status with shorter duration of disease and more severe symptoms suggests a possible role of antibodies at onset in some patients and should be the focus of future studies.

Source: Giannoccaro MP, Cossins J, Sørland K, Fluge Ø, Vincent A. Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome. Clin Ther. 2019 Apr 30. pii: S0149-2918(19)30163-8. doi: 10.1016/j.clinthera.2019.04.001. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31053295

Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients

Abstract:

BACKGROUND: Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations. Although the aetiology of CFS/ME remains elusive, immunological dysfunction and more particularly reduced cytotoxic activity in natural killer (NK) cells is the most consistent laboratory finding. The Transient Receptor Potential (TRP) superfamily of cation channels play a pivotal role in the pathophysiology of immune diseases and are therefore potential therapeutic targets. We have previously identified single nucleotide polymorphisms in TRP genes in peripheral NK cells from CFS/ME patients. We have also described biochemical pathway changes and calcium signaling perturbations in NK cells from CFS/ME patients. Notably, we have previously reported a decrease of TRP cation channel subfamily melastatin member 3 (TRPM3) function in NK cells isolated from CFS/ME patients compared with healthy controls after modulation with pregnenolone sulfate and ononetin using a patch-clamp technique. In the present study, we aim to confirm the previous results describing an impaired TRPM3 activity in a new cohort of CFS/ME patients using a whole cell patch-clamp technique after modulation with reversible TRPM3 agonists, pregnenolone sulfate and nifedipine, and an effective TRPM3 antagonist, ononetin. Indeed, no formal research has commented on using pregnenolone sulfate or nifedipine to treat CFS/ME patients while there is evidence that clinicians prescribe calcium channel blockers to improve different symptoms.

METHODS: Whole-cell patch-clamp technique was used to measure TRPM3 activity in isolated NK cells from twelve age- and sex-matched healthy controls and CFS/ME patients, after activation with pregnenolone sulfate and nifedipine and inhibition with ononetin.

RESULTS: We confirmed a significant reduction in amplitude of TRPM3 currents after pregnenolone sulfate stimulation in isolated NK cells from another cohort of CFS/ME patients compared with healthy controls. The pregnenolone sulfate-evoked ionic currents through TRPM3 channels were again significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients. In addition, we used nifedipine, another reversible TRPM3 agonist to support the previous findings and found similar results confirming a significant loss of the TRPM3 channel activity in CFS/ME patients.

CONCLUSIONS: Impaired TRPM3 activity was validated in NK cells isolated from CFS/ME patients using different pharmacological tools and whole-cell patch-clamp technique as the gold standard for ion channel research. This investigation further helps to establish TRPM3 channels as a prognostic marker and/ or a potential therapeutic target for CFS/ME.

Source: Cabanas H, Muraki K, Balinas C, Eaton-Fitch N, Staines D, Marshall-Gradisnik S. Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients. Mol Med. 2019 Apr 23;25(1):14. doi: 10.1186/s10020-019-0083-4. https://www.ncbi.nlm.nih.gov/pubmed/31014226

Cellular immune function in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with unknown aetiology, unclear pathophysiology and with no diagnostic test or biomarker available. Many patients report their ME/CFS began after an acute infection, and subsequent increased frequency of infections, such as colds or influenza, is common. These factors imply an altered immunological status exists in ME/CFS, in at least a proportion of patients, yet previous studies of peripheral immunity have been discrepant and inconclusive.

The UK ME/CFS Biobank, which has collected blood samples from nearly 300 clinically-confirmed ME/CFS patients, enables large-scale studies of immunological function in phenotypically well-characterised participants. In this study, herpes virus serological status and T cell, B cell, NK cell and monocyte populations were investigated in 251 ME/CFS patients, including 54 who were severely affected, and compared with those from 107 healthy participants and with 46 patients with Multiple Sclerosis.

There were no differences in seroprevalence for six human herpes viruses between ME/CFS and healthy controls, although seroprevalence for the Epstein-Barr virus was higher in multiple sclerosis patients. Contrary to previous reports, no significant differences were observed in NK cell numbers, subtype proportions or in vitro responsiveness between ME/CFS patients and healthy control participants. In contrast, the T cell compartment was altered in ME/CFS, with reduced proportions of effector memory CD8+ T cells and of intermediately differentiated CD8+ T cells in ME/CFS. Conversely, there was a significantly increased proportion of mucosal associated invariant T cells (MAIT) cells, especially in severely affected ME/CFS patients.

These abnormalities demonstrate that an altered immunological state does exist in ME/CFS, particularly in severely affected people. This may simply reflect ongoing or recent infection, or may indicate future increased susceptibility to infection. Longitudinal studies of ME/CFS patients are needed to help to determine cause and effect and thus any potential benefits of immuno-modulatory treatments for ME/CFS.

Source: Jacqueline M. Cliff, Elizabeth C. King, Ji-Sook Lee, Nuno Sepulveda, Asia-Sofia Wolf, Caroline Kingdon, Erinna Bowman, Hazel M. Dockrell, Luis C. Nacul, Eliana Lacerda and Eleanor Riley. Cellular immune function in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Front. Immunol. | doi: 10.3389/fimmu.2019.00796 https://www.frontiersin.org/articles/10.3389/fimmu.2019.00796/full (Full article)