Category: Immune System

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.

Copyright © 2019. Published by Elsevier B.V.

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).

Copyright © 2019. Published by Elsevier B.V.

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.

Copyright © 2019. Published by Elsevier Inc.

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)

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