Category: Immune System

Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis

Abstract:

Chronic fatigue syndrome (CFS) is an often-debilitating condition of unknown origin. There is a general consensus among CFS researchers that the symptoms seem to reflect an ongoing immune response, perhaps due to viral infection. Thus, most CFS research has focused upon trying to uncover that putative immune system dysfunction or specific pathogenic agent. However, no single causative agent has been found.

In this speculative article, I describe a new hypothesis for the etiology of CFS: infection of the vagus nerve. When immune cells of otherwise healthy individuals detect any peripheral infection, they release proinflammatory cytokines. Chemoreceptors of the sensory vagus nerve detect these localized proinflammatory cytokines, and send a signal to the brain to initiate sickness behavior. Sickness behavior is an involuntary response that includes fatigue, fever, myalgia, depression, and other symptoms that overlap with CFS.

The vagus nerve infection hypothesis of CFS contends that CFS symptoms are a pathologically exaggerated version of normal sickness behavior that can occur when sensory vagal ganglia or paraganglia are themselves infected with any virus or bacteria. Drawing upon relevant findings from the neuropathic pain literature, I explain how pathogen-activated glial cells can bombard the sensory vagus nerve with proinflammatory cytokines and other neuroexcitatory substances, initiating an exaggerated and intractable sickness behavior signal. According to this hypothesis, any pathogenic infection of the vagus nerve can cause CFS, which resolves the ongoing controversy about finding a single pathogen. The vagus nerve infection hypothesis offers testable hypotheses for researchers, animal models, and specific treatment strategies.

Copyright © 2013 Elsevier Ltd. All rights reserved.

 

Source: VanElzakker MB. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med Hypotheses. 2013 Sep;81(3):414-23. doi: 10.1016/j.mehy.2013.05.034. Epub 2013 Jun 19. https://www.ncbi.nlm.nih.gov/pubmed/23790471

 

Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity.

METHODS: Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days.

RESULTS: Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.

CONCLUSIONS: Our results support the role of cytokines in the pathophysiology of CFS.

 

Source: Stringer EA, Baker KS, Carroll IR, Montoya JG, Chu L, Maecker HT, Younger JW. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013 Apr 9;11:93. doi: 10.1186/1479-5876-11-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637529/ (Full article)

 

Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a debilitating neuro-immune disorder of unknown etiology diagnosed by an array of clinical manifestations. Although several immunological abnormalities have been described in CFS, their heterogeneity has limited diagnostic applicability.

METHODS: Immunological features of CFS were screened in 22 CFS diagnosed individuals fulfilling Fukuda criteria and 30 control healthy individuals. Peripheral blood T, B and NK cell function and phenotype were analyzed by flow cytometry in both groups.

RESULTS: CFS diagnosed individuals showed similar absolute numbers of T, B and NK cells, with minor differences in the percentage of CD4+ and CD8+ T cells. B cells showed similar subset frequencies and proliferative responses between groups. Conversely, significant differences were observed in T cell subsets. CFS individuals showed increased levels of T regulatory cells (CD25+/FOXP3+) CD4 T cells, and lower proliferative responses in vitro and in vivo. Moreover, CD8 T cells from the CFS group showed significantly lower activation and frequency of effector memory cells. No clear signs of T-cell immunosenescence were observed. NK cells from CFS individuals displayed higher expression of NKp46 and CD69 but lower expression of CD25 in all NK subsets defined. Overall, T cell and NK cell features clearly clustered CFS individuals.

CONCLUSIONS: Our findings suggest that alterations in T-cell phenotype and proliferative response along with the specific signature of NK cell phenotype may be useful to identify CFS individuals. The striking down modulation of T cell mediated immunity may help to understand intercurrent viral infections in CFS.

 

Source: Curriu M, Carrillo J, Massanella M, Rigau J, Alegre J, Puig J, Garcia-Quintana AM, Castro-Marrero J, Negredo E, Clotet B, Cabrera C, Blanco J. Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome. J Transl Med. 2013 Mar 20;11:68. doi: 10.1186/1479-5876-11-68. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614537/ (Full article)

 

Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disorder of unknown aetiology characterized by disabling fatigue, headaches, sleep disturbance and several other symptoms. The onset of CFS may follow a viral infection or period of stress. Patients with CFS do not have hypogammaglobulinaemia, predisposition to recurrent bacterial infections or symptoms of autoimmunity.

To date, defects in B cell numbers or function have not been shown in the literature. However, treatment with anti-B cell therapy using Rituximab has recently shown benefit to CFS patients. We therefore postulated that patients with CFS had a subtle humoral immune dysfunction, and performed extended B cell immunophenotyping.

We undertook a detailed characterization of the proportions of the different B cell subsets in 33 patients with CFS fulfilling the Canadian and Fukada criteria for CFS and compared these with 24 age- and gender-matched healthy controls (HC). CFS patients had greater numbers of naive B cells as a percentage of lymphocytes: 6·3 versus 3·9% in HC (P = 0·034), greater numbers of naive B cells as a percentage of B cells: 65 versus 47% in controls (P = 0·003), greater numbers of transitional B cells: 1·8 versus 0·8% in controls (P = 0·025) and reduced numbers of plasmablasts: 0·5 versus 0·9% in controls (P = 0·013). While the cause of these changes is unclear, we speculate whether they may suggest a subtle tendency to autoimmunity.

© 2012 British Society for Immunology.

 

Source: Bradley AS, Ford B, Bansal AS. Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls. Clin Exp Immunol. 2013 Apr;172(1):73-80. doi: 10.1111/cei.12043. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719933/ (Full article)

 

Humoral and cellular immune responses after influenza vaccination in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a clinical condition characterized by severe and disabling fatigue that is medically unexplained and lasts longer than 6 months. Although it is possible to effectively treat CFS, the nature of the underlying physiology remains unclear. Various studies have sought evidence for an underlying disturbance in immunity. The aim of this study was to compare the humoral and cellular immune responses upon influenza vaccination in CFS patients and healthy controls.

RESULTS: Identical antibody titers were observed in CFS patients and healthy controls. Patients and controls demonstrated similar seroprotection rates against all three virus-strains of the influenza vaccine, both pre- and post-vaccination. Functional T cell reactivity was observed in both CFS patients and healthy controls. CFS patients showed a non-significant, numerically lower cellular proliferation at baseline compared to controls. Vaccination induced a significant increase in cellular proliferation in CFS patients, but not in healthy controls. Cytokine production and the number of regulatory T cells were comparable in patients and controls.

CONCLUSIONS: The humoral and cellular immune responses upon influenza vaccination were comparable in CFS patients and healthy controls. Putative aberrations in immune responses in CFS patients were not evident for immunity towards influenza. Standard seasonal influenza vaccination is thus justified and, when indicated, should be recommended for patients suffering from CFS.

 

Source: Prinsen H, de Vries IJ, Torensma R, Pots JM, Mulder SF, van Herpen CM, Elving LD, Bleijenberg G, Stelma FF, van Laarhoven HW. Humoral and cellular immune responses after influenza vaccination in patients with chronic fatigue syndrome. BMC Immunol. 2012 Dec 17;13:71. doi: 10.1186/1471-2172-13-71. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534525/ (Full article)

 

Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor

Abstract:

BACKGROUND: Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive [CFS(+)] and negative [CFS(-)] autoantibodies.

METHODOLOGY: Five CFS(+) and six CFS(-) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-[(11)C]methyl-3-piperidyl benzilate [(11)C](+)3-MPB for the mAChR binding and N-[(11)C]methyl-4-piperidyl acetate [(11)C]MP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain [(11)C](+)3-MPB binding in CFS(-) patients did not differ from normal controls, CFS(+) patients showed significantly lower [(11)C](+)3-MPB binding than CFS(-) patients and normal controls. In contrast, the [(11)C]MP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups.

CONCLUSION: The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.

 

Source: Yamamoto S, Ouchi Y, Nakatsuka D, Tahara T, Mizuno K, Tajima S, Onoe H, Yoshikawa E, Tsukada H, Iwase M, Yamaguti K, Kuratsune H, Watanabe Y. Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS One. 2012;7(12):e51515. doi: 10.1371/journal.pone.0051515. Epub 2012 Dec 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519853/ (Full article)

 

Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome

Abstract:

BACKGROUND: A Giardia outbreak was associated with development of post-infectious functional gastrointestinal disorders (PI-FGID) and chronic fatigue syndrome (PI-CFS). Markers of immune dysfunction have given conflicting results in CFS and FGID patient populations. The aim of this study was to evaluate a wide selection of markers of immune dysfunction in these two co-occurring post-infectious syndromes.

METHODS: 48 patients, reporting chronic fatigue in a questionnaire study, were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS (n=19) and idiopathic chronic fatigue (n=5) and Rome II criteria for FGIDs (n=54). 22 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. Peripheral blood lymphocyte subsets were analyzed by flow cytometry.

RESULTS: In peripheral blood we found significantly higher CD8 T-cell levels in PI-FGID, and significantly lower NK-cell levels in PI-CFS patients. Severity of abdominal and fatigue symptoms correlated negatively with NK-cell levels. A tendency towards lower T-cell CD26 expression in FGID was seen.

CONCLUSION: Patients with PI-CFS and/or PI-FGID 5 years after Giardia lamblia infection showed alterations in NK-cell and CD8-cell populations suggesting a possible immunological abnormality in these conditions. We found no significant changes in other markers examined in this well-defined group of PI-CFS and PI-FGID elicited by a gastrointestinal infection. Controlling for co-morbid conditions is important in evaluation of CFS-biomarkers.

 

Source: Hanevik K, Kristoffersen EK, Sørnes S, Mørch K, Næss H, Rivenes AC, Bødtker JE, Hausken T, Langeland N. Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome. BMC Infect Dis. 2012 Oct 14;12:258. doi: 10.1186/1471-2334-12-258. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553045/ (Full article)

 

Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue

Abstract:

BACKGROUND: As Chronic Fatigue Syndrome (CFS) has been known to follow Epstein-Bar virus (EBV) and other systemic infections; our objective was to describe differences in immune activation in post-infective CFS (PI-CFS) patients and recovered controls. We studied 301 adolescents prospectively over 24 months following the diagnosis of monospot-positive infectious mononucleosis (IM). We found an incidence of CFS at 6, 12 and 24 months of 13%, 7% and 4% respectively.

METHODS: Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFN-γ, TNF-α and TNF-β in duplicate plasma samples available in bio-bank from 9 PI-CFS subjects and 12 recovered controls at 24 months post-infection.

RESULTS: Standard comparative analysis indicated significant differences in IL-8 and 23 across subject groups. In constructing a linear classification model IL-6, 8 and 23 were selected by two different statistical approaches as discriminating features, with IL-1a, IL-2 and IFN-γ also selected in one model or the other. This supported an assignment accuracy of better than 80% at a confidence level of 0.95 into PI-CFS versus recovered controls.

CONCLUSION: These results suggest that co-expression patterns in as few as 5 cytokines associated with Th17 function may hold promise as a tool for the diagnosis of post-infectious CFS.

 

Source: Broderick G, Katz BZ, Fernandes H, Fletcher MA, Klimas N, Smith FA, O’Gorman MR, Vernon SD, Taylor R. Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue. J Transl Med. 2012 Sep 13;10:191. doi: 10.1186/1479-5876-10-191. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480896/ (Full article)

 

Can persistent Epstein-Barr virus infection induce chronic fatigue syndrome as a Pavlov reflex of the immune response?

Abstract:

Chronic fatigue syndrome is a protracted illness condition (lasting even years) appearing with strong flu symptoms and systemic defiances by the immune system. Here, by means of statistical mechanics techniques, we study the most widely accepted picture for its genesis, namely a persistent acute mononucleosis infection, and we show how such infection may drive the immune system towards an out-of-equilibrium metastable state displaying chronic activation of both humoral and cellular responses (a state of full inflammation without a direct ’causes-effect’ reason).

By exploiting a bridge with a neural scenario, we mirror killer lymphocytes T(K) and B cells to neurons and helper lymphocytes [Formula: see text] and [Formula: see text] to synapses, hence showing that the immune system may experience the Pavlov conditional reflex phenomenon: if the exposition to a stimulus (Epstein-Barr virus antigens) lasts for too long, strong internal correlations among B,T(K) and T(H) may develop ultimately resulting in a persistent activation even though the stimulus itself is removed. These outcomes are corroborated by several experimental findings.

 

Source: Agliari E, Barra A, Vidal KG, Guerra F. Can persistent Epstein-Barr virus infection induce chronic fatigue syndrome as a Pavlov reflex of the immune response? J Biol Dyn. 2012;6:740-62. doi: 10.1080/17513758.2012.704083. https://www.ncbi.nlm.nih.gov/pubmed/22873615

 

Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression

Abstract:

BACKGROUND: Depression is an inflammatory disorder while many authors declare myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to be a functional disorder. The aim of the present study is to compare inflammatory and cell-mediated immune (CMI) responses between depression and ME/CFS.

METHODS: We measured two proinflammatory cytokines (PICs) in plasma, interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), with enzyme-linked immunosorbent assays, and serum neopterin with a radioimmunoassay in controls, ME/CFS and depressive patients.

RESULTS: Plasma PICs were significantly higher in ME/CFS than in depression and higher in both patient groups than in controls. Increased PIC levels in depression were attributable to the presence of fatigue and physio-somatic symptoms. Serum neopterin did not differ significantly between depression and ME/CFS but was higher in both patient groups than in controls. The significant positive correlations between neopterin and either IL-1 or TNF-α were significantly greater in depression than in ME/CFS.

CONCLUSIONS: Since PICs cause depression-like behaviors and fatigue/malaise, we suggest that inflammation may play a role in the pathophysiology of ME/CFS and depression. Increased neopterin also seems to contribute to the pathophysiology of both disorders. This study has detected a shared ‘pathway phenotype’, i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. ME/CFS and depression are discriminated from each other by increased PICs in ME/CFS and differences in the immune cell communication networks.

Copyright © 2012 S. Karger AG, Basel.

 

Source: Maes M, Twisk FN, Ringel K. Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother Psychosom. 2012;81(5):286-95. doi: 10.1159/000336803. Epub 2012 Jul 20. https://www.ncbi.nlm.nih.gov/pubmed/22832503