Category: Pathogenesis

Chronic fatigue syndrome–a neuroimmunological model

Abstract:

The aetiological and pathophysiological basis of chronic fatigue syndrome (CFS) remains a controversial field of inquiry in the research community. While CFS and similar disease conditions such as fibromyalgia (FM) and post-infectious encephalopathy have been the focus of intense scrutiny for the past 20 years, results of research were often contradictory and a cohesive pathological model has remained elusive. However, recent developments in understanding the unique immunophysiology of the brain may provide important clues for the development of a truly comprehensive explanation of the pathology of CFS.

We argue that CFS pathogenesis lies in the influence of peripheral inflammatory events on the brain and the unique immunophysiology of the central nervous system. There is also evidence that CFS patients have a relative immunodeficiency that predisposes to poor early control of infection that leads to chronic inflammatory responses to infectious insults.

The neurological and endocrine changes have been described in CFS patients support the view that CFS has an inflammatory pathogenesis when considered as a whole. An inflammatory model of disease also provides an explanation for the marked female sex bias associated with CFS.

This review therefore posits the hypothesis that CFS as a disease of long-term inflammatory processes of the brain. We will also provide an investigative framework that could be used to justify the use of anti-TNF biological agents as a reliable and effective treatment approach to CFS, a syndrome that to date remains frustratingly difficult for both patients and health care professionals to manage.

Copyright © 2011 Elsevier Ltd. All rights reserved.

 

Source: Arnett SV, Alleva LM, Korossy-Horwood R, Clark IA. Chronic fatigue syndrome–a neuroimmunological model. Med Hypotheses. 2011 Jul;77(1):77-83. doi: 10.1016/j.mehy.2011.03.030. Epub 2011 Apr 6. https://www.ncbi.nlm.nih.gov/pubmed/21474251

 

Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome

Abstract:

BACKGROUND: Neurologic Post Treatment Lyme disease (nPTLS) and Chronic Fatigue (CFS) are syndromes of unknown etiology. They share features of fatigue and cognitive dysfunction, making it difficult to differentiate them. Unresolved is whether nPTLS is a subset of CFS.

METHODS AND PRINCIPAL FINDINGS: Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins. Preliminary pathway analysis demonstrated that the data could be useful for hypothesis generation on the pathogenetic mechanisms underlying these two related syndromes.

CONCLUSIONS: nPTLS and CFS have distinguishing CSF protein complements. Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis. Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.

 

Source: Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH. Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome. PLoS One. 2011 Feb 23;6(2):e17287. doi: 10.1371/journal.pone.0017287. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044169/ (Full article)

 

Heterologous immunity: immunopathology, autoimmunity and protection during viral infections

There is a strong association between infection-related cell-mediated immunity and autoimmune diseases such as diabetes, multiple sclerosis (MS), rheumatoid arthritis (RA) and lupus erythematosis (SLE)1. Infections have also been associated with unusual immunopathologies of unknown origin, such as Wegner granulomatosis, sarcoidosis, colitis, panniculitis, bronchiolitis obliterans and even chronic fatigue syndrome. Despite exhaustive efforts, a definitive link between one particular pathogen and any of one these pathologies has never been found. More often several pathogens have become associated with each of these conditions. For instance multiple sclerosis has been associated with Epstein Barr virus (EBV), measles virus, HHV-6, varicella-zoster virus, and Picornaviruses2-6. Panniculitis in the form of erythema nodosum and bronchiolitis obliterans have both been associated with unusual cell-mediated immune responses that occur following non-specified viral or intracellular bacterial infections 7-9. Erythema nodosum, which has also been associated with Crohn’s disease8, is a very painful condition, where nodules of inflamed subcutaneous fat often on the shins and forearms persist for months. There is no known therapy. Bronchiolitis obliterans is a lethal condition in humans where the bronchioles become occluded with immune cells and fibrinous material, with no known cause or treatment9.

Chronic fatigue syndrome (CFS) is another unusual multisystem disease which is thought to be associated with immune dysregulation. Over the past two decades millions of patients world wide have suffered from a clinical syndrome of disabling fatigue, myalgias, palpitations and cognitive dysfunction that lasts longer than 6 months. In 50% of cases it develops after a mild viral illness. Cases may appear sporadically or in clusters10,11. Many attempts have been made to define the syndrome on the basis of an etiologic agent. These agents have included Epstein-Barr virus10, Brucella12, Candida albicans13, Borrelia burgdorferi, and human herpesvirus-614,15. More recently it has been associated with enteroviruses and xenoretroviruses 16-18. The general conclusion has been that it is unlikely that the syndrome is caused by a single etiologic agent. The mechanisms mediating CFS are poorly understood, and there are few well designed studies examining its cause. The symptoms of CFS are similar to those experienced during viral infections such as infectious mononucleosis or influenza or in the setting of therapy with cytokines such as interferon or interleukin-2. It has been speculated that some or all the symptoms are reflective of an altered immune response to some pathogen with over production of one or more cytokines. An alternative hypothesis suggests that a number of infectious agents are involved and result in a regulatory imbalance of cytokines and the patient with CFS is unable to reestablish the appropriate balance of cytokines. These theories have been supported by reports of immune deficiency seen associated with CFS19.

 

Source: Selin LK, Wlodarczyk MF, Kraft AR, Nie S, Kenney LL, Puzone R, Celada F. Heterologous immunity: immunopathology, autoimmunity and protection during viral infections. Autoimmunity. 2011 Jun;44(4):328-47. doi: 10.3109/08916934.2011.523277. Epub 2011 Jan 20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633594/ (Full article)

 

The HPA axis in the pathogenesis of chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a clinical syndrome characterized by profound disabling chronic fatigue associated with a wide array of other physical symptoms. Its etiology is currently unknown. Among the various hypotheses, considerable interest has been placed in the hypothalamus-pituitary-adrenal axis as a possible target of the pathogenesis of CFS. This article reviews the available scientific evidence about a role of hypothalamic-pituitary-adrenal axis in the pathogenesis of chronic fatigue syndrome.

 

Source: Ursini F, Succurro E, Grembiale A, Gagliardi DA, Arturi F. The HPA axis in the pathogenesis of chronic fatigue syndrome. Clin Ter. 2010;161(5):461-4. [Article in Italian] https://www.ncbi.nlm.nih.gov/pubmed/20949245

 

Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome

Abstract:

The etiology of chronic fatigue syndrome remains unknown. Oxidative stress may be involved in its pathogenesis. Vitamin E is a major endogenous lipid-soluble antioxidative substance, and is consumed during the lipid peroxidation process.

We studied a population comprising 27 patients with chronic fatigue syndrome (10 men and 17 women, 29 +/- 6 years of age) and 27 age- and sex-matched control subjects. Serum vitamin E (alpha-tocopherol) concentrations were determined and expressed as mg/g total lipids (total cholesterol and triglyceride) to evaluate oxidative stress. Serum alpha-tocopherol concentrations (mg/g lipids) were significantly (P < 0.001) lower in the patients with chronic fatigue syndrome (2.81 +/- 0.73) than in the control subjects (3.88 +/- 0.65).

The patients with chronic fatigue syndrome were re-examined during a follow-up interval. After 8 +/- 2 months, 16 patients exhibited a status that warranted re-examination during remission of the symptoms at a regular visit to our hospital (Group 1), while the remaining 11 did not (Group 2). The serum alpha-tocopherol levels were significantly elevated during remission as compared with those at baseline in Group 1 (2.71 +/- 0.62 –> 3.24 +/- 0.83, P < 0.001). The levels did not significantly change after the interval in Group 2 (2.97 +/- 0.86 –> 2.85 +/- 0.73, not significant).

In conclusion, serum alpha-tocopherol concentrations were significantly lower in the patients with chronic fatigue syndrome as compared with the control subjects, suggesting increased oxidative stress in the former. The low level of serum alpha-tocopherol was ameliorated during the remission phase as compared with the exacerbation phase in the patients with chronic fatigue syndrome, suggesting that increased oxidative stress may be involved in the pathogenesis of chronic fatigue syndrome and might also be directly related to the severity of the symptoms of chronic fatigue syndrome.

 

Source: Miwa K, Fujita M. Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart Vessels. 2010 Jul;25(4):319-23. doi: 10.1007/s00380-009-1206-6. Epub 2010 Jul 31. https://www.ncbi.nlm.nih.gov/pubmed/20676841

 

A case of chronic fatigue syndrome triggered by influenza H1N1 (swine influenza)

Abstract:

This case report describes an adolescent boy who was diagnosed as suffering from chronic fatigue syndrome 5 months after infection with H1N1 influenza.

 

Source: Vallings R. A case of chronic fatigue syndrome triggered by influenza H1N1 (swine influenza) .J Clin Pathol. 2010 Feb;63(2):184-5. doi: 10.1136/jcp.2009.071944. Epub 2009 Oct 26. https://www.ncbi.nlm.nih.gov/pubmed/19858526

 

Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS) and viral persistence

Abstract:

AIMS: Enteroviruses are well-known causes of acute respiratory and/or gastrointestinal infections and non-specific flu-like illness. Although enterovirus protein, RNA and non-cytopathic viruses have been demonstrated in the stomach biopsies of patients with myalgia encephalomyelitis/chronic fatigue syndrome (ME/CFS), causality for chronic diseases is difficult to establish without having well-documented cases of acute enterovirus infections. The aim of this study was to link acute enteroviral infection to viral persistence in patients with ME/CFS.

METHOD: Patients admitted to the hospital with acute febrile illnesses were screened for enteroviral infections. Acutely infected patients were followed longitudinally, and those who developed symptoms of ME/CFS underwent oesophagogastroduodenoscopy and biopsies of the antrum to document viral persistence by immunoperoxidase staining for viral protein and viral RNA assay.

RESULTS: Three representative patients with different manifestations of acute enterovirus infections progressed to have chronic symptoms of ME/CFS. Persistent viral infection was demonstrated in the antrum years later.

CONCLUSION: After acute infections, enteroviruses can persist in patients resulting in manifestation of ME/CFS. Chronic enterovirus infection in an immunocompetent host may be an example of a stalemate between attenuated, intracellular viruses and an ineffective immune response.

 

Source: Chia J, Chia A, Voeller M, Lee T, Chang R. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS) and viral persistence. J Clin Pathol. 2010 Feb;63(2):165-8. doi: 10.1136/jcp.2009.070466. Epub 2009 Oct 14. https://www.ncbi.nlm.nih.gov/pubmed/19828908

 

Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating disease of unknown etiology that is estimated to affect 17 million people worldwide. Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), in 68 of 101 patients (67%) as compared to 8 of 218 (3.7%) healthy controls. Cell culture experiments revealed that patient-derived XMRV is infectious and that both cell-associated and cell-free transmission of the virus are possible. Secondary viral infections were established in uninfected primary lymphocytes and indicator cell lines after their exposure to activated PBMCs, B cells, T cells, or plasma derived from CFS patients. These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.

Comment in:

Erratum in: Partial retraction. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. [Science. 2011]

Retraction in: Retraction. [Science. 2011]

 

Source: Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009 Oct 23;326(5952):585-9. doi: 10.1126/science.1179052. Epub 2009 Oct 8. http://science.sciencemag.org/content/326/5952/585.long (Full article)

 

Cardiac function fluctuates during exacerbation and remission in young adults with chronic fatigue syndrome and “small heart”

Abstract:

BACKGROUND: “Small heart syndrome”, previously referred to as so-called “neurocirculatory asthenia” associated with a small heart shadow on the chest roentgenogram, is characterized by weakness or fatigue even after mild exertion, palpitation, dyspnea, and fainting, many of which resemble symptoms in patients with chronic fatigue syndrome (CFS).

METHODS AND RESULTS: The study population comprised 42 patients with CFS younger than 40 years of age. Cardiothoracic ratio was determined on the chest roentgenogram and echocardiographic examination was performed to evaluate both the cardiac chamber size and function. “Small heart” (cardiothoracic ratio < or = 42%) on the chest X-ray photograph was noted in 26 (62%) of the study CFS patients. Echocardiographic examination demonstrated significantly smaller mean values of both the left ventricular (LV) end-diastolic and end-systolic dimensions, stroke volume indexes and cardiac indexes in CFS patients with “small heart” than in those without it and also in 20 control subjects. Thus, CFS patients with “small heart” had an actually small LV chamber and poor cardiac performance. During a long follow-up period of 10 CFS patients with “small heart”, all echocardiographic parameters mentioned above improved and cardiothoracic ratios increased significantly during the remission phase as compared with exacerbation phase.

CONCLUSIONS: “Small heart” on the chest X-ray photograph was prevalently noted in CFS patients. Echocardiographic examination revealed that CFS patients with “small heart” had an actually small LV chamber and poor cardiac performance. Cardiac functional changes evaluated by repeated examinations appeared to be directly associated with the severity of their symptoms. Small heart syndrome with impaired cardiac function may contribute to the development of CFS through low cardiac output as a constitutional factor.

 

Source: Miwa K, Fujita M. Cardiac function fluctuates during exacerbation and remission in young adults with chronic fatigue syndrome and “small heart”. J Cardiol. 2009 Aug;54(1):29-35. doi: 10.1016/j.jjcc.2009.02.008. Epub 2009 Mar 28. http://www.journal-of-cardiology.com/article/S0914-5087(09)00066-5/fulltext (Full article)

 

Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study

Abstract:

Chronic fatigue syndrome (CFS) is a disabling condition characterized by unexplained chronic fatigue that impairs normal activities. Although immunological and psychological aspects are present, symptoms related to skeletal muscles, such as muscle soreness, fatigability and increased lactate accumulation, are prominent in CFS patients.

In this case-control study, the phenotype of the same biopsy samples was analyzed by determining i) fibre-type proportion using myosin isoforms as fibre type molecular marker and gel electrophoresis as a tool to separate and quantify myosin isoforms, and ii) contractile properties of manually dissected, chemically made permeable and calcium-activated single muscle fibres.

The results showed that fibre-type proportion was significantly altered in CSF samples, which showed a shift from the slow- to the fast-twitch phenotype. Cross sectional area, force, maximum shortening velocity and calcium sensitivity were not significantly changed in single muscle fibres from CSF samples. Thus, the contractile properties of muscle fibres were preserved but their proportion was changed, with an increase in the more fatigue-prone, energetically expensive fast fibre type.

Taken together, these results support the view that muscle tissue is directly involved in the pathogenesis of CSF and it might contribute to the early onset of fatigue typical of the skeletal muscles of CFS patients.

 

Source: Pietrangelo T, Toniolo L, Paoli A, Fulle S, Puglielli C, Fanò G, Reggiani C. Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study. Int J Immunopathol Pharmacol. 2009 Apr-Jun;22(2):427-36. https://www.ncbi.nlm.nih.gov/pubmed/19505395