Category: Pathogenesis

Chronic fatigue syndrome with autoantibodies–the result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) that defines by prolonged fatigue and other manifestations, was recently integrated into a spectrum of central sensitivity syndromes including several diseases as fibromylagia. CFS etiology is multi-factorial commonly triggered by infectious agents. Vaccines, induce an immune response similarly to infections, and may trigger just like infections autoimmune diseases, CFS and fibromyalgia. Furthermore vaccines contain an adjuvant which enhances their immune stimulation.

CASE PRESENTATION: A 56-year-old woman was diagnosed with CFS accompanied by fibromyalgia, demyelination and autoantibodies. Her illness begun following the 2nd dose of hepatitis-B vaccine, and was aggravated by the 3rd vaccination. She underwent silicone breast implantation 6 years before vaccination with no adverse events. However, between the 2nd and 3rd vaccination she suffered a breast injury with local inflammation. Upon explanation of her breast implants silicone leak was observed.

DISCUSSION: Vaccines have been reported to precede CFS mainly following exposure to multiple vaccinations (e.g. the Gulf war syndrome), or as an adverse response to the vaccine adjuvant (e.g. the macrophagic myofasciitis syndrome). Silicone is considered an adjuvant to the immune system, and may induce “the adjuvant disease”. Silicone implant, especially silicone leak relationship with autoimmunity and CFS has been the focus of considerable debates.

CONCLUSION: Our patient illness started following hepatitis-B vaccine, suggesting that it was caused or accelerated by vaccination. In parallel to vaccination our patient suffered from breast injury, which might represent the time of silicone leak. The exposure to the adjuvant, silicone, might have augmented her immune response to the vaccine. To the best of our knowledge this is the first case of combined adverse effect to vaccine and silicone. Vaccine safety in individuals with silicone implants requires further studies.

 

Source: Nancy AL, Shoenfeld Y. Chronic fatigue syndrome with autoantibodies–the result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant. Autoimmun Rev. 2008 Oct;8(1):52-5. doi: 10.1016/j.autrev.2008.07.026. Epub 2008 Aug 24. https://www.ncbi.nlm.nih.gov/pubmed/18725327

 

Possible role for early-life immune insult including developmental immunotoxicity in chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME)

Abstract:

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME) in some countries, is a debilitating disease with a constellation of multi-system dysfunctions primarily involving the neurological, endocrine and immune systems. While substantial information is available concerning the complex dysfunction-associated symptoms of CFS, environmental origins of the disease have yet to be determined.

Part of the dilemma in identifying the cause(s) has been the focus on biomarkers (hormones, neurotransmitters, cytokines, infectious agents) that are contemporary with later-life CFS episodes. Yet, recent investigations on the origins of environmental diseases of the neurological, endocrine, reproductive, respiratory and immune systems suggest that early life toxicologic and other insults are pivotal in producing later-life onset of symptoms. As with autism and childhood asthma, CFS can also occur in children where the causes are certainly early-life events.

Immune dysfunction is recognized as part of the CFS phenotype but has received comparatively less attention than aberrant neurological or endocrine function. However, recent research results suggest that early life immune insults (ELII) including developmental immunotoxicity (DIT), which is induced by xenobiotics, may offer an important clue to the origin(s) of CFS.

The developing immune system is a sensitive and novel target for environmental insult (xenobiotic, infectious agents, stress) with major ramifications for postnatal health risks. Additionally, many prenatal and early postnatal neurological lesions associated with postnatal neurobehavioral diseases are now recognized as linked to prenatal immune insult and inflammatory dysregulation. This review considers the potential role of ELII including DIT as an early-life component of later-life CFS.

 

Source: Dietert RR, Dietert JM. Possible role for early-life immune insult including developmental immunotoxicity in chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME). Toxicology. 2008 May 2;247(1):61-72. doi: 10.1016/j.tox.2008.01.022. Epub 2008 Feb 8. https://www.ncbi.nlm.nih.gov/pubmed/18336982

 

Chronic fatigue syndrome: characteristics and possible causes for its pathogenesis

Abstract:

Chronic fatigue syndrome is a heterogeneous disorder with unknown pathogenesis and etiology, characterized by disabling fatigue, difficulty in concentration and memory, and concomitant skeletal and muscular pain. Several mechanisms have been suggested to play a role in CFS, such as excessive oxidative stress following exertion, immune imbalance characterized by decreased natural killer cell and macrophage activity, immunoglobulin G subclass deficiencies (IgG1, IgG3) and decreased serum concentrations of complement component. Autoantibodies were also suggested as a possible factor in the pathogenesis of CFS. Recent studies indicate that anti-serotonin, anti-microtubule-associated protein 2 and anti-muscarinic cholinergic receptor 1 may play a role in the pathogenesis of CFS. It has been demonstrated that impairment in vasoactive neuropeptide metabolism may explain the symptoms of CFS.

 

Source: Bassi N, Amital D, Amital H, Doria A, Shoenfeld Y. Chronic fatigue syndrome: characteristics and possible causes for its pathogenesis. Isr Med Assoc J. 2008 Jan;10(1):79-82. http://www.ima.org.il/IMAJ/ViewArticle.aspx?year=2008&month=01&page=79 (Full article)

 

Genetic background of chronic fatigue syndrome

Abstract:

Although previous twin and family studies have suggested the involvement of genetic factor(s) in the pathogenesis of chronic fatigue syndrome (CFS), responsible gene for CFS was not known. We have recently reported the association of serotonin transporter gene polymorphism in CFS. A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls. Compared to S allele, the L allele is believed to retain higher transcriptional activity, which causes decreased concentration of serotonin in the extracellular space, namely, active serotonin in CFS. These results thus support the serotonin hypothesis in the pathogenesis of CFS.

 

Source: Narita M, Narita N. Genetic background of chronic fatigue syndrome. Nihon Rinsho. 2007 Jun;65(6):997-1002. [Article in Japanese] https://www.ncbi.nlm.nih.gov/pubmed/17561688

 

Viral infections in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous illness in which patients can have different, overlapping signs and symptoms. No single underlying cause has been established for all CFS patients. Epidemiological studies reveal that a flu-like sickness precedes the onset in the majority of cases. The major hypothesis of the pathogenesis of CFS is that infectious agents such as viruses, may trigger and lead to chronic activation of the immune system with abnormal regulation of cytokine production. Many studies have been performed to identify the possible microbial triggers and to understand the epidemiological microbial agents. We have summarized the recent progressive literature of virus, rickettsia, and mycoplasma implicated in the pathogenesis of CFS.

 

Source: Sairenji T, Nagata K. Viral infections in chronic fatigue syndrome. Nihon Rinsho. 2007 Jun;65(6):991-6. [Article in Japanese] https://www.ncbi.nlm.nih.gov/pubmed/17561687

 

Infection and vaccination in chronic fatigue syndrome: myth or reality?

Abstract:

Chronic fatigue syndrome (CFS) is characterized by severe disabling fatigue lasting for more than 6 months associated with physical and mental disturbances such as headache, arthralgia, myalgia, memory impairment, sore throat and tender lymph nodes. The exact pathogenesis is still unknown. Several models were proposed to explain its etiology including chronic infection, endocrine dysfunction, autonomic imbalance, depression, decreased immunity states and an aberrant reaction to infection. No convincing evidence was found to support any of the suggested pathogenic mechanisms.

The current concept is that CFS pathogenesis is a multi factorial condition in which an infective agent cause an aberrant immune response characterized by a shift to Th-2 dominant response. When the response fails to be switched-off, a chronic immune activation occurs and clinically expressed as the symptomatology of CFS. Vaccinations are used in order to stimulate the immune system to induce a persistent immunity against the favorable antigens.

Several syndromes that contain chronic fatigue as one of their symptoms, such as “Gulf war syndrome” and macrophagic myofasciitis were related to vaccinations. Can vaccinations induce the aberrant immune response of CFS? Little is known about this issue. There are some reports on CFS occurring after vaccination, but few prospective and retrospective studies failed to find such an association. A working group of the Canadian Laboratory Center for Disease Control (LCDC) that was founded in order to examine the suspected association between CFS and vaccinations concluded that there is no evidence that relates CFS to vaccination.

Further studies are requested to examine this issue since it is very conceivable that if infection can lead to CFS, vaccination may also lead to it in the same immune-mediated pathogenesis.

 

Source: Appel S, Chapman J, Shoenfeld Y. Infection and vaccination in chronic fatigue syndrome: myth or reality? Autoimmunity. 2007 Feb;40(1):48-53. https://www.ncbi.nlm.nih.gov/pubmed/17364497

 

Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Human herpesvirus 6 (HHV-6) and 7 (HHV-7) have been suggested as possible triggering agents for chronic fatigue syndrome(CFS).

OBJECTIVES: To determine the possible association of HHV-6 and HHV-7 infections with CFS.

STUDY DESIGN: The prevalence of latent/persistent and active viral infections by nPCR, characteristic of HHV-6 variants using restriction endonuclease analysis and changes of lymphocyte subsets in peripheral blood by laser flow-cytometry in 17 CFS patients was examined. In addition, 12 patients with unexplained chronic fatigue and 20 blood donors (BD) were studied.

RESULTS: No difference in prevalence of latent/persistent single viral infections between the patients and BD was found but dual infection rate was significantly higher in CFS patients. Active HHV-6 and dual (HHV-6 + HHV-7) infections were detected in CFS patients only and frequency of HHV-7 reactivation was also significantly higher in these patients. HHV-6 variant B was predominant in CFS patients (12/13). The changes of immunological parameters in CFS patients with active dual infection were characterized by significant decrease of CD3+ and CD4+ T cells, significant increase of CD95+ cells and decrease of CD4+/CD8+ ratio.

CONCLUSIONS: HHV-6 and HHV-7 may be involved in the pathogenesis of CFS and reactivation of both viruses may provoke changes in the phenotype of circulating lymphocytes.

 

Source: Chapenko S, Krumina A, Kozireva S, Nora Z, Sultanova A, Viksna L, Murovska M. Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome. J Clin Virol. 2006 Dec;37 Suppl 1:S47-51. https://www.ncbi.nlm.nih.gov/pubmed/17276369

 

Erythrocyte oxidative damage in chronic fatigue syndrome

Abstract:

BACKGROUND: It has been hypothesized that a link exists between erythrocyte metabolism (particularly redox metabolism) and erythrocyte shape and that both are related to erythrocyte deformability. The aim of this research is to confirm the results of earlier studies and to investigate a correlation between erythrocyte morphology and erythrocyte oxidative damage in chronic fatigue syndrome (CFS).

METHODS: Reduced glutathione (GSH), malondialdehyde (MDA), methemoglobin (metHb) and 2,3-diphosphoglyceric acid (2,3-DPG) were measured in 31 patients suffering from CFS and 41 healthy control subjects. Scanning electron microscopic studies of the erythrocytes from both groups were also carried out.

RESULTS: There was evidence of oxidative damage in CFS with statistically significant increases in 2,3-DPG (p < 0.05), metHb (p < 0.005) and MDA (p < 0.01). The CFS patients in this study also had significantly more stomatocytes in their blood than the normal subjects (p < 0.005).

CONCLUSIONS: There is a strong likelihood that the increase in erythrocyte antioxidant activity is associated with the presence of stomatocytes. The results of this study provide further evidence for the role of free radicals in the pathogenesis of CFS and a link between erythrocyte metabolism and erythrocyte shape.

 

Source: Richards RS, Wang L, Jelinek H. Erythrocyte oxidative damage in chronic fatigue syndrome. Arch Med Res. 2007 Jan;38(1):94-8. Epub 2006 Nov 3. https://www.ncbi.nlm.nih.gov/pubmed/17174731

 

Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study

Abstract:

OBJECTIVE: To delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections.

DESIGN: Prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis).

SETTING: The region surrounding the township of Dubbo in rural Australia, encompassing a 200 km geographical radius and 104,400 residents.

PARTICIPANTS: 253 patients enrolled and followed at regular intervals over 12 months by self report, structured interview, and clinical assessment.

OUTCOME MEASURES: Detailed medical, psychiatric, and laboratory evaluations at six months to apply diagnostic criteria for chronic fatigue syndrome. Premorbid and intercurrent illness characteristics recorded to define risk factors for chronic fatigue syndrome. Self reported illness phenotypes compared between infective groups.

RESULTS: Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors.

CONCLUSIONS: A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome.

 

Source: Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006 Sep 16;333(7568):575. Epub 2006 Sep 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569956/ (Full article)

 

Exploration of the gene expression correlates of chronic unexplained fatigue using factor analysis

Abstract:

OBJECTIVE: To identify biomarkers of chronic fatigue syndrome (CFS) and related disorders through analysis of microarray data, pathology test results and self-report symptom profiles.

METHOD: To empirically derive the symptom domains of the illnesses, factor analysis was performed on responses to self-report questionnaires (multidimensional fatigue inventory, Centers for Disease Control and Prevention (CDC) symptom inventory and Zung depression scale) before validation with independent datasets. Gene expression patterns that distinguished subjects across each factor dimension were then sought.

RESULTS: A four-factor solution was favored, featuring ‘fatigue’ and ‘mood disturbance’ factors. Scores on these factors correlated with measures of disability on the Short Form (SF)-36. A total of 57 genes that distinguished subjects along each factor dimension were identified, although the separation was significant only for subjects beyond the extreme (15th and 85th) percentiles of severity. Clustering of laboratory parameters with expression of these genes revealed associations with serum measurements of pH, electrolytes, glucose, urea, creatinine, and liver enzymes (aspartate amino transferase [AST] and alanine amino transferase [AST]); as well as hematocrit and white cell count.

CONCLUSION: CFS is a complex syndrome that cannot simply be associated with changes in individual laboratory tests or expression levels of individual genes. No clear association with gene expression and individual symptom domains was found. However, analysis of such multifacetted datasets is likely to be an important means to elucidate the pathogenesis of CFS.

 

Source: Fostel J, Boneva R, Lloyd A. Exploration of the gene expression correlates of chronic unexplained fatigue using factor analysis. Pharmacogenomics. 2006 Apr;7(3):441-54. https://www.ncbi.nlm.nih.gov/pubmed/16610954