Tag: inflammation

Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS

Abstract:

There is evidence that disorders in inflammatory and oxidative and nitrosative (IO&NS) pathways and a lowered antioxidant status are important pathophysiological mechanisms underpinning myalgic encephalomyelitis / chronic fatigue syndrome(ME/CFS). Important precipitating and perpetuating factors for ME/CFS are (amongst others) bacterial and viral infections; bacterial translocation due to an increased gut permeability; and psychological stress.

Recently, Jason et al (2006) reported that the mean age of patients with myalgic encephalomyelitis/chronic fatigue syndrome dying from heart failure, i.e. 58.7 years, is significantly lower than the age of those dying from heart failure in the general US population, i.e. 83.1 years. These findings implicate that ME/CFS is a risk factor to cardio-vascular disorder.

This review demonstrates that disorders in various IO&NS pathways provide explanations for the earlier mortality due to cardiovascular disorders in ME/CFS. These pathways are: a) chronic low grade inflammation with extended production of nuclear factor kappa B and COX-2 and increased levels of tumour necrosis factor alpha; b) increased O&NS with increased peroxide levels, and phospholipid oxidation including oxidative damage to phosphatidylinositol; c) decreased levels of specific antioxidants, i.e. coenzyme Q10, zinc and dehydroepiandrosterone-sulphate; d) bacterial translocation as a result of leaky gut; e) decreased omega-3 polyunsatutared fatty acids (PUFAs), and increased omega-6 PUFA and saturated fatty acid levels; and f) the presence of viral and bacterial infections and psychological stressors. The mechanisms whereby each of these factors may contribute towards cardio-vascular disorder in ME/CFS are discussed.

ME/CFS is a multisystemic metabolic-inflammatory disorder. The aberrations in IO&NS pathways may increase the risk for cardiovascular disorders.

 

Source: Maes M, Twisk FN. Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 2009;30(6):677-93. https://www.ncbi.nlm.nih.gov/pubmed/20038921

 

Plasma cytokines in women with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) studies from our laboratory and others have described cytokine abnormalities. Other studies reported no difference between CFS and controls. However, methodologies varied widely and few studies measured more than 4 or 5 cytokines. Multiplex technology permits the determination of cytokines for a large panel of cytokines simultaneously with high sensitivity and with only 30 ul of plasma per sample. No widely accepted laboratory test or marker is available for the diagnosis or prognosis of CFS. This study screened plasma factors to identify circulating biomarkers associated with CFS.

METHODS: Cytokines were measured in plasma from female CFS cases and female healthy controls. Multiplex technology provided profiles of 16 plasma factors including the pro -inflammatory cytokines: tumor necrosis factor alpha (TNFalpha), lymphotoxin alpha (LTalpha), interleukin (IL) – IL-Ialpha, IL-1beta, IL-6; TH1 cytokines: interferon gamma (IFNgamma), IL-12p70, IL-2, IL-15; TH2: IL-4, IL-5; TH17 cytokines, IL-17 and IL-23; anti-inflammatory cytokines IL-10, IL-13; the inflammatory mediator and neutrophil attracting chemokine IL-8 (CXCL8). Analysis by receiver operating characteristic (ROC) curve assessed the biomarker potential of each cytokine.

RESULTS: The following cytokines were elevated in CFS compared to controls: LTalpha, IL-1alpha, IL-1beta, IL-4, IL-5, IL-6 and IL-12. The following cytokines were decreased in CFS: IL-8, IL-13 and IL-15. The following cytokines were not different: TNFalpha, IFNgamma, IL-2, IL-10, IL-23 and IL-17. Applying (ROC) curve analyses, areas under the curves (AUC) for IL-5 (0. 84), LTalpha (0.77), IL-4 (0.77), IL-12 (0.76) indicated good biomarker potential. The AUC of IL-6 (0.73), IL-15 (0.73), IL-8 (0.69), IL-13 (0.68) IL-1alpha (0.62), IL-1beta (0.62) showed fair potential as biomarkers.

CONCLUSION: Cytokine abnormalities are common in CFS. In this study, 10 of 16 cytokines examined showed good to fair promise as biomarkers. However, the cytokine changes observed are likely to more indicative of immune activation and inflammation, rather than specific for CFS. As such, they are targets for herapeutic strategies. Newer techniques allow evaluation of large panels of cytokines in a cost effective fashion.

 

Source: Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009 Nov 12;7:96. doi: 10.1186/1479-5876-7-96. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779802/ (Full article)

 

Molecular study of receptor for advanced glycation endproduct gene promoter and identification of specific HLA haplotypes possibly involved in chronic fatigue syndrome

Abstract:

The receptor for advanced glycation end product (RAGE) is thought to play an important role in inflammation. Chronic fatigue syndrome (CFS) is a long-lasting fatigue that compromises at least 50% of a subject’s daily activities without other known cause. Immune dysfunction has been implicated and an association with a peculiar genetic cytokine profile, predisposing to an immunomodulatory response of inflammatory nature, was found.

The aim of this study is to analyse RAGE polymorphisms and HLA-DRB1 alleles in seventy-five Italian CFS patients and 141 controls matched for age, sex and ethnicity. These two groups underwent genomic study for RAGE 374T/A and 429C/T promoter polymorphisms; moreover, 46 patients and 186 controls were typed for HLA-DRB1 at low resolution molecular level. Of these, 31 patients and 99 controls also underwent high resolution analysis to define the HLA-DRB1*11 and DRB1*13 alleles.

The haplotypes RAGE-374T, DRB1*04; RAGE-374T, DRB1*09; RAGE-374T, DRB1*11; RAGE-374A, DRB1*13; RAGE-429T, DRB1*04 and RAGE-429C, DRB1*11 were significantly more frequent in CFS patients, whereas RAGE-429C, DRB1*07 would seem protective. A significantly lower frequency of DRB1*1104 (5.4% vs 12.9% p=0.04, OR=0.39) and a significantly higher frequency of HLA-DRB1*1301 (13.0% vs 5.1% p=0.006, OR= 2.79) were found in CFS patients. A synergic effect was observed with RAGE polymorphism.

The OR values strengthened in the following cis combinations: RAGE-374A, HLA-DRB1*1104 (OR=0.27) and RAGE-374A, HLADRB1*1301 (OR=6.23). HLA haplotypes rather than single alleles of RAGE or of DRB1 genes seem to be involved in CFS, probably including a subregion of major interest.

 

Source: Carlo-Stella N, Bozzini S, De Silvestri A, Sbarsi I, Pizzochero C, Lorusso L, Martinetti M, Cuccia M. Molecular study of receptor for advanced glycation endproduct gene promoter and identification of specific HLA haplotypes possibly involved in chronic fatigue syndrome. Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):745-54. https://www.ncbi.nlm.nih.gov/pubmed/19822091

 

Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms

Abstract:

PURPOSE OF REVIEW: The aim of this paper is to review recent findings on inflammatory and oxidative and nitrosative stress (IO&NS) pathways in chronic fatigue and somatization disorder.

RECENT FINDINGS: Activation of IO&NS pathways is the key phenomenon underpinning chronic fatigue syndrome (CFS): intracellular inflammation, with an increased production of nuclear factor kappa beta (NFkappabeta), cyclo-oxygenase-2 (COX-2) and inducible NO synthase (iNOS); and damage caused by O&NS to membrane fatty acids and functional proteins. These IO&NS pathways are induced by a number of trigger factors, for example psychological stress, strenuous exercise, viral infections and an increased translocation of LPS from gram-bacteria (leaky gut). The ‘psychosomatic’ symptoms experienced by CFS patients are caused by intracellular inflammation (aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection); damage caused by O&NS (aches and pain, muscular tension and fatigue); and gut-derived inflammation (complaints of irritable bowel). Inflammatory pathways (monocytic activation) are also detected in somatizing disorder.

SUMMARY: ‘Functional’ symptoms, as occurring in CFS and somatization, have a genuine organic cause, that is activation of peripheral and central IO&NS pathways and gut-derived inflammation. The development of new drugs, aimed at treating those disorders, should target these IO&NS pathways.

 

Source: Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009 Jan;22(1):75-83. https://www.ncbi.nlm.nih.gov/pubmed/19127706

 

Association of peripheral inflammatory markers with chronic fatigue in a population-based sample

Abstract:

Alterations in the innate immune response may contribute to the pathogenesis of chronic fatigue syndrome (CFS). However, studies have been limited by small sample sizes, use of patients from tertiary care settings, inappropriate selection of controls, and failure to control for confounding demographic, medical and behavioral factors independently associated with immune activity. It is also not known whether specific symptoms account for observed associations between CFS and the innate immune response.

To address these limitations, the current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with CFS (n=102) and in subjects with unwellness symptoms that did not meet diagnostic criteria for CFS (defined as “insufficient fatigue” [ISF]) (n=240) when compared to subjects who were well (n=115). Log transformed WBC was increased in ISF and was increased at a trend level in CFS. The combined inflammation factor was increased in both CFS and ISF. Subjects with CFS and ISF did not differ on any of the inflammation measures.

In the entire subject population, the physical component summary score (PCS), but not the mental component summary score (MCS), from the Medical Outcomes Study Short Form-36 (SF-36) was negatively associated with each of the inflammation measures. Depressive symptoms were also associated with increased log hs-CRP. After adjustment for age, sex, race, location of residence, BMI, depressive status and immune-modulating medications, subjects classified as ISF continued to demonstrate increased log hs-CRP, WBC and elevations on the inflammation factor when compared to well controls; however, associations between CFS and log hs-CRP and the inflammation factor were no longer statistically significant. After adjustment, PCS score also remained independently associated with each of the inflammation measures.

These findings support a role for innate immune activation in unexplained fatigue and unwellness, but do not suggest that immune activation is specific to CFS.

Comment in: Chronic fatigue syndrome and the immune system: “findings in search of meanings”. [Brain Behav Immun. 2009]

 

Source: Raison CL, Lin JM, Reeves WC. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 2009 Mar;23(3):327-37. doi: 10.1016/j.bbi.2008.11.005. Epub 2008 Dec 11. https://www.ncbi.nlm.nih.gov/pubmed/19111923

 

Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome

Abstract:

Complement activation resulting in significant increases of C4a split product may be a marker of postexertional malaise in individuals with chronic fatigue syndrome (CFS). This study focused on identification of the transcriptional control that may contribute to the increased C4a in CFS subjects after exercise.

We used quantitative reverse-transcription polymerase chain reaction to evaluate differential expression of genes in the classical and lectin pathways in peripheral blood mononuclear cells (PBMCs). Calibrated expression values were normalized to the internal reference gene peptidylpropyl isomerase B (PPIB), the external reference gene ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (rbcL), or the geometric mean (GM) of the genes ribosomal protein, large, P0 (RPLP0) and phosphoglycerate kinase 1 (PGK1). All nine genes tested, except mannose-binding lectin 2 (MBL2), were expressed in PBMCs.

At 1 hour postexercise, C4, mannan-binding lectin serine protease 2 (MASP2) and ficolin 1 (FCN1) transcripts were detected at higher levels (> or = 2-fold) in at least 50% (4 of 8) of CFS subjects and were detected in 88% (7 of 8) CFS subjects when subjects with overexpression of either C4 or MASP2 were combined. Only an increase in the MASP2 transcript was statistically significant (PPIB, P = 0.001; GM, P = 0.047; rbcL, P = 0.045). This result may be due to the significant but transient downregulation of MASP2 in control subjects (PPIB, P = 0.023; rbcL, P = 0.027). By 6 hours postexercise, MASP2 expression was similar in both groups.

In conclusion, lectin pathway responded to exercise differentially in CFS than in control subjects. MASP2 down-regulation may act as an antiinflammatory acute-phase response in healthy subjects, whereas its elevated level may account for increased C4a and inflammation-mediated postexertional malaise in CFS subjects.

 

Source: Sorensen B, Jones JF, Vernon SD, Rajeevan MS. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Mol Med. 2009 Jan-Feb;15(1-2):34-42. doi: 10.2119/molmed.2008.00098. Epub 2008 Nov 10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/ (Full article)

 

Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood

Abstract:

BACKGROUND: Genomic profiling of peripheral blood reveals altered immunity in chronic fatigue syndrome (CFS) however interpretation remains challenging without immune demographic context. The object of this work is to identify modulation of specific immune functional components and restructuring of co-expression networks characteristic of CFS using the quantitative genomics of peripheral blood.

METHODS: Gene sets were constructed a priori for CD4+ T cells, CD8+ T cells, CD19+ B cells, CD14+ monocytes and CD16+ neutrophils from published data. A group of 111 women were classified using empiric case definition (U.S. Centers for Disease Control and Prevention) and unsupervised latent cluster analysis (LCA). Microarray profiles of peripheral blood were analyzed for expression of leukocyte-specific gene sets and characteristic changes in co-expression identified from topological evaluation of linear correlation networks.

RESULTS: Median expression for a set of 6 genes preferentially up-regulated in CD19+ B cells was significantly lower in CFS (p = 0.01) due mainly to PTPRK and TSPAN3 expression. Although no other gene set was differentially expressed at p < 0.05, patterns of co-expression in each group differed markedly. Significant co-expression of CD14+ monocyte with CD16+ neutrophil (p = 0.01) and CD19+ B cell sets (p = 0.00) characterized CFS and fatigue phenotype groups. Also in CFS was a significant negative correlation between CD8+ and both CD19+ up-regulated (p = 0.02) and NK gene sets (p = 0.08). These patterns were absent in controls.

CONCLUSION: Dissection of blood microarray profiles points to B cell dysfunction with coordinated immune activation supporting persistent inflammation and antibody-mediated NK cell modulation of T cell activity. This has clinical implications as the CD19+ genes identified could provide robust and biologically meaningful basis for the early detection and unambiguous phenotyping of CFS.

 

Source: Aspler AL, Bolshin C, Vernon SD, Broderick G. Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood. Behav Brain Funct. 2008 Sep 26;4:44. doi: 10.1186/1744-9081-4-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569951/ (Full article)

 

Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients

Abstract:

Chronic fatigue syndrome (CFS) is characterized by immune dysfunctions including chronic immune activation, inflammation, and alteration of cytokine profiles. T helper 17 (Th17) cells belong to a recently identified subset of T helper cells, with crucial regulatory function in inflammatory and autoimmune processes. Th17 cells are implicated in allergic inflammation, intestinal diseases, central nervous system inflammation, disorders that may all contribute to the pathophysiology of CFS. IL-17F is one of the pro-inflammatory cytokines secreted by Th17 cells.

We investigated the association between CFS and the frequency of rs763780, a C/T genetic polymorphism leading to His161Arg substitution in the IL-17F protein. The His161Arg variant (C allele) antagonizes the pro-inflammatory effects of the wild-type IL-17F. A significantly lower frequency of the C allele was observed in the CFS population, suggesting that the His161Arg variant may confer protection against the disease. These results suggest a role of Th17 cells in the pathogenesis of CFS.

 

Source: Metzger K, Frémont M, Roelant C, De Meirleir K. Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Biochem Biophys Res Commun. 2008 Nov 7;376(1):231-3. doi: 10.1016/j.bbrc.2008.08.135. Epub 2008 Sep 5. https://www.ncbi.nlm.nih.gov/pubmed/18774769

 

Post-radiation syndrome as a NO/ONOO- cycle, chronic fatigue syndrome-like disease

Abstract:

Post-radiation syndrome is proposed to be chronic fatigue syndrome (CFS) or a chronic fatigue syndrome-like illness, initiated by exposure to ionizing radiation. This view is supported by the nitric oxide/peroxynitrite (NO/ONOO-) cycle mechanism, the putative etiologic mechanism for CFS and related illnesses.

Ionizing radiation may initiate illness by increasing nitric oxide levels via increased activity of the transcription factor NF-kappaB and consequent increased synthesis of the inducible nitric oxide synthase. Two types of components of the nitric oxide/peroxynitrite cycle have been studied in post-radiation syndrome patients and shown to be elevated.

The symptoms and signs of post-radiation syndrome and its chronicity are similar or identical to those of chronic fatigue syndrome and can be explained as being a consequence of nitric oxide/peroxynitrite cycle etiology. While the data available to test this view are limited, it provides for the first time a comprehensive explanation for post-radiation syndrome.

 

Source: Pall ML. Post-radiation syndrome as a NO/ONOO- cycle, chronic fatigue syndrome-like disease. Med Hypotheses. 2008 Oct;71(4):537-41. doi: 10.1016/j.mehy.2008.05.023. Epub 2008 Jul 29. https://www.ncbi.nlm.nih.gov/pubmed/18667279

 

Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins

Abstract:

This study examined 328 CFS sera in a study with 17 CCFP, 8 Gulf War Veterans (GWV), 24 Prostate Cancer (PC), and 52 normal sera in the modified Membrane Immunobead Assay (MIA) procedure for CTX. Three hundred and twenty-eight CFS patients’ sera were examined by the modified MIA with purified MAb-CTX and 91.2% gave a titre > or =1:40. 76% of the 17 CCFP sera samples and 100% of the 8 GWV sera samples also had a titre > or =1:40. 92.3% of 52 normal sera showed titres of 1:20 or less, while 4 gave titres of > or =1:40.

In addition, 41 sera were examined for Anti-Cardiolipin (aCL) by a commercial ELISA procedure with 87.8% demonstrating IgM, IgM+IgA, or IgM+IgG aCL antibodies. These results showed mostly the IgM aCL antibody alone in the sera samples. In addition, 41 serum samples were examined for aCL, with 37 showing positive for aCL, representing 90.2% positive for the three disease categories examined: CFS, CCFP and GWV. Examination for antiMitochondrial-M2 autoantibody (aM-M2) in 28 patients (CFS (18), CCFP (5), and GWV (5)) was negative for aM-M2.

Inhibition analysis with antigens, CTX, CFS “Acute Phase Lipids”, commercial Cardiolipin (CL) and 1,2-Dipalmitoyl-sn-Glycero-3-[Phospho-L-Serine] (PS) and antibodies, MAb-CTX and aCL from patients’ serum show that the phospholipids in CL and CTX are antigenically indistinguishable with antibodies MAb-CTX and CFS-aCL. Preliminary chemical analyses have shown the lipids to be phospholipids associated with CL of the mitochondria.

We designate this “Acute Phase Lipid” comparable to “Acute Phase Proteins” (C-reactive protein (CRP) and Serum Amyloid A (SAA)) in inflammatory conditions.

(Copyright ) 2008 Wiley-Liss, Inc.

 

Source: Hokama Y, Empey-Campora C, Hara C, Higa N, Siu N, Lau R, Kuribayashi T, Yabusaki K. Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins. J Clin Lab Anal. 2008;22(2):99-105. doi: 10.1002/jcla.20217. https://www.ncbi.nlm.nih.gov/pubmed/18348309