ME and CFS Medical Abnormalities – Additional Immune Issues

 

Following is a list of articles about additional immune abnormalities in ME and CFS.

Links to the more than 1,000 peer-reviewed journal articles are listed on the ME and CFS Medical Abnormalities page of this website.

 

Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C; European Network on ME/CFS(EUROMENE). Myalgic Encephalomyelitis/Chronic Fatigue  – Evidence for an autoimmune disease. Autoimmun Rev. 2018 Jun;17(6):601-609. PMID: 29635081

In this review, the authors discuss current autoimmune aspects for ME/CFS.

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Singh S, Stafford P, Schlauch KA, Tillett RR, Gollery M, Johnston SA, Khaiboullina SF, De Meirleir KL, Rawat S, Mijatovic T, Subramanian K, Palotás A, Lombardi VC. Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity. Mol Neurobiol. 2018 Jan;55(1):633-641. PMID: 27981498

In contrast to identifying biomarkers that are directly involved in the pathological process, an immunosignature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process. Although these proteins might be unknown, it is possible to detect antibodies that react to these proteins using random peptide arrays. Our analysis revealed a subset of 25 peptides that distinguished ME cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self-antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens.

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Yamamura T, Ono H, Sato W. Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome(ME/CFS). Brain Nerve. 2018 Jan;70(1):35-40. PMID: 29348373

The researchers hypothesize that immune abnormalities, such as enhanced autoimmune responses, may play an essential role in the neuroinflammatory pathogenesis of ME/CFS.

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Balinas C, Nguyen T, Johnston S, Smith P, Staines D, Marshall-Gradisnik S. Investigation of mast cell toll-like receptor 3 in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Systemic Mastocytosis participants using the novel application of autoMACS magnetic separation and flow cytometry. Asian Pac J Allergy Immunol. 2017 Dec 10. PMID: 29223146

Mast Cells (MC) uniquely mediate type 1 hypersensitivities and resolve viral infections via toll-like receptor 3 (TLR3). This pilot investigation provides a novel methodology to characterise mast cell progenitors (MCPs) in a rapid, inexpensive and less invasive fashion. The researchers reported a significant decrease in HLA-DR+/CD154- expression between CFS/ME and systemic mastocytosis (SM) participants, and an observed increase in HLA-DR-/CD154+ expression post Poly I:C stimulation in CFS/ME participants. Peripheral MCPs may be present in CFS/ME pathophysiology, however further investigation is required to determine their immunological role.

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Theorell J, Bileviciute-Ljungar I, Tesi B, Schlums H, Johnsgaard MS, Asadi-Azarbaijani B, Bolle Strand E, Bryceson YT. Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front Immunol. 2017 Jun 26;8:723. PMID: 28694809

Forty-eight patients from two independent cohorts fulfilling the Canada 2003 criteria for ME/CFS were evaluated with respect to cytotoxic lymphocyte phenotype and function. In summary, employing sensitive assays and analyses for quantification of cytotoxic lymphocyte differentiation and function, cytotoxicity lymphocyte aberrances were not found among ME/CFS patients. These assessments of cytotoxic lymphocytes therefore do not provide useful biomarkers for the diagnosis of ME/CFS.

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Nguyen CB, Alsøe L, Lindvall JM, Sulheim D, Fagermoen E, Winger A, Kaarbø M, Nilsen H, Wyller VB. Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival. J Transl Med. 2017 May 11;15(1):102. PMID: 28494812

This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group. The researchers found that adolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise.

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Bouquet J, Gardy JL, Brown S, Pfeil J, Miller RR, Morshed M, Avina-Zubieta A, Shojania K, McCabe M, Parker S, Uyaguari M, Federman S, Tang P, Steiner T, Otterstater M, Holt R, Moore R, Chiu CY, Patrick DM; Complex Chronic Disease Study Group. RNA-Seq Analysis of Gene Expression, Viral Pathogen, and B-Cell/T-Cell Receptor Signatures in Complex Chronic Disease. Clin Infect Dis. 2017 Feb 15;64(4):476-481. PMID: 28172519

The authors performed blinded RNA-seq analysis of whole blood collected from 25 adults diagnosed with CFS and 13 alternatively diagnosed chronic Lyme syndrome (ADCLS) patients, comparing these cases to 25 matched controls and 11 patients with well-controlled systemic lupus erythematosus (SLE). Samples were collected at patient enrollment and not during acute symptom flares. RNA-seq data were used to study host gene expression, B-cell/T-cell receptor profiles (BCR/TCR), and potential viral infections. No differentially expressed genes (DEGs) were found to be significant when CFS or ADCLS cases were compared to controls. The authors state that their observations do not support a theory of transcriptionally mediated immune cell dysregulation in CFS and ADCLS, at least outside of periods of acute symptom flares.

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Nguyen T, Johnston S, Chacko A, Gibson D, Cepon J, Smith P, Staines D, Marshall-Gradisnik S. Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients. Asian Pac J Allergy Immunol. 2017 Jun;35(2):75-81. PMID: 27362406:

This preliminary study investigates mast cell phenotypes from PBMCs in healthy controls. The authors report significant increase of naïve mast cells in moderate and severe CFS/ME patients compared with healthy controls. Moreover, a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cells in severe CFS/ME patients.

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Brenu EW, Broadley S, Nguyen T, Johnston S, Ramos S, Staines D, Marshall-Gradisnik S. A Preliminary Comparative Assessment of the Role of CD8+ T Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis. J Immunol Res. 2016;2016:9064529. PMID: 26881265

The study suggests significant deficits in the expression of receptors and adhesion molecules on subsets of CD8+ T cells in both MS and CFS/ME patients.

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Keijmel SP, Raijmakers RP, Bleeker-Rovers CP, van der Meer JW, Netea MG, Schoffelen T, van Deuren M.Altered interferon-γ response in patients with Q-fever fatigue syndrome. J Infect. 2016 Apr;72(4):478-85. PMID: 26820634

Researchers explored the specific IFNγ production and IFNγ/IL-2 ratio in Q-fever fatigue syndrome (similar to CFS) patients. Results point to an altered cell-mediated immunity in QFS, and suggest a different immune response than in chronic Q-fever.

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Maes M, Bosmans E, Kubera M. Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers. Neuro Endocrinol Lett. 2015;36(5):439-46. PMID: 26707044

The study results support that a) increased CD38 and HLA-DR expression on CD8+ T cells are biomarkers of ME/CFS; b) increased CD38 antigen expression may contribute to suppression of the CD4+/CD8+ ratio and CD19+ expression; c) there are different immune subgroups of ME/CFS patients, e.g. increased CD8+ activation marker expression versus inflammation or O&NS processes; and d) viral infections or reactivation may play a role in a some ME/CFS patients.

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Mensah F, Bansal A, Berkovitz S, Sharma A, Reddy V, Leandro MJ, Cambridge G. Extended B-cell phenotype in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A cross-sectional study. Clin Exp Immunol. 2015 Dec 8. PMID: 26646713

The authors identified possible changes in B-cell phenotype in patients with ME/CFS. These may reflect altered B-cell function and if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab-therapy.

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Guenther S, Loebel M, Mooslechner AA, Knops M, Hanitsch LG, Grabowski P, Wittke K, Meisel C, Unterwalder N, Volk HD, Scheibenbogen C. Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome. Hum Immunol. 2015 Oct;76(10):729-35. PMID: 26429318

The authors retrospectively analysed 300 patients with CFS for immunoglobulin and mannose binding lectin (MBL) levels, and B-cell subset frequencies. 25% of the CFS patients had decreased serum levels of at least one antibody class or subclass with IgG3 and IgG4 subclass deficiencies as most common phenotypes. They found elevated immunoglobulin levels with an excess of IgM and IgG2 in particular in another 25% of patients. Deficiency of MBL was found in 15% of the CFS patients in contrast to 6% in a historical control group. Thus, humoral immune defects are frequent in CFS patients and are associated with infections of the respiratory tract.

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Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Fluge Ø, Mella O,Scheibenbogen C. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. 2016 Feb;52:32-9. PMID: 26399744

Serum samples from a patient cohort from Berlin (n=268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and β adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108). Antibodies against β2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Patients with high β2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies.

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Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, Staines D, Marshall-Gradisnik S. Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. J Transl Med. 2015 Sep 14;13:299. PMID: 26370228

Severe CFS/ME patients differed from controls and moderate CFS/ME patients over time and expressed significant alterations in iNKT cell phenotypes, CD8(+)T cell markers, NK cell receptors and γδT cells at 6 months.

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Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, Peterson DL, Gottschalk CG, Schultz AF, Che X, Eddy ML, Komaroff AL, Lipkin WI. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015 Feb;1(1). pii: e1400121. PMID: 26079000

The authors leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration, and other clinical variables. Early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks.

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Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Wong N, Ramos S, Staines D, Marshall-Gradisnik S. Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). BMC Immunol. 2015 Jun 2;16:35. PMID: 26032326

CFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4(+)T and CD8(+)T cells. Moderate CFS/ME patients had increased CD8(+) CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5(+) on CD4(+)T cells and BTLA4(+) on CD4(+)T central memory cells. Moderate CFS/ME patients also had reduced CD8(+)T central memory LFA-1, total CD8(+)T KLRG1, naïve CD4(+)T KLRG1 and CD56(dim)CD16(-) NK cell CD2(+) and CD18(+)CD2(+). Severe CFS/ME patients had increased CD18(+)CD11c(-) in the CD56(dim)CD16(-) NK cell phenotype and reduced NKp46 in CD56(bright)CD16(dim) NK cells.

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Gambuzza ME, Salmeri FM, Soraci L, Soraci G, Sofo V, Marino S, Bramanti P. The Role of Toll-Like Receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A New Promising Therapeutic Approach? CNS Neurol Disord Drug Targets. 2015;14(7):903-14. PMID: 25808894

The paper examines the role of TLR-mediated innate immunity in CFS/ME with evaluation of the current literature, also discussing about innovative therapeutic approaches represented by immunomodulators TLR-targeting.

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Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J. Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. Exerc Immunol Rev. 2014;20:94-116. PMID: 24974723

Compared to the normal response of the immune system to exercise as seen in healthy subjects, patients with CFS have a more pronounced response in the complement system (i.e. C4a split product levels), oxidative stress system (i.e. enhanced oxidative stress combined with a delayed and reduced anti-oxidant response), and an alteration in the immune cells’ gene expression profile (increases in post-exercise interleukin-10 and toll-like receptor 4 gene expression), but not in circulating pro- or anti-inflammatory cytokines.

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Loebel M, Strohschein K, Giannini C, Koelsch U, Bauer S, Doebis C, Thomas S, Unterwalder N, von Baehr V, Reinke P, Knops M, Hanitsch LG, Meisel C, Volk HD, Scheibenbogen C. Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PLoS One. 2014 Jan 15;9(1):e85387. PMID: 24454857

Taken together, the findings of this study give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.

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Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, Johnston S, Ramos SB, Staines DR, Marshall-Gradisnik SM. Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis. Int Immunol. 2014 Apr;26(4):233-42. PMID: 24343819

Thirty patients with CFS/ME and 25 non-fatigued controls were recruited for this study. Significant changes were observed in B-cell subsets, Tregs, CD4(+)CD73(+)CD39(+) T cells, cytotoxic activity, granzyme B, neutrophil antigens, TNF-α and IFN-γ in the CFS/ME patients in comparison with the non-fatigued controls. Alterations in B cells, Tregs, NK cells and neutrophils suggest significant impairments in immune regulation in CFS/ME.

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Maes M, Ringel K, Kubera M, Anderson G, Morris G, Galecki P, Geffard M. In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. J Affect Disord. 2013 Sep 5;150(2):223-30. PMID: 23664637

The incidence of positive autoimmune activity against serotonin was significantly higher in ME/CFS than in patients with chronic fatigue or controls. ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.

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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. PMID:23514202

CFS patients showed increased levels of T regulatory cells (CD25+/FOXP3+) CD4 T cells, and lower proliferative responses. Moreover, CD8 T cells from the CFS group showed significantly lower activation and frequency of effector memory cells. NK cells from CFS individuals displayed higher expression of NKp46 and CD69 but lower expression of CD25 in all NK subsets defined.

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Maes M, Ringel K, Kubera M, Anderson G, Morris G, Galecki P, Geffard M. In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. J Affect Disord. 2013 May 9. PMID: 23664637

The study’s results show that, in ME/CFS, increased serotonin (5-HT) autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions.

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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. PMID: 23480187

Compared to healthy controls, CFS patients had greater numbers of naive B cells as a percentage of lymphocytes, greater numbers of naive B cells as a percentage of B cells, greater numbers of transitional B cells and reduced numbers of plasmablasts. The authors speculate whether this may suggest a subtle tendency to autoimmunity.

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Brenu EW, Ashton KJ, van Driel M, Staines DR, Peterson D, Atkinson GM, Marshall-Gradisnik SM. Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Affect Disord. 2012 Dec 10;141(2-3):261-9. PMID: 22572093

There was a significant reduction in the expression levels of microRNA(miR)-21, in both the natural killer and CD8(+)T cells in the CFS/ME sufferers. Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 was significantly decreased in NK cells of CFS/ME patients in comparison to the non-fatigued controls.

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Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun. 2011 Jul 2. PMID: 21756995

CFS is a heterogeneous disorder with a common set of symptoms. Slightly increased parameters of inflammation and pro-inflammatory cytokines such as interleukin (IL) 1, IL6 and tumour necrosis factor (TNF) α are likely present. Additionally, impaired natural killer cell function appears evident. Alterations in T cell numbers have been described by some and not others. There is some evidence of viral persistence and inadequate containment of viral replication. The ability of certain herpes viruses to impair the development of T cell memory may explain this viral persistence and the continuation of symptoms.

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Brenu EW, Staines DR, Baskurt OK, Ashton KJ, Ramos SB, Christy RM, Marshall-Gradisnik SM. Immune and hemorheological changes in chronic fatigue syndrome. J Transl Med. 2010 Jan 11;8:1. PMID: 20064266

CFS patients (n = 10) had significant decreases in neutrophil respiratory burst, NK cytotoxic activity and CD56(bright)CD16(-) NK phenotypes in comparison to healthy controls (n = 10). Hemorheological characteristic, aggregation, deformability, fibrinogen, lymphocyte numbers and CD56(dim)CD16(+) NK cells were similar between the two groups.

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Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev. 2009 Feb;8(4):287-91. PMID: 18801465

Immunological problems in CFS include an alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies, and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported, and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed.

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Torres-Harding S, Sorenson M, Jason LA, Maher K, Fletcher MA. Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS). Bull IACFS ME. 2008 Fall;16(3):19-33. PMID: 21234277

This investigation measured the percentage of Th1-like and Th2-like memory cells using cell surface flow cytometry in 114 individuals with CFS. Results indicated that individuals who exhibited a more extreme shift towards a Th2 immune response also exhibited poorer sleep and high levels of basal salivary cortisol. The implications of these findings are discussed.

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Meeus M, Nijs J, McGregor N, Meeusen R, De Schutter G, Truijen S, Frémont M, Van Hoof E, De Meirleir K. Unravelling intracellular immune dysfunctions in chronic fatigue syndrome: interactions between protein kinase R activity, RNase L cleavage and elastase activity, and their clinical relevance. In Vivo. 2008 Jan-Feb;22(1):115-21. PMID: 18396793

CFS patients have a variety of immunological abnormalities, including Rnase L-cleavage, protein kinase R and elastase activity.

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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. PMID: 18822143

CFS patients have B cell dysfunction with coordinated immune activation supporting persistent inflammation and antibody-mediated NK cell modulation of T cell activity. The CD19+ genes have potential as a biomarker.

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Mihaylova I, DeRuyter M, Rummens JL, Bosmans E, Maes M. Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. Neuro Endocrinol Lett. 2007 Aug;28(4):477-83. PMID: 17693977

The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects, indicating immune abnormalities.

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Maher KJ, Klimas NG, Fletcher MA. Chronic fatigue syndrome is associated with diminished intracellular perforin. Clin Exp Immunol. 2005 Dec;142(3):505-11. PMID: 16297163

CFS patients had a significant reduction in the NK cell associated perforin levels and a reduced perforin level within the cytotoxic T cells.

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Kennedy G, Spence V, Underwood C, Belch JJ. Increased neutrophil apoptosis in chronic fatigue syndrome. J Clin Pathol. 2004 Aug;57(8):891-3. PMID: 15280416

CFS patients had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V binding, and increased expression of the death receptor, tumour necrosis factor receptor-I, on their neutrophils than did the 34 healthy controls. Patients with CFS also had raised concentrations of active TGFbeta1.

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Sabath DE, Barcy S, Koelle DM, Zeh J, Ashton S, Buchwald D. Cellular immunity in monozygotic twins discordant for chronic fatigue syndrome. J Infect Dis. 2002 Mar 15;185(6):828-32. PMID: 11920301

The objective of this study was to assess the nature and extent of abnormalities in lymphocyte cell surface markers and NK cell activity in patients with CFS while controlling for genetic factors. In a twin study, significantly greater variability was noted in twins discordant for CFS than in the concordant healthy twins for 20 of 48 variables examined.

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Patarca R. Cytokines and chronic fatigue syndrome. Ann N Y Acad Sci. 2001 Mar;933:185-200. PMID:12000020

Chronic fatigue syndrome (CFS) patients show evidence of immune activation, as demonstrated by increased numbers of activated T lymphocytes, including cytotoxic T cells, as well as elevated levels of circulating cytokines. Nevertheless, immune cell function of CFS patients is poor, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3. Immune dysfunction in CFS, with predominance of so-called T-helper type 2 and proinflammatory cytokines, can be episodic and associated with either cause or effect of the physiological and psychological function derangement and/or activation of latent viruses or other pathogens.

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Visser J, Blauw B, Hinloopen B, Brommer E, de Kloet ER, Kluft C, Nagelkerken L. CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone. J Infect Dis. 1998 Feb;177(2):451-4. PMID: 9466535

CD4 T cells from CFS patients produced less interferon-gamma than did cells from controls. With CD4 T cells from CFS patients (compared with cells from controls), a 10- to 20-fold lower DEX concentration was needed to achieve 50% inhibition of interleukin-4 production and proliferation, indicating an increased sensitivity to DEX in CFS patients. A differential sensitivity of cytokines or CD4 T cell subsets to glucocorticoids might explain an altered immunologic function in CFS patients.

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Vojdani A, Ghoneum M, Choppa PC, Magtoto L, Lapp CW. Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. J Intern Med. 1997 Dec;242(6):465-78. PMID: 9437407

Increased apoptotic cell population in peripheral blood lymphocytes was observed in CFS individuals. This was accompanied by an abnormal cell arrest in the S phase and the G2/M boundary of the cell cycle and by enhanced PKR mRNA and protein levels as compared to healthy controls. Protein kinase RNA-mediated apoptosis in CFS individuals may contribute to the pathogenesis and the fatigue symptomatology associated with CFS.

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Mawle AC, Nisenbaum R, Dobbins JG, Gary HE Jr, Stewart JA, Reyes M, Steele L, Schmid DS, Reeves WC. Immune responses associated with chronic fatigue syndrome: a case-control study. J Infect Dis. 1997 Jan;175(1):136-41. PMID: 8985207

Immune responses of CFS patients compared to normal people were more pronounced when they were grouped by type of disease onset (gradual or sudden) or by how they were feeling on the day of the test.

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Tirelli U, Marotta G, Improta S, Pinto A. Immunological abnormalities in patients with chronic fatigue syndrome. Scand J Immunol. 1994 Dec;40(6):601-8. PMID: 7997849

The authors examined blood of CFS patients. Whilst no significant differences were found in the absolute numbers of circulating total T cells (CD3+) and of total helper/inducer (CD4+) or suppressor/cytotoxic (CD8+) T cells, an evident reduction in CD3-/CD16+ and CD57+/CD56+ NK lymphocytes along with an expansion of the CD8+/CD56+ and CD16-/CD56+ NK subsets, were found in the CFS group. In addition, CD56+ NK cells from CFS subjects were found to express an increased amount of cell adhesion molecules (CD11b, CD11c, CD54) and activation antigens (CD38). Both the percentage and absolute numbers of CD4+ T cells bearing the CD45RA antigen appeared significantly reduced in CFS patients, and CD4+ T lymphocytes from CFS subjects displayed an increased expression of the intercellular adhesion molecule-1 (ICAM-1/CD54). Finally, the total numbers of circulating (CD19+) B lymphocytes, were significantly higher in CFS cases than in controls, and in 11 out of 30 CFS patients the increase in circulating B cells was sustained by the expansion of the CD5+/CD19+ subset of B lymphocytes.

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Levy JA. Viral studies of chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S117-20. PMID: 8148437

Immunologic studies have demonstrated activated CD8+ cells and reduced function of natural killer cells suggesting a host response to an infection that has led to persistent immune disorders. Some of the symptoms of CFS may be due to cytokines produced by this hyperactive immune response to a virus that is still present in the host or that has been eliminate but leaves abnormal immunologic sequelae.

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Barker E, Fujimura SF, Fadem MB, Landay AL, Levy JA. Immunologic abnormalities associated with chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S136-41. PMID: 8148441

Compared with those of healthy individuals, CFS patients’ CD8+ T cells expressed reduced levels of CD11b and expressed the activation markers CD38 and HLA-DR at elevated levels. In many of the individuals in whom expression of CD11b was reduced the expression of CD28 was increased. These findings indicate expansion of a population of activated CD8+ cytotoxic T lymphocytes. A marked decrease in NK cell activity was found in almost all patients with CFS.

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Straus SE, Fritz S, Dale JK, Gould B, Strober W. Lymphocyte phenotype and function in the chronic fatigue syndrome. J Clin Immunol. 1993 Jan;13(1):30-40. PMID: 8095270

Compared to controls, in CFS patients the percentage of CD4 T cells and CD4,CD45RA, or naive T cells, was reduced. The CD4,CD45RO, or memory T-cell, subset was numerically normal but expressed increased levels of adhesion markers (CD29, CD54, and CD58). CFS patient lymphocytes showed reduced proliferative responses to phytohemagglutinin, concanavalin A, and staphylococcal enterotoxin B.

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Lloyd A, Hickie I, Hickie C, Dwyer J, Wakefield D. Cell-mediated immunity in patients with chronic fatigue syndrome, healthy control subjects and patients with major depression. Clin Exp Immunol. 1992 Jan;87(1):76-9. PMID: 1733640

Patients with CFS demonstrated impaired lymphocyte responses to phytohaemagglutinin (PHA) stimulation, and reduced or absent delayed-type hypersensitivity (DTH) skin responses.

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Landay AL, Jessop C, Lennette ET, Levy JA. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet. 1991 Sep 21;338(8769):707-12. PMID: 1679864

CAreduced CD8 suppressor cell population and increased activation markers (CD38, HLA-DR) on CD8 cells were found in CFS sufferers.

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Gupta S, Vayuvegula B. A comprehensive immunological analysis in chronic fatigue syndrome. Scand J Immunol. 1991 Mar;33(3):319-27. PMID: 1849315

Natural killer cells as defined by CD16, CD56 and CD57 antigens were significantly reduced in a group of CFS patients. A significant increase in the proportions of CD4+ ICAM 1+ T cells was observed in CFS. Monocytes from CFS displayed increased density (as determined by mean fluorescence channel numbers) of intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function associated antigen 1 (LFA-1), but showed decreased enhancing response to recombinant interferon-gamma in vitro. The lymphocyte DNA synthesis in response to phytohaemoglobulin (PHA), Concanavalin A (Con A) and pokeweed mitogen (PWM) was normal but the response to soluble antigens was significantly reduced. In vivo specific antibody response to pneumococcus vaccine was depressed in CFS. Forty percent of patients showed titres of anti-human herpes virus 6 (anti-HHV-6) antibody higher than that in the controls (greater than or equal to 1/80).

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Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol. 1990 Jun;28(6):1403-10. PMID: 2166084

CFS patients immunological abnormalities are profiled. The most consistent was low natural killer (NK) cell cytotoxicity. The number of NK cells, as defined by reactivity with monoclonal antibody NKH.1 (CD56), was elevated, but the killing of K562 tumor cells per CD56 cell was significantly diminished. Lymphoproliferative responses after stimulation with phytohemagglutinin and pokeweed mitogen were decreased in most patients, as was the production of gamma interferon following mitogen stimulation. Lymphocyte phenotypic marker analysis of peripheral blood lymphocytes showed that there were significant differences between patients with CFS and controls. There was an increase in the percentage of suppressor-cytotoxic T lymphocytes, CD8, and a proportionally larger increase in the number of CD8 cells expressing the class II activation marker. Most patients had an elevated number of CD2 cells which expressed the activation marker CDw26. The numbers of CD4 cells and the helper subset of CD4+CD29+ cells in patients with CFS were not different from those in controls. There was, however, a significant decrease in the suppressor inducer subset of CD4+ CD45RA+ cells. The number of B cells, CD20 and CD21, were elevated, as were the numbers of a subset of B cells which coexpressed CD20 and CD5.

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Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Immunological abnormalities in the chronic fatigue syndrome. Med J Aust. 1989 Aug 7;151(3):122-4. PMID: 2787888

In patients with CFS, a significant reduction was found in the absolute number of peripheral blood lymphocytes in the total T-cell (CD2), the helper/inducer T-cell (CD4) and the suppressor/cytotoxic T-cell (CD8) subsets. A significant reduction also was found in T-cell function. Reduced immunoglobulin (Ig) levels were common (56% of patients), with the levels of serum IgG3- and IgG1-subclasses particularly affected.

 

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