Immunological Studies

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Extended List of Studies (by year)

2019

Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study. [Full Text] [PDF]
Pedersen M, Asprusten TT, Godang K, Leegaard TM, Osnes LT, Skovlund E, Tjade T, Øie MG, Wyller VBB. Brain Behav Immun. 2019

2015-2018

Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. [Full Text] [PDF]
Cabanas H, Muraki K, Eaton N, Balinas C, Staines D, Marshall-Gradisnik S. Mol Med. 2018

Circulating extracellular vesicles as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis: an exploratory pilot study. [Full Text] [PDF]
Castro-Marrero J, Serrano-Pertierra E, Oliveira-Rodríguez M, Zaragozá MC, Martínez-Martínez A, Blanco-López MDC, Alegre J. J Extracell Vesicles. 2018

Low omega-3 index and polyunsaturated fatty acid status in patients with chronic fatigue syndrome/myalgic encephalomyelitis. [Full Text] [PDF]
Castro-Marrero J, Zaragozá MC, Domingo JC, Martinez-Martinez A, Alegre J, von Schacky C. Prostaglandins Leukot Essent Fatty Acids. 2018

Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis.
[Full Text] [PDF]
De Meirleir KL, Mijatovic T, Subramanian K, Schlauch KA, Lombardi VC. J Transl Med. 2018

Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome. [Full Text] [PDF]
de Vega WC, Erdman L, Vernon SD, Goldenberg A, McGowan PO. Epigenomics. 2018

Rituximab impedes natural killer cell function in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients: A pilot in vitro investigation. [Full Text] [PDF]
Eaton N, Cabanas H, Balinas C, Klein A, Staines D, Marshall-Gradisnik S. BMC Pharmacol Toxicol. 2018

Immunosignature Analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). [Full Text] [PDF]
Günther OP, Gardy JL, Stafford P, Fluge Ø, Mella O, Tang P, Miller RR, Parker SM, Johnston SA, Patrick DM. Mol Neurobiol. 2018

Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome. [Full Text] [PDF]
Mandarano AH, Giloteaux L, Keller BA, Levine SM, Hanson MR. PeerJ. 2018

CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. [Full Text] [PDF]
Mensah FFK, Armstrong CW, Reddy V, Bansal AS, Berkovitz S, Leandro MJ, Cambridge G. Front Immunol. 2018

Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome. [PDF]
Nguyen CB, Kumar S, Zucknick M, Kristensen VN, Gjerstad J, Nilsen H, Wyller VB. Brain Behav Immun. 2018

Association of chronic fatigue syndrome with premature telomere attrition. [Full Text] [PDF]
Rajeevan MS, Murray J, Oakley L, Lin JS, Unger ER. J Transl Med. 2018

Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome. [Full Text] [PDF]
Rekeland IG, Fluge Ø, Alme K, Risa K, Sørland K, Mella O, de Vries A, Schjøtt J. Clin Ther. 2018

Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). [Full Text] [PDF]
Rivas JL, Palencia T, Fernández G, García M. Front Immunol. 2018

Pitfalls in cytokine measurements - Plasma TGF-β1 in chronic fatigue syndrome. [Full Text] [PDF]
Roerink ME, van der Schaaf ME, Hawinkels LJAC, Raijmakers RPH, Knoop H, Joosten LAB, van der Meer JWM. Neth J Med. 2018

[HIGHLIGHT] Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome.
Saha, A.K, Schmidt BR, Wilhelmy J, Nguyen V, Do J, Suja VC, Nemat-Gorgani M, Ramasubramanian AK, Davis RW. Blood Journal. 2018
"Our data demonstrates that the significant decrease in deformability of RBCs from ME/CFS patients may have origins in oxidative stress, and suggests that altered microvascular perfusion can be a possible cause for ME/CFS symptoms. Our data also suggests that RBC deformability may serve as a potential biomarker for ME/CFS, albeit further studies are necessary for non-specific classification of the disease."

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME.
[Full Text] [PDF]
Scheibenbogen C, Loebel M, Freitag H, Krueger A, Bauer S, Antelmann M, Doehner W, Scherbakov N, Heidecke H, Reinke P, Volk HD, Grabowski P. PLoS One. 2018

No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls. [Full Text] [PDF]
Schurink-Van't Klooster TM, Kemmeren JM, van der Maas NAT, van de Putte EM, Ter Wolbeek M, Nijhof SL, Vanrolleghem AM, van Vliet JA, Sturkenboom M, de Melker HE. Vaccine. 2018

[HIGHLIGHT] Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease. [PDF]
Sotzny F, et al. Autoimmun Rev. 2018.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Extra notes:

ME/CFS disease onset is often reported to be triggered by infections and the link between infections and autoimmune diseases is well established [2]. Although the exact pathogenesis is still unknown, the most plausible hypothesis is that dysregulation of immune system, autonomic nervous system and metabolic disturbances contribute to this complex syndrome, in which severe fatigue and cognitive impairment are a central feature (Fig. 1). Stressful life events are frequently associated with disease onset concomitantly with a history of frequent recurrent infections, immune deficiency and autoimmunity [1,3]. There are numerous studies showing immunological, genetic and metabolic alterations consistent with an autoimmune mechanism. Further, the identification of autoantibodies in ME/CFS patients and the clinical benefit associated with B cell depleting therapy provide strong evidence that, at least in a subset of ME/CFS patients, the disease has an autoimmune etiology.

DIAGRAM

Dysregulation of immune system, autonomic nervous system (ANS) and metabolic disturbances contribute to this complex syndrome, in which severe fatigue and cognitive impairment are core features. In most patients, disease onset is triggered by infection with stress, immune deficiency and autoimmunity as known risk factors.

VERY IMPORTANT

2.6. Energy metabolism and autoimmunity
Immunometabolism represents the interface between immunology and metabolism and is an exciting emerging field of research in autoimmunity [[106], [107], [108]]. The metabolic requirements of immune cells depend on their state of resting or activation and differentiation. Their activation results in a metabolic switch to aerobic glycolysis in order to provide enough energy and bio-precursors to meet the requirements for supporting rapid cell proliferation and immune functions. A growing body of evidence suggests that energy metabolism is crucial for the maintenance of chronic inflammation, not only in terms of energy supply but also in the control of the immune response through metabolic signals [106,107]. It has been suggested that disturbances in this intricate metabolic-immune cross-talk may be closely linked with and contribute to autoimmunity, although the precise pathomechanisms involved still remain to be elucidated [107,108]. It is also striking that several glycolytic enzymes act as autoantigens in rheumatic inflammatory disorders [109], although their role in ME/CFS remains unclear.

The profound and debilitating fatigue experienced by ME/CFS individuals led to the hypothesis that energy metabolism may be dysregulated. Defects in mitochondrial function in ME/CFS were shown in various studies from our group and others [[110], [111], [112], [113]]. Metabolic profile had revealed disturbances related to energy, amino acids, nucleotides, nitrogen metabolism and oxidative stress in ME/CFS [[114], [115], [116], [117], [118], [119]]. A metabolic shift toward aerobic glycolysis resulting in insufficient tricarboxylic acid (TCA) cycle and inadequate ATP production was reported recently, although the underlying basis has yet to be established [116,119]. Interestingly, the 2016 Fluge et al. study points to a secondary metabolic change driven by a serum factor in ME/CFS patients [116].
As dysfunctional metabolic pathways can directly influence and exacerbate defective immune responses, establishing the bioenergetic metabolism status of the different subsets of immune cells in ME/CFS has become a topic of increasing interest.

Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns. [Full Text] [PDF]
Trivedi MS, Oltra E, Sarria L, Rose N, Beljanski V, Fletcher MA, Klimas NG, Nathanson L. PLoS One. 2018

C-Reactive Protein Response in Patients With Post-Treatment Lyme Disease Symptoms Versus Those With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. [Full Text]
Uhde M, Indart A, Fallon BA, Wormser GP, Marques AR, Vernon SD, Alaedini A. Clin Infect Dis. 2018

Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function.
[Full Text] [PDF]
Wang T, Yu L, Xu C, Pan K, Mo M, Duan M, Zhang Y, Xiong H. PLoS One. 2018

[HIGHLIGHT] Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Yamamura T, et al. Brain Nerve. 2018
Recent study on the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has revealed an elevation of inflammatory and anti-inflammatory cytokines in the sera and cerebrospinal fluids of the patients and presence of autoantibodies in subgroups of ME/CFS patients. Based on these findings, we hypothesize that immune abnormalities, such as enhanced autoimmune responses, may play an essential role in the neuroinflammatory pathogenesis of ME/CFS.

The expression signature of very long non-coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome. [Full Text] [PDF]
Yang CA, Bauer S, Ho YC, Sotzny F, Chang JG, Scheibenbogen C. J Transl Med. 2018

Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome. [PDF]
Miwa K. J Cardiol. 2017

Cytokine signature associated with disease severity in chronic fatigue syndrome patients. [PDF]
Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, Chu L, Younger JW, Tato CM, Davis MM. PNAS. 2017

Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels. [PDF]
Nguyen T, et al. Clin Exp Immunol. 2017

Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. [PDF]
Theorell J, Bileviciute-Ljungar I, Tesi B, Schlums H, Johnsgaard MS, Asadi-Azarbaijani B, Strand EB, Bryceson YT. Frontiers in Immunology. 2017

ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56 dim CD16+ and CD56 bright CD16 dim/- natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. [PDF]
Huth TK, et al. J Transl Med. 2016

Altered interferon-γ response in patients with Q-fever fatigue syndrome. [PDF]
Keijmel SP, Raijmakers RP, Bleeker-Rovers CP, van der Meer JW, Netea MG, Schoffelen T, van Deuren M.
J Infect. 2016
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.

Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. [PDF]
Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Fluge Ø, Mella O, Scheibenbogen C. Brain Behav Immun. 2016

The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders. [PDF]
Morris G, Walder K, Puri BK, Berk M, Maes M. Mol Neurobiol. 2016

[HIGHLIGHT] Illness progression in chronic fatigue syndrome: a shifting immune baseline. [PDF]
Russell L, Broderick G, Taylor R, Fernandes H, Harvey J, Barnes Z, Smylie A, Collado F, Balbin EG, Katz BZ, Limas NG, Fletcher MA. BMC Immunology. 2016
There is mounting evidence suggesting that ME/CFS may be characterized by a significant imbalance in immune and endocrine function and that this imbalance may be perpetuated by an altered homeostatic response. Cytokine profiles that are characteristic of this persistent imbalance in immune regulation function have been reported previously by our group as well as by others described [10, 15, 34, 35]. Broad use of cytokine expression patterns as markers of illness is not without its challenges as these can be difficult to measure and are affected by a variety of factors even in a healthy population such as age, sex, BMI, etc.…This study is a continued exploration of how characteristic cytokine expression might be in ME/CFS and how such a signature could be used to reliably isolate ME/CFS subjects from their healthy counterparts regardless of age and duration of illness.

Chronic fatigue syndrome and circulating cytokines: A systematic review.
Blundell S, et al. Brain Behav Immun. 2015

Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome. [PDF]
Brown AE, Jones DE, Walker M, Newton JL. PLoS ONE. 2015

[HIGHLIGHT] B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. [PDF]
Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella, O. PLoS One. 2015
In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse after B-cell depletion and regeneration, a three times higher disease prevalence in women than in men, and a previously demonstrated increase in B-cell lymphoma risk for elderly ME/CFS patients, suggest that ME/CFS may be a variant of an autoimmune disease.

Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). [PDF]
Hardcastle SL, et al. BMC Immunol. 2015

Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. [PDF]
Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, Staines D, Marshall-Gradisnik S.
J Transl Med. 2015
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.

Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. [PDF]
Hardcastle SL, et al. Int J Med Sci. 2015

Distinct plasma immune signatures in ME/CFS are present early in the course of illness.
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. Sci Adv. 2015
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.

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

Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity. [PDF]
Strayer D, Scott V, Carter W. J Clin Cell Immunol. 2015

2010-2014

A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome.
Craddock TJ, Fritsch P, Rice MA Jr, del Rosario RM, Miller DB, Fletcher MA, Klimas NG, Broderick G. PLoS One. 2014
In female CFS subjects, expression of endocrine-immune markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis.

Characterization of Natural Killer Cell Phenotypes in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. [PDF]
Huth TK, Brenu EW, Nguyen T, Hardcastle SL, Johnston S, et al. J Clin Cell Immunol. 2014

The Function of CD3 + CD56 + NKT-Like Cells in HIV-Infected Individuals. [PDF]
Jiang Y, Cui X, Cui C, Zhang J, Zhou F, Zhang Z, Fu Y, Xu J, Chu Z, Liu J, Han X, Liao C, Wang Y, Cao Y, Shang H. BioMed Research International. 2014

Deficient EBVSpecific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome. [PDF]
Koreck A, Surányi A, Szöny BJ, 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.
PLoS ONE. 2014

Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. [Full Text] [PDF]
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. PLoS One. 2014
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.

Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). [PDF]
Morris G, et al. Curr Neuropharmacol. 2014

The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs).
Morris G, et al. Mol Neurobiol. 2014

Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. [PDF]
Nijs J, et al. Exerc Immunol Rev. 2014

Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls. [Full Text] [PDF]
Bradley AS, Ford B, Bansal AS. Clin Exp Immunol. 2013
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.

Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis. [PDF]
Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, Johnston S, Ramos SB, Staines DR, Marshall-Gradisnik SM. International Immunology. 2013

Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome.
[PDF]
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. Journal of Translational Medicine. 2013

Antibody to Epstein-Barr Virus Deoxyuridine Triphosphate Nucleotidohydrolase and Deoxyribonucleotide Polymerase in a Chronic Fatigue Syndrome Subset. [PDF]
Lerner AM, Ariza ME, Williams M, Jason L, Beqaj S, Fitzgerald JT, Lemeshow S, Glaser R. PLoS ONE. 2012

In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immunoinflammatory pathways and bacterial translocation. [Full Text] [PDF]
Maes M, Ringel K, Kubera M, Anderson G, Morris G, Galecki P, Geffard M. Journal of Affective Disorders. 2013

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome.
Montoya JG, et al. J Med Virol. 2013

Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. [PDF]
Brenu EW, et al. J Transl Med. 2012

Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin.
Maes M, et al. J Affect Disord. 2012

Chronic fatigue syndrome, the immune system and viral infection. [Full Text]
Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Brain Behav Immun. 2011
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.

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. [PDF]
Brenu EW, et al. J Transl Med. 2011

Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. [PDF]
Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O.
PLoS ONE. 2011

A formal analysis of cytokine networks in chronic fatigue syndrome. [PDF]
Broderick G, et al. Brain Behav Immun. 2010

Biomarkers in Chronic Fatigue Syndrome: Evaluation of Natural Killer Cell Function and Dipeptidyl Peptidase IV/CD26. [PDF]
Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, Broderick G, Klimas NG. PLoS ONE. 2010

2005-2009

Immunological aspects of chronic fatigue syndrome.
Lorusso L, et al. Autoimmun Rev. 2009

Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue?
[Full Text] [PDF]
*Meeus M, Mistiaen W, Lambrecht L, Nijs J. Anticancer Res. 2009
CFS patients display a number of immunological abnormalities also seen in cancer, including abnormalities of ribonuclease (RNase) L, hyperactivation of nuclear factor kappa beta (NF-kappa B), high oxidative stress and natural killer cell malfunction.

Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood. [Full Text] [PDF]
Aspler AL, Bolshin C, Vernon SD, Broderick G. Behav Brain Funct. 2008
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.

Unravelling intracellular immune dysfunctions in chronic fatigue syndrome: interactions between protein kinase R activity, RNase L cleavage and elastase activity, and their clinical relevance. [PDF]
Meeus M, Nijs J, McGregor N, Meeusen R, De Schutter G, Truijen S, Frémont M, Van Hoof E, De Meirleir K.
In Vivo. 2008
CFS patients have a variety of immunological abnormalities, including Rnase L-cleavage, protein kinase R and elastase activity.

The Multitasking Mast Cell: Positive and Negative Roles in the Progression of Autoimmunity. [PDF]
Christy AL, Brown MA. J Immunol. 2007
Among the potential outcomes of an aberrantly functioning immune system are allergic disease and autoimmunity. Although it has been assumed that the underlying mechanisms mediating these conditions are completely different, recent evidence shows that mast cells provide a common link. Mast cells reside in most tissues, are particularly prevalent at sites of Ag entry, and act as sentinel cells of the immune system. They express many inflammatory mediators that affect both innate and adaptive cellular function. They contribute to pathologic allergic inflammation but also serve an important protective role in bacterial and parasite infections. Given the proinflammatory nature of autoimmune responses, it is not surprising that studies using murine models of autoimmunity clearly implicate mast cells in the initiation and/or progression of autoimmune disease. In this review, we discuss the defined and hypothesized mechanisms of mast cell influence on autoimmune diseases, including their surprising and newly discovered role as anti-inflammatory cells.

Intracellular immune dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: state of the art and therapeutic implications. [Full Text]
*Nijs J, Frémont M. Expert Opin Ther Targets. 2008
Proteolytic cleavage of the native RNase L enzyme is characteristic of the dysregulation of intracellular immunity in CFS.

Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression.
Maes M, Mihaylova I, Leunis JC. Neuro Endocrinol Lett. 2007

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.
Mihaylova I, DeRuyter M, Rummens JL, Bosmans E, Maes M. Neuro Endocrinol Lett. 2007
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.

Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue.
Kogelnik AM, et al. J Clin Virol. 2006

Chronic fatigue syndrome is associated with diminished intracellular perforin. [PDF]
Maher KJ, et al. Clin Exp Immunol. 2005

Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome. [PDF]
Nijs J, De Meirleir K. In Vivo. 2005
The 2-5A synthetase/RNase L pathway in CFS patients appears to be both up-regulated (i.e. increased levels of bioactive 2-5A synthetase and increased activity of the RNase L enzyme) and deregulated (elastase and calpain initiate 83 kDa RNase L proteolysis, generating two major fragments with molecular masses of 37 and 30 kDa, respectively). The deregulation of the 2-5A synthetase/RNase L pathway in CFS accompanies decreased NK-function and deregulation of apoptotic pathways. Various components of the pathway appear to be related to performance during a graded exercise stress test.

2000-2004

Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. [PDF]
Tanaka S, Kuratsune H, Hidaka Y, Hakariya Y, Tatsumi KI, Takano T, Kanakura Y, Amino N. Int J Mol Med. 2003

CD3 + CD56 + NK T cells are significantly decreased in the peripheral blood of patients with psoriasis. [PDF]
Farkas Á, Bata-Csörgö Z, Kemény L, Dobozy A. Clinical and Experimental Immunology. 2002

Antinuclear autoantibodies (ANA) in Gulf War-related illness and chronic fatigue syndrome (CFS) patients. [PDF]
Skowera A, Stewart E, Davis ET, Cleare AJ, Unwin C, Hull L, Ismail K, Hossain G, Wessely SC, Peakman M. Clinical and Experimental Immunology. 2002

Elevated Nitric Oxide/Peroxynitrite Mechanism for the Common Etiology of Multiple Chemical Sensitivity, Chronic Fatigue Syndrome, and Posttraumatic Stress Disorder. [PDF]
Pall ML, Satterlee JD. Annals of the New York Academy of Sciences. 2001

Cytokines and chronic fatigue syndrome. [Full Text] [PDF]
Patarca R. Ann N Y Acad Sci. 2001
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.

Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors.
Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L. J Investig Med. 2001
In conclusion, peripheral blood mononuclear cells of CFS patients display an increased sensitivity to glucocorticoids.

Altered glucocorticoid regulation of the immune response in the chronic fatigue syndrome.
Visser JT, De Kloet ER, Nagelkerken L. Ann N Y Acad Sci. 2000
In CFS patients a decreased Th1/Th2 balance may be the result of selective effects of glucocortiocoids on the IL-10/IL-12 regulatory circuit.

Pre-2000

Reproductive correlates of chronic fatigue syndrome.
Harlow BL, Signorello LB, Hall JE, Dailey C, Komaroff AL. Am J Med. 1998
Women with CFS reported increased gynecologic complications, a lower incidence of premenstrual symptomatology. Issues included self-reported irregular cycles, periods of amenorrhea, sporadic bleeding between menstrual periods, and factors suggestive of abnormal ovarian function (such as a history of polycystic ovarian syndrome, hirsutism, and ovarian cysts).

Changes in growth hormone, insulin, insulin like growth factors (IGFs), and IGF-binding protein-1 in chronic fatigue syndrome.
Allain TJ, Bearn JA, Coskeran P, Jones J, Checkley A, Butler J, Wessely S, Miell JP. Biol Psychiatry. 1997
In CFS patients, the authors found attenuated basal levels of IGF-I and IGF-II; reduced GH response to hypoglycemia; higher insulin levels; and lower IGFBP-1 levels.

Viral studies of chronic fatigue syndrome.
Levy JA. Clin Infect Dis. 1994
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 eliminated but leaves abnormal immunologic sequelae.

Immunological abnormalities in patients with chronic fatigue syndrome.
Tirelli U, et al. Scand J Immunol. 1994

Immunologic abnormalities in chronic fatigue syndrome. [PDF]
Klimas NG, et al. J Clin Microbiol. 1990

Abnormal red-blood-cell morphology in myalgic encephalomyelitis.
Mukherjee TM, Smith K, Maros K. Lancet. 1987