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

MCare4U Outpatient Clinics, Olmenlaan 9, 2610 Wilrijk, Belgium.
Neuro endocrinology letters (Impact Factor: 0.8). 09/2007; 28(4):477-83.
Source: PubMed


There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T- and natural killer (NK) cell activation. We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol. 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. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area under the ROC curve was around 89%. No differences either in the number of leukocytes or in the number or percentage of lymphocytes, i.e. CD3, CD4, CD8 and CD19, could be found between CFS patients and the controls. Patients with CFS show defects in T- and NK cell activation. Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in CFS there is a disorder in the early activation of the immune system involving PKC.

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    • "The covalent binding of IgG antibodies to Complement component 3 (C3) generates a complex that is cytotoxic and that damages the cell membranes. This than provokes inflammatory reaction (Mihaylova et al. 2007) characterised by the excessive production of cytokines (e.g. Interleukin 6) and activation of the biosynthesis of inflammatory Eprostaglandins from arachidonic acid and DGLA by the Cyclo-oxygenase enzymes 1 & 2 (COX 1&2) (fig. 1) "
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    ABSTRACT: Many patients with myalgic encephalopathy (fibromyalgia/chronic fatigue syndrome) localise the beginning of their disease at a time period of emotional, or professional, or social stress, or an infectious or traumatic/surgical incident. It is suggested that these may have temporarily suppressed their immunological system, after which a "rebound" of hyper-immunity has occurred. Hyper-immunity against external aggressors is commonly characterized by an extremely high titre of Immunolobulin G against the Epstein-Barr virus (Herpes 4), or elevated Anti-Streptolysin-O titre (ASLO). In a proportion of patients, hyper-immunity proceeds to auto-immunity with IgG antibodies against the thyroid gland (Hashimoto's disease), Antinuclear antibodies (ANF or ANA), and sometimes positive rheumatism-tests. The IgG covalently binds to Complement C3, which complex is cytotoxic by damaging the cell membrane, and induces inflammation. Simultaneously large quantities of reactive oxygen species (ROS) are produced. This causes muscular pain, poor energy production by the mitochondria, and increased permeability of the capillary vessels, also in the brain. The latter disturbs the thalamo-hypothalamo-pituitary regulation, impairs cognitive function, mood and the working memory. It disturbs the nycthemeral rhythm and the sleep pattern, and may cause neuro-vegetative dysfunction. Antibodies against the myelin sheet as well as impaired neurotransmission may be involved in polyneuropathy. Conventional treatment must correct possible endocrine deficiencies and can help alleviating particular symptoms. Causal treatment addresses the immune dysfunction using corticosteroids, gamma globulin infusions, or immune-suppressors. Immune modulators can selectively be attempted. However, treatment should also address the pathogenic mechanisms by prescribing an appropriate diet, and particular food supplements (Complementary and Alternative Medicine, CAM). We have developed a *; Brakelmeersstraat, 18; B 9830 Sint Martens-Latem; Belgium. Frank H. Comhaire 2 specific nutraceutical containing several anti-oxidants (Astaxanthin, Oxido-reductase ubiquinone Q10), a strong natural anti-inflammatory substance (pine bark extract, Pycnogenol®), the fyto-adaptogen Lepidium meyenii (MACA), acetyl-carnitine, zinc, and vitamins B6, B9 and B12. To this supplement long-chain poly-unsaturated omega-3 fatty acids are added (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA). The CAM approach induces and maintains improvement in 85% of patients, but it seldom results in the complete disappearance of signs and symptoms.
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    • "Early work associated CFS with a general status of immune activation assessed by CD38 or HLA-DR expression in CD8 T cells [12]. However, other authors found similar expression of these markers in CFS and healthy individuals [21], while lower expression of the activation markers CD69 or soluble CD26 has also been described as a feature of CFS [22,23]. Similarly, B-cell function [24], B-cell mediated autoimmunity or unbalanced cytokine network have been linked to CFS [9,25-27] again with inconclusive results. "
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    ABSTRACT: Background Chronic Fatigue Syndrome (CFS) is a debilitating neuro-immune disorder of unknown etiology diagnosed by an array of clinical manifestations. Although several immunological abnormalities have been described in CFS, their heterogeneity has limited diagnostic applicability. Methods Immunological features of CFS were screened in 22 CFS diagnosed individuals fulfilling Fukuda criteria and 30 control healthy individuals. Peripheral blood T, B and NK cell function and phenotype were analyzed by flow cytometry in both groups. Results CFS diagnosed individuals showed similar absolute numbers of T, B and NK cells, with minor differences in the percentage of CD4+ and CD8+ T cells. B cells showed similar subset frequencies and proliferative responses between groups. Conversely, significant differences were observed in T cell subsets. CFS individuals showed increased levels of T regulatory cells (CD25+/FOXP3+) CD4 T cells, and lower proliferative responses in vitro and in vivo. Moreover, CD8 T cells from the CFS group showed significantly lower activation and frequency of effector memory cells. No clear signs of T-cell immunosenescence were observed. NK cells from CFS individuals displayed higher expression of NKp46 and CD69 but lower expression of CD25 in all NK subsets defined. Overall, T cell and NK cell features clearly clustered CFS individuals. Conclusions Our findings suggest that alterations in T-cell phenotype and proliferative response along with the specific signature of NK cell phenotype may be useful to identify CFS individuals. The striking down modulation of T cell mediated immunity may help to understand intercurrent viral infections in CFS.
    Journal of Translational Medicine 03/2013; 11(1):68. DOI:10.1186/1479-5876-11-68 · 3.93 Impact Factor
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    • "Chronic elevation of Th2 and Th1 cytokines may conspire to create additional and more complex pathologies, for example, accelerating the rate of glucose homeostasis in the brain [118]. Other well documented immune abnormalities in ME/CFS, which are not germane to sickness behavior, include dysregulated forkhead box P3 (FoxP3) expression [119], disrupted T cell homeostasis as indicated by reports of increased CD26 expression [120], decreased expression of CD69 [121] and elevated B cell numbers [122]. "
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    ABSTRACT: It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions.
    BMC Medicine 03/2013; 11(1):64. DOI:10.1186/1741-7015-11-64 · 7.25 Impact Factor
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