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      Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

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          Abstract

          Background

          Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients.

          Methods

          We included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8 +T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4 +T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56 bright and CD56 dim) and regulatory T cells expressing FoxP3 transcription factor.

          Results

          Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10, IFN-γ, TNF-α, CD4 +CD25 + T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8 +T cells and NK phenotypes, in particular the CD56 bright NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients.

          Conclusions

          Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.

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          Most cited references36

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          Death by a thousand cuts: granzyme pathways of programmed cell death.

          The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.
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            Immunological aspects of chronic fatigue syndrome.

            Chronic fatigue syndrome (CFS) is a specific clinical condition that characterises unexplained disabling fatigue and a combination of non-specific accompanying symptoms for at least 6 months, in the absence of a medical diagnosis that would otherwise explain the clinical presentation. Other common symptoms include headaches, myalgia, arthralgia, and post-exertional malaise; cognitive difficulties, with impaired memory and concentration; unrefreshing sleep; and mood changes. Similar disorders have been described for at least two centuries and have been differently named neurasthenia, post-viral fatigue, myalgic encephalomyelitis and chronic mononucleosis. Recent longitudinal studies suggest that some people affected by chronic fatigue syndrome improve with time but that most remain functionally impaired for several years. The estimated worldwide prevalence of CFS is 0.4-1% and it affects over 800,000 people in the United States and approximately 240,000 patients in the UK. No physical examination signs are specific to CFS and no diagnostic tests identify this syndrome. The pathophysiological mechanism of CFS is unclear. The main hypotheses include altered central nervous system functioning resulting from an abnormal immune response against a common antigen; a neuroendocrine disturbance; cognitive impairment caused by response to infection or other stimuli in sentient people. The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. 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. This review discusses the immunological aspects of CFS and offers an immunological hypothesis for the disease processes.
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              Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes.

              Chronic inflammatory diseases are characterized by local tissue injury caused by immunocompetent cells, in particular CD4(+) T lymphocytes, that are involved in the pathogenesis of these disorders via the production of distinctive sets of cytokines. Here, we have characterized single CD4(+) T cells that infiltrate inflamed tissue taken from patients with psoriasis, Crohn's disease, rheumatoid arthritis, or allergic asthma. Results from a cytokine production and gene profile analysis identified a population of in vivo differentiatedretinoid-related orphan receptor gamma-expressing T cells, producing high levels of IL-17, that can represent up to 30% of infiltrating T lymphocytes. Activated Th17 cells produced IL-26, TNF-alpha, lymphotoxin-beta, and IL-22. IL-17 and IL-22 concentrations secreted by tissue infiltrating Th17 cells could reach up to 100 nM and were inversely correlated with the production of Th1- and Th2-associated cytokines. In addition, tissue-infiltrating Th17 cells are also characterized by high cell surface expression of CCR6, a chemokine receptor that was not expressed by Th1 and Th2 cells, isolated from the same lesions, and by the production of CCL20/MIP3alpha, a CCR6 ligand, associated with tissue infiltration. Culture supernatants of activated Th17 cells, isolated from psoriatic lesions, induced the expression of gene products associated with inflammation and abnormal keratinocyte differentiation in an IL-17 and IL-22-dependent manner. These results show that tissue-infiltrating Th17 cells contribute to human chronic inflammatory disease via the production of several inflammatory cytokines and the creation of an environment contributing to their migration and sequestration at sites of inflammation.
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                Author and article information

                Journal
                J Transl Med
                Journal of Translational Medicine
                BioMed Central
                1479-5876
                2011
                28 May 2011
                : 9
                : 81
                Affiliations
                [1 ]Population Health and Neuroimmunology Unit, Faculty of Health Science and Medicine, Bond University, Robina, Queensland, Australia
                [2 ]Faculty of Health Science and Medicine, Bond University, Robina, Queensland, Australia
                [3 ]Queensland Health, Gold Coast Public Health Unit, Southport, Gold Coast, Queensland, Australia
                [4 ]Miami Veterans Affairs Medical Center, Miami, FL, USA
                Article
                1479-5876-9-81
                10.1186/1479-5876-9-81
                3120691
                21619669
                bc386bfa-6185-45e1-942a-9ddb263b429b
                Copyright ©2011 Brenu et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 April 2011
                : 28 May 2011
                Categories
                Research

                Medicine
                Medicine

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