From the Journal of Translational Medicine, published online 9 May 2012.
Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis
Ekua W Brenu(￼1,2), Mieke L van Driel(1,2,4), Donald R Staines(1,5), Kevin J Ashton(2), Sharni L Hardcastle(1,2), James Keane(2), Lotti Tajouri(2), Daniel Peterson(6), Sandra B Ramos 2), and Sonya M Marshall-Gradisnik (1,2,3).
(1) Faculty of Health Science and Medicine, Population Health and Neuroimmunology Unit, Bond University, Robina, QLD, Australia
(2) Faculty of Health Science and Medicine, Bond University, Robina, QLD 4229, Australia
(3) School of Medical Science, Griffith Health Institute, Griffith University, Gold Coast Campus, Gold Coast, QLD, Australia
(4) Discipline of General Practice, School of Medicine, The University of Queensland, Brisbane, Australia
(5) Queensland Health, Gold Coast Public Health Unit, Robina, Gold Coast, QLD, Australia
(6) Sierra Internal Medicine, Incline Village, Nevada, USA
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an etiologically unexplained disorder characterised by irregularities in various aspects of the immunological function. Presently, it is unknown whether these immunological changes remain consistent over time. This study investigates Natural Killer (NK) cell cytotoxic activity, NK cell subsets (CD56brightCD16- and CD56dimCD16+) and cytokines, over the course of a12 month period in patients with CFS/ME.
The participants in the study comprised 65 (47.2￼±￼11.5￼years) CFS/ME participants and 21 (45.2 ±9.3￼years) non-fatigued controls. Flow cytometry protocols were used to assess NK subsets and NK cytotoxic activity at various time points that included baseline (T1), 6 (T2) and 12￼months (T3). Cytokine secretions were measured following mitogenic stimulation of peripheral blood mononuclear cells.
NK cytotoxic activity was significantly decreased in the CFS/ME patients at T1, T2 and T3 compared to the non-fatigued group.
Additionally, in comparison to the non-fatigued controls, the CFS/ME group had significantly lower numbers of CD56brightCD16- NK cells at both T1 and T2. Interestingly, following mitogenic stimulation, cytokine secretion revealed significant increases in IL-10, IFN-γ and TNF-α at T1 in the CFS/ME group. A significant decrease was observed at T2 in the CFS/ME group for IL-10 and IL-17A while at T3, IL-2 was increased in the CFS/ME group in comparison to the non-fatigued controls. Overall cytotoxic activity was significantly decreased at T3 compared to T1 and T2. CD56brightCD16- NK cells were much lower at T2 compared to T1 and T3. IL-10 and IL-17A secretion was elevated at T2 in comparison to T1 and T3.
These results confirm decreases in immune function in CFS/ME patients, suggesting an increased susceptibility to viral and other infections. Furthermore, NK cytotoxic activity may be a suitable biomarker for diagnosing CFS/ME as it was consistently decreased during the course of the 12￼months study.
From BMC Clinical Pathology, 17 December 2012.
Unique immunologic patterns in fibromyalgia.
Behm FG, Gavin IM, Karpenko O, Lindgren V, Gaitonde S, Gashkoff PA, Gillis BS.
Department of Pathology, University of Illinois at Chicago (UIC), Chicago, IL, USA.
Fibromyalgia (FM) is a clinical syndrome characterized by chronic pain and allodynia. The diagnosis of FM has been one of exclusion as a test to confirm the diagnosis is lacking. Recent data highlight the role of the immune system in FM. Aberrant expressions of immune mediators, such as cytokines, have been linked to the pathogenesis and traits of FM. We therefore determined whether cytokine production by immune cells is altered in FM patients by comparing the cellular responses to mitogenic activators of stimulated blood mononuclear cells of a large number of patients with FM to those of healthy matched individuals.
Plasma and peripheral blood mononuclear cells (PBMC) were collected from 110 patients with the clinical diagnosis of FM and 91 healthy donors. Parallel samples of PBMC were cultured overnight in medium alone or in the presence of mitogenic activators; PHA or PMA in combination with ionomycin. The cytokine concentrations of IFN-γ, IL-5, IL-6, IL-8, IL-10, MIP-1β , MCP-1, and MIP1-α in plasma as well as in cultured supernatants were determined using a multiplex immunoassay using bead array technology.
Cytokine levels of stimulated PBMC cultures of healthy control subjects were significantly increased as compared to matched non-stimulated PBMC cultures. In contrast, the concentrations of most cytokines were lower in stimulated samples from patients with FM compared to controls. The decreases of cytokine concentrations in patients samples ranged from 1.5-fold for MIP-1β to 10.2-fold for IL-6 in PHA challenges. In PMA challenges, we observed 1.8 to 4-fold decreases in the concentrations of cytokines in patient samples.
The cytokine responses to mitogenic activators of PBMC isolated from patients with FM were significantly lower than those of healthy individuals, implying that cell-mediated immunity is impaired in FM patients. This novel cytokine assay reveals unique and valuable immunologic traits, which, when combined with clinical patterns, can offer a diagnostic methodology in FM.
From Molecular Neurobiology, 26 February 2013. [Epub ahead of print]
Role of the Toll Like Receptor (TLR) Radical Cycle in Chronic Inflammation:
Possible Treatments Targeting the TLR4 Pathway.
Lucas K, Maes M.
Sportzenkoppel 54, 22359, Hamburg, Germany.
Activation of the Toll-like receptor 4 (TLR4) complex, a receptor of the innate immune system, may underpin the pathophysiology of many human diseases, including asthma, cardiovascular disorder, diabetes, obesity, metabolic syndrome, autoimmune disorders, neuroinflammatory disorders, schizophrenia, bipolar disorder, autism, clinical depression, chronic fatigue syndrome, alcohol abuse, and toluene inhalation.
TLRs are pattern recognition receptors that recognize damage-associated molecular patterns and pathogen-associated molecular patterns, including lipopolysaccharide (LPS) from gram-negative bacteria.
Here we focus on the environmental factors, which are known to trigger TLR4, e.g., ozone, atmosphere particulate matter, long-lived reactive oxygen intermediate, pentachlorophenol, ionizing radiation, and toluene.
Activation of the TLR4 pathways may cause chronic inflammation and increased production of reactive oxygen and nitrogen species (ROS/RNS) and oxidative and nitrosative stress and therefore TLR-related diseases.
This implies that drugs or substances that modify these pathways may prevent or improve the above mentioned diseases.
Here we review some of the most promising drugs and agents that have the potential to attenuate TLR-mediated inflammation, e.g., anti-LPS strategies that aim to neutralize LPS (synthetic anti-LPS peptides and recombinant factor C) and TLR4/MyD88 antagonists, including eritoran, CyP, EM-163, epigallocatechin-3-gallate, 6-shogaol, cinnamon extract, N-acetylcysteine, melatonin, and molecular hydrogen.
The authors posit that activation of the TLR radical (ROS/RNS) cycle is a common pathway underpinning many “civilization” disorders and that targeting the TLR radical cycle may be an effective method to treat many inflammatory disorders.
Journal of the Australasian College of Nutritional and Environmental Medicine, 3 December 2012.
The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy
Borody, Thomas J(1); Nowak, Anna(2); Finlayson, Sarah(3)
(1) Director, Centre for Digestive Diseases, Five Dock NSW 2046, Australia
(2) Research Assistant, Centre for Digestive Diseases, Five Dock NSW 2046, Australia
(3) Research Assistant, Centre for Digestive Diseases, Five Dock NSW 2046, Australia
Chronic Fatigue Syndrome (CFS) has a complex and multifactorial etiology making treatment and definitive diagnosis, currently made through exclusion, difficult. Current therapies, such as cognitive behaviour therapy and graded exercises, are inadequate and targeted to address symptoms, rather than the underlying disease pathology. Increasing evidence implicates the microbiota of the gut in a number of conditions previously thought distinct from the gastrointestinal system. Previous work with bacteriotherapy in CFS has suggested a link between the condition and the composition and health of the gut microbiota. Here, we review and further examine a larger cohort of CFS patients who had undergone bacteriotherapy for their CFS.
A total of 60 patients from the Centre for Digestive Diseases presented with CFS. Of these, 52 patients had concurrent IBS and 4 patients additionally had constipation. All underwent initial transcolonoscopic infusion of 13 non-pathogenic enteric bacteria. 52/60 patients undertook an additional rectal infusion a day later and 3/60 undertook an additional 2 rectal infusions.
35/60 patients who underwent initial bacteriotherapy responded to treatment. 10/15 patients who failed this course were offered a secondary transcolonoscopic infusion followed by a rectal infusion or an oral course of cultured bacteria. Of these 7/10 responded, giving a total of 42/60 (70%) patients who responded to treatment. Contact was achieved with 12 patients after 15-20 year follow-up.
Complete resolution of symptoms was maintained in seven of the twelve patients and 5/12 did not experience recurrence for approximately 1.5-3 years post bacteriotherapy.
Bacteriotherapy achieves initial success rate of 70% in CFS and a 58% sustained response. Given that manipulation of the colonic microbiota improved CFS symptoms, bacteriotherapy for CFS warrants further investigation and may provide further insight into a
possible etiology of CFS.
From Multiple Sclerosis, 25 February 2013[Epub ahead of print]
Fatigue heralding multiple sclerosis.
Berger JR, Pocoski J, Preblick R, Boklage S.
Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, USA.
Fatigue is a common symptom in multiple sclerosis (MS) and is an important determinant of overall well-being and disability.
To assess the frequency with which fatigue precedes the diagnosis of MS using a retrospective database analysis.
Between January 1, 2003 and September 30, 2008, patients diagnosed with fatigue with and without fatigue-related medications within a 3-year period prior to newly diagnosed MS were identified from the MarketScan Databases. All statistical analysis was performed using SAS.
Of the 16,976 patients with MS in the overall population, 5305 (31.3%) were newly diagnosed with MS and had three years of continuous healthcare coverage prior to MS diagnosis. Of these patients, 1534 (28.9%) were labeled with chronic fatigue syndrome (ICD9-780.71) or malaise or fatigue (ICD9-780.79) prior to the diagnosis of MS.
One-third of these patients were labeled with fatigue one to two years before the diagnosis; 30.8% were diagnosed only with fatigue and had no other MS symptoms prior to their MS diagnosis. Among the patients diagnosed with fatigue, 10.4% were also prescribed medication for fatigue.
This study demonstrates that fatigue may herald MS, often by years. A careful history for transient neurological symptoms and a
physical examination is warranted in any patient presenting with fatigue.
From the Journal of Clinical and Experimental Rheumatology, 17 December 2012.
Dysfunctional syndromes and fibromyalgia: a 2012 critical digest.
Sarzi-Puttini P, Atzeni F, Di Franco M, Buskila D, Alciati A, Giacomelli C, Rossi A, Bazzichi L.
Rheumatology Unit, L. Sacco University Hospital, Milan, Italy.
Medically ‘unexplained’ chronic disorders remain a challenge for clinicians because the patients with these syndromes have a wide range
of symptoms, including pain, impaired concentration, sleep disturbances, fatigue and mood disorders, as well as functional problems and difficulties in carrying out the activities of daily living.
Such disorders are the result of a complex physiological interaction of central and peripheral nervous signaling that leads to a highly individual symptom complex, although some of them seem to be related to one another, especially in terms of the mechanism of chronicity and pain amplification, and the co-occurrence of fatigue, sleep alterations, mood disturbances and cognitive impairment.
This review will discuss the recent literature concerning the most common dysfunctional disorders: fibromyalgia syndrome, myalgic
encephalomyelitis/chronic fatigue syndrome, and irritable bowel syndrome.