cytokines – Page 10 – American ME and CFS Society

Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression

Abstract:

BACKGROUND: Depression is an inflammatory disorder while many authors declare myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to be a functional disorder. The aim of the present study is to compare inflammatory and cell-mediated immune (CMI) responses between depression and ME/CFS.

METHODS: We measured two proinflammatory cytokines (PICs) in plasma, interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), with enzyme-linked immunosorbent assays, and serum neopterin with a radioimmunoassay in controls, ME/CFS and depressive patients.

RESULTS: Plasma PICs were significantly higher in ME/CFS than in depression and higher in both patient groups than in controls. Increased PIC levels in depression were attributable to the presence of fatigue and physio-somatic symptoms. Serum neopterin did not differ significantly between depression and ME/CFS but was higher in both patient groups than in controls. The significant positive correlations between neopterin and either IL-1 or TNF-α were significantly greater in depression than in ME/CFS.

CONCLUSIONS: Since PICs cause depression-like behaviors and fatigue/malaise, we suggest that inflammation may play a role in the pathophysiology of ME/CFS and depression. Increased neopterin also seems to contribute to the pathophysiology of both disorders. This study has detected a shared ‘pathway phenotype’, i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. ME/CFS and depression are discriminated from each other by increased PICs in ME/CFS and differences in the immune cell communication networks.

Source: Maes M, Twisk FN, Ringel K. Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother Psychosom. 2012;81(5):286-95. doi: 10.1159/000336803. Epub 2012 Jul 20. https://www.ncbi.nlm.nih.gov/pubmed/22832503

Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

Source: Brenu EW, van Driel ML, Staines DR, Ashton KJ, Hardcastle SL, Keane J, Tajouri L, Peterson D, Ramos SB, Marshall-Gradisnik SM. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2012 May 9;10:88. doi: 10.1186/1479-5876-10-88. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464733/ (Full article)

Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data

Abstract:

There is much debate on the diagnostic classification of Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS) and chronic fatigue (CF). Post-exertional malaise (PEM) is stressed as a key feature. This study examines whether CF and CFS, with and without PEM, are distinct diagnostic categories.

Fukuda’s criteria were used to diagnose 144 patients with chronic fatigue and identify patients with CFS and CF, i.e. those not fulfilling the Fukuda’s criteria. PEM was rated by means of a scale with defined scale steps between 0 and 6. CFS patients were divided into those with PEM lasting more than 24h (labeled: ME) and without PEM (labeled: CFS). The 12-item Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to measure severity of illness. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, and lysozyme, and serum neopterin were employed as external validating criteria.

Using fatigue, a subjective feeling of infection and PEM we found that ME, CFS, and CF were distinct categories. Patients with ME had significantly higher scores on concentration difficulties and a subjective experience of infection, and higher levels of IL-1, TNFα, and neopterin than patients with CFS. These biomarkers were significantly higher in ME and CFS than in CF patients. PEM loaded highly on the first two factors subtracted from the data set, i.e. “malaise-sickness” and “malaise-hyperalgesia”. Fukuda’s criteria are adequate to make a distinction between ME/CFS and CF, but ME/CFS patients should be subdivided into ME (with PEM) and CFS (without PEM).

Source: Maes M, Twisk FN, Johnson C. Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res. 2012 Dec 30;200(2-3):754-60. doi: 10.1016/j.psychres.2012.03.031. Epub 2012 Apr 21. https://www.ncbi.nlm.nih.gov/pubmed/22521895

Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome

Abstract:

OBJECTIVES: Stressors and emotional distress responses impact chronic fatigue syndrome (CFS) symptoms, including fatigue. Having better stress management skills might mitigate fatigue by decreasing emotional distress. Because CFS patients comprise a heterogeneous population, we hypothesized that the role of stress management skills in decreasing fatigue may be most pronounced in the subgroup manifesting the greatest neuroimmune dysfunction.

METHODS: In total, 117 individuals with CFS provided blood and saliva samples, and self-report measures of emotional distress, perceived stress management skills (PSMS), and fatigue. Plasma interleukin-1-beta (IL-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α), and diurnal salivary cortisol were analyzed. We examined relations among PSMS, emotional distress, and fatigue in CFS patients who did and did not evidence neuroimmune abnormalities.

RESULTS: Having greater PSMS related to less fatigue (p=.019) and emotional distress (p<.001), greater diurnal cortisol slope (p=.023) and lower IL-2 levels (p=.043). PSMS and emotional distress related to fatigue levels most strongly in CFS patients in the top tercile of IL-6, and emotional distress mediated the relationship between PSMS and fatigue most strongly in patients with the greatest circulating levels of IL-6 and a greater inflammatory (IL-6):anti-inflammatory (IL-10) cytokine ratio.

DISCUSSION: CFS patients having greater PSMS show less emotional distress and fatigue, and the influence of stress management skills on distress and fatigue appear greatest among patients who have elevated IL-6 levels. These findings support the need for research examining the impact of stress management interventions in subgroups of CFS patients showing neuroimmune dysfunction.

Source: Lattie EG, Antoni MH, Fletcher MA, Penedo F, Czaja S, Lopez C, Perdomo D, Sala A, Nair S, Fu SH, Klimas N. Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome. Brain Behav Immun. 2012 Aug;26(6):849-58. doi: 10.1016/j.bbi.2012.02.008. Epub 2012 Mar 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572196/ (Full article)

Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome

Abstract:

BACKGROUND/PURPOSE: It has been shown that the abnormality in immune cells in chronic fatigue syndrome (CFS) patients is closely associated with the participation of TGF-β. In order to study the relationship between TGF-β1 and CFS, we investigated the mRNA levels of TGF-β1 in peripheral blood mononuclear cells (PBMCs) in patients with CFS.

METHODS: Fluorescent quantitative real time reverse-transcription polymerase chain reaction (FQ-RT-PCR) was performed to test TGF-β1 mRNA expression in PBMCs in 63 cases of CFS, 50 cases of disease controls, and 50 cases of healthy controls.

RESULTS: The mean value of TGF-β1 mRNA expression in CFS patients was ΔΔCt=1.17±0.58, which was significantly higher than the disease controls (ΔΔCt=0.07±1.08, df=111, p < 0.01) and the healthy controls (ΔΔCt=0.00±1.63, df=111, p < 0.01). No significant difference was detected between disease and healthy controls (p > 0.05).

CONCLUSION: The expression of TGF-β1 in PBMCs is significantly elevated in patients with CFS. It might be correlated to the pathogenesis of the disease.

Source: Zhang HY, Liu ZD, Hu CJ, Wang DX, Zhang YB, Li YZ. Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. J Formos Med Assoc. 2011 Nov;110(11):701-4. doi: 10.1016/j.jfma.2011.09.006. Epub 2011 Oct 22. http://www.jfma-online.com/article/S0929-6646(11)00070-2/fulltext (Full article)

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

Abstract:

BACKGROUND: There is evidence that inflammatory pathways and cell-mediated immunity (CMI) play an important role in the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Activation of inflammatory and CMI pathways, including increased levels of cytokines, is known to induce fatigue and somatic symptoms. Given the broad spectrum inflammatory state in ME/CFS, the aim of this study was to examine whether inflammatory and CMI biomarkers are increased in individuals with ME/CFS.

METHODS: In this study we therefore measured plasma interleukin-(IL)1, tumor necrosis factor (TNF)α, and PMN-elastase, and serum neopterin and lysozyme in 107 patients with ME/CFS, 37 patients with chronic fatigue (CF), and 20 normal controls. The severity of ME/CFS was measured with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

RESULTS: Serum IL-1, TNFα, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. Plasma PMN-elastase is significantly higher in patients with ME/CFS than in controls and CF patients and higher in the latter than in controls. Increased IL-1 and TNFα are significantly correlated with fatigue, sadness, autonomic symptoms, and a flu-like malaise; neopterin is correlated with fatigue, autonomic symptoms, and a flu-like malaise; and increased PMN-elastase is correlated with concentration difficulties, failing memory and a subjective experience of infection.

CONCLUSIONS: The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI. The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNFα.

Source: Maes M, Twisk FN, Kubera M, Ringel K. 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. J Affect Disord. 2012 Feb;136(3):933-9. doi: 10.1016/j.jad.2011.09.004. Epub 2011 Oct 4. https://www.ncbi.nlm.nih.gov/pubmed/21975140

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

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.

Source: Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J, Klimas NG, Marshall-Gradisnik SM. Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med. 2011 May 28;9:81. doi: 10.1186/1479-5876-9-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120691/ (Full article)

Immunologic and psychosocial status in chronic fatigue syndrome

Abstract:

OBJECTIVE: The aim of the study was to investigate the immunologic functions and psychosocial status in patients with chronic fatigue syndrome (CFS).

METHODS: Twenty-five patients with CFS diagnosed by the international CFS definition criteria and 20 age- and gender-matched healthy controls were recruited. Depression was assessed by Beck Depression Inventory (BDI) and health status was assessed by Nottingham Health Profile (NHP). Monoclonal antibodies (MAbs) were measured to identify the following NK cell subsets: CD3, CD4, CD8 and CD56 and cytokine measurements were performed for IL2r, IL6 and IL8 in both patients and control subjects.

RESULTS: The BDI and NHP scores of CFS group were found to be significantly higher than in the control group. The absolute numbers of CD56 cell were also significantly decreased in the patients with CFS compared with the healthy controls. There were no other significant differences of NK cell activity (CD3, CD4 and CD8) and there were significant differences in IL6 and IL2r levels between patients and controls. There were significant correlations between serum IL-6 level and sleep, social isolation and physical ability NHP subscores, and between CD56 NK cell activity and emotional reaction NHP sub score in CFS patients.

CONCLUSION: Significantly higher ratios of psychological and physical disturbances were found in patients with CFS. Decreased CD56 NK cell activity and increased IL2r levels seem to be important immunopathologic changes in CFS. IL-6 and CD 56 NK cell activity may play an important role in sleep, physical, social, and physicological manifestations of CFS (Tab. 3, Fig. 1, Ref. 36).

Full Text in free PDF http://bmj.fmed.uniba.sk/2011/11204-12.pdf

Source: Nas K, Cevik R, Batum S, Sarac AJ, Acar S, Kalkanli S. Immunologic and psychosocial status in chronic fatigue syndrome. Bratisl Lek Listy. 2011;112(4):208-12. https://www.ncbi.nlm.nih.gov/pubmed/21585130

Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature

Abstract:

BACKGROUND: The recent identification of xenotropic murine leukemia virus-related virus (XMRV) in the blood of patients with chronic fatigue syndrome (CFS) establishes that a retrovirus may play a role in the pathology in this disease. Knowledge of the immune response might lead to a better understanding of the role XMRV plays in this syndrome. Our objective was to investigate the cytokine and chemokine response in XMRV-associated CFS.

MATERIALS AND METHODS: Using Luminex multi-analyte profiling technology, we measured cytokine and chemokine values in the plasma of XMRV-infected CFS patients and compared these data to those of healthy controls. Analysis was performed using the Gene Expression Pattern Analysis Suite and the Random Forest tree classification algorithm.

RESULTS: This study identifies a signature of 10 cytokines and chemokines which correctly identifies XMRV/CFS patients with 93% specificity and 96% sensitivity.

CONCLUSION: These data show, for the first time, an immunological pattern associated with XMRV/CFS.

Source: Lombardi VC, Hagen KS, Hunter KW, Diamond JW, Smith-Gagen J, Yang W, Mikovits JA. Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature. In Vivo. 2011 May-Jun;25(3):307-14. https://www.ncbi.nlm.nih.gov/pubmed/21576403

Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study

Abstract:

Fatigue is a common complaint among adolescents. We investigated the course of fatigue in females during the transition from adolescence to young adulthood and examined psychological, immunological, and life style risk factors for development of fatigue and chronic fatigue syndrome (CFS)-related symptoms.

Six hundred and thirty-three healthy females (age 14.63±1.37 years) filled out questionnaires measuring fatigue severity, depressive symptoms, anxiety, chronic fatigue syndrome (CFS)-related symptoms, sleep features, and life style characteristics at baseline and 4½ years thereafter.

Of 64 participants LPS- and CD2CD28-induced cytokine data at baseline were available. The best predictor of fatigue in young adulthood was previous fatigue severity. In participants who were non-fatigued during adolescence and who experienced a notable increase in fatigue, fatigue development was preceded by emotional problems and CFS-related complaints during adolescence. Increases as well as decreases in fatigue severity were accompanied by respectively increase and decrease in depressive symptoms and anxiety, suggesting that these symptoms cluster and co-vary over time.

Higher interferon (IFN)-γ, higher IFN-γ/interleukin (IL)-4 ratio, lower tumor necrosis factor-α and lower IL-10 at baseline were related to fatigue severity at follow up. The rise in total number of CFS-related symptoms at follow up was predicted by anxiety and decreased physical activity during adolescence. Sleep and substance use were associated with fatigue severity and anxiety and depression.

In conclusion, vulnerability to develop fatigue and associated symptoms in young adulthood can to a certain extent be identified already years before the manifestation of complaints.

Source: ter Wolbeek M, van Doornen LJ, Kavelaars A, Tersteeg-Kamperman MD, Heijnen CJ. Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study. Brain Behav Immun. 2011 Aug;25(6):1249-55. doi: 10.1016/j.bbi.2011.04.015. Epub 2011 Apr 28. https://www.ncbi.nlm.nih.gov/pubmed/21549830