Tag: cytokines

Cytokines and chronic fatigue syndrome

Abstract:

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. The interplay of these factors can account for the perpetuation of disease with remission/exacerbation cycles. A T-helper type 2 predominance has been seen among Gulf War syndrome patients and this feature may also be present in other related disorders, such as multiple chemical sensitivity. Therapeutic intervention aimed at induction of a more favorable cytokine expression pattern and immune status appears promising.

 

Source: Patarca R. Cytokines and chronic fatigue syndrome.  Ann N Y Acad Sci. 2001 Mar;933:185-200. http://www.ncbi.nlm.nih.gov/pubmed/12000020

 

Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue

Abstract:

To investigate whether cytokine responses may have a bearing on the symptoms and outcome of parvovirus B19 infection, circulating cytokines were measured during acute infection (n=51), follow-up of acute infection (n=39) and in normal healthy controls (n=50).

At acute B19 virus infection (serum anti-B19 IgM-positive), patients ranged in age from 4 to 54 years, with a mean age of 28.2 years. The male:female ratio was 1:4.1 and symptoms were rash (n=15), arthralgia (n=31), fatigue (n=8), lymphadenopathy (n=4), foetal hydrops (n=3), transient aplastic crisis (n=2), neutropenia (n=2), myelodysplasia (n=1), thrombocytopenia (n=1) and pancytopenia (n=1). Of these patients, 39 were contacted after a follow-up period of 2-37 months (mean of 22.5 months).

In comparison with normal controls, detectable IL-6 was associated with acute B19 virus infection (26%; P=0.0003), but not with follow-up (6%; P=0.16). Detection of interferon (IFN)-gamma was associated with acute B19 virus infection (67%; P<0.0001) and follow-up (67%; P<0.0001). Detection of tumour necrosis factor (TNF)-alpha was associated with acute B19 virus infection (49%; P<0.0001) and follow-up (56%; P<0.0001). IL-1beta was detected in acute infection (20%), but not at follow-up. At acute B19 virus infection, detection of serum/plasma IL-6 was associated with rheumatoid factor (P=0.038) and IFN-gamma (> or =7 pg/ml) was associated with fatigue in those patients of > or =15 years of age (P=0.022). At follow-up, fatigue was associated with IFN-gamma (> or =7 pg/ml) and/or TNF-alpha (> or =40 pg/ml) (P=0.0275).

Prolonged upregulation of serum IFN-gamma and TNF-alpha appears to represent a consistent host response to symptomatic B19 virus infection.

 

Source: Kerr JR, Barah F, Mattey DL, Laing I, Hopkins SJ, Hutchinson IV, Tyrrell DA. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol. 2001 Dec;82(Pt 12):3011-9. http://www.ncbi.nlm.nih.gov/pubmed/11714978

 

LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone

Abstract:

Several causes have been held responsible for the chronic fatigue syndrome (CFS), including an altered hypothalamus-pituitary-adrenal gland (HPA)-axis activity, viral infections and a reduced Th1 activity. Therefore, it was investigated whether the regulation of IL-10 is different in CFS.

LPS-induced cytokine secretion in whole blood cultures showed a significant increase in IL-10 and a trend towards a decrease in IL-12 as compared with healthy controls. In patients and controls, IL-12 secretion was equally sensitive to suppression by dexamethasone, whereas IL-10 secretion appeared more sensitive in CFS-patients. In controls, IL-10 and IL-12 secretion were inversely correlated with free serum cortisol (r=-0.492, p<0.02 and r=-0.434, p<0.05, respectively). In CFS, such an inverse correlation was found for IL-12 (r=-0.611, p<0.02) but not for IL-10 (r=-0.341, ns).

These data are suggestive for a disturbed glucocorticoid regulation of IL-10 in CFS.

 

Source: Visser J, Graffelman W, Blauw B, Haspels I, Lentjes E, de Kloet ER, Nagelkerken L. LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. J Neuroimmunol. 2001 Oct 1;119(2):343-9. http://www.ncbi.nlm.nih.gov/pubmed/11585638

 

Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors

Abstract:

The literature is reviewed and data are presented that relate to a model we have developed to account for the perpetuation of the perplexing disorder currently termed chronic fatigue syndrome (CFS). In patients with CFS there is chronic lymphocyte overactivation with cytokine abnormalities that include perturbations in plasma levels of proinflammatory cytokines and decrease in the ratio of Type 1 to Type 2 cytokines produced by lymphocytes in vitro following mitogen stimulation. The initiation of the syndrome is frequently sudden and often follows an acute viral illness.

Our model for the subsequent chronicity of this disorder holds that the interaction of psychological factors (distress associated with either CFS-related symptoms or other stressful life events) and the immunologic dysfunction contribute to (a) CFS-related physical symptoms (e.g., perception of fatigue and cognitive difficulties, fever, muscle and joint pain) and increases in illness burden and (b) impaired immune surveillance associated with cytotoxic lymphocytes with resulting activation of latent herpes viruses.

 

Source: Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG. Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Appl Neuropsychol. 2001;8(1):51-64. http://www.ncbi.nlm.nih.gov/pubmed/11388124

 

Acute phase responses and cytokine secretion in chronic fatigue syndrome

Abstract:

This study addresses the hypothesis that clinical manifestations of chronic fatigue syndrome (CFS) are due in part to abnormal production of or sensitivity to cytokines such as interleukin-1beta (IL-1beta) and IL-6 under basal conditions or in response to a particular physical stress: 15 min of exercise consisting of stepping up and down on a platform adjusted to the height of the patella. The study involved 10 CFS patients and 11 age-, sex-, and activity-matched controls: of these, 6 patients and 4 controls were tested in both the follicular and the luteal phases of the menstrual cycle, and the remainder were tested in only one phase, for a total of 31 experimental sessions.

Prior to exercise, plasma concentrations of the acute phase reactant alpha2-macroglobulin were 29% higher in CFS patients (P < 0.008) compared to controls. Secretion of IL-6 was generally higher for CFS patients (approximately 38%), however, this difference was statistically significant only if all values over a 3-day period were analyzed by repeated-measures ANOVA (P = 0.035). IL-6 secretion correlated with plasma alpha2-macroglobulin in control subjects at rest (R = 0.767, P = 0.001).

Immediately after exercise, the CFS patients reported greater ratings of perceived exertion (P=0.027) compared to the healthy control subjects. Ratings of perceived exertion correlated with IL-1beta secretion by cells from healthy control subjects (R = 0.603, P = 0.022), but not from CFS patients, and IL-1beta secretion was not different between groups. Exercise induced a slight (< 12%) but significant (P = 0.006) increase in IL-6 secretion, but the responses of the CFS patients were not different than controls. Furthermore, no significant exercise-induced changes in body temperature or plasma alpha2-macroglobulin were observed.

These data indicate that under basal conditions, CFS is associated with increased IL-6 secretion which is manifested by chronically elevated plasma alpha2-macroglobulin concentrations. These modest differences suggest that cytokine dysregulation is not a singular or dominant factor in the pathogenesis of CFS.

 

Source: Cannon JG, Angel JB, Ball RW, Abad LW, Fagioli L, Komaroff AL. Acute phase responses and cytokine secretion in chronic fatigue syndrome. J Clin Immunol. 1999 Nov;19(6):414-21. http://www.ncbi.nlm.nih.gov/pubmed/10634215

 

TNF-alpha and chronic fatigue syndrome

Abstract:

Based upon the clinical presentation of chronic fatigue syndrome (CFS), we hypothesized that proinflammatory cytokines may play a role in the pathogenesis of the disease. We therefore undertook a retrospective cross-sectional study to examine the role of TNF-alpha in patients with CFS. Our results suggest a significant increase serum TNF-alpha in patients with CFS (P<0.0001) compared to non-CFS controls. This study supports the further examination of the role of proinflammatory mediators in CFS. Furthermore, the clinical testing of TNF-alpha blockers and other antiinflammatory agents for the treatment of this disease is warranted.

 

Source: Moss RB, Mercandetti A, Vojdani A. TNF-alpha and chronic fatigue syndrome. J Clin Immunol. 1999 Sep;19(5):314-6. http://www.ncbi.nlm.nih.gov/pubmed/10535608

 

Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion

Abstract:

This study was conducted to evaluate the immunological response to an exhaustive treadmill exercise test in 20 female chronic fatigue syndrome patients compared to 14 matched sedentary controls. Venipuncture was performed at baseline and 4 min, 1 hr, and 24 hr postexercise.

White blood cells were labeled for monoclonal antibody combinations and were quantified by FACsan. Cytokines were assayed utilizing quantitative RT/PCR. No group difference was seen in VO2peak (28.6 +/- 1.6 vs 30.9 +/- 1.2 ml.kg-1.min-1; P > 0.05). However, 24 hr after exercise the patients’ fatigue levels were significantly increased (P < 0.05).

The counts of WBC, CD3+ CD8+ cells, CD3+ CD4+ cells, T cells, B cells, natural killer cells, and IFN-gamma changed across time (P’s < 0.01). No group differences were seen for any of the immune variables at baseline or after exercise (P’s > 0.05). The immune response of chronic fatigue syndrome patients to exhaustive exercise is not significantly different from that of healthy nonphysically active controls.

 

Source: LaManca JJ, Sisto SA, Zhou XD, Ottenweller JE, Cook S, Peckerman A, Zhang Q, Denny TN, Gause WC, Natelson BH. Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion. J Clin Immunol. 1999 Mar;19(2):135-42. http://www.ncbi.nlm.nih.gov/pubmed/10226888

 

Cytokine dysregulation in the post-Q-fever fatigue syndrome

Abstract:

The post-Q-fever fatigue syndrome (QFS) (inappropriate fatigue, myalgia and arthralgia, night sweats, changes in mood and sleep patterns) follows about 20% of laboratory-proven, acute primary Q-fever cases. Cytokine dysregulation resulting from chronic immune stimulation and modulation by persistence of Coxiella burnetii cells or their antigens is hypothesized.

We studied cytokine release patterns of peripheral blood mononuclear cells (PBMC) stimulated with various ligands in short-term culture, from 18 patients with active QFS, and 27 controls: six with resolving QFS, five who had had acute primary Q-fever without subsequent QFS, eight healthy Q-fever vaccinees and eight healthy subjects without Q-fever antibody. Conditioned media (CM) from PBMC stimulated in short-term culture with Q-fever antigens, PHA or measles antigen (as an unrelated antigen) were assayed for IL-2, IL-4, IL-5, IL-6, IL-10 and IFN gamma by AgEIA, and for IL-1 and TNF alpha/beta by bioassay.

Aberrant cytokine release patterns were observed with PBMC from QFS patients when stimulated with Q-fever antigens: an accentuated release of IL-6 which was significantly [p = 0.01, non-parametric one-way analysis of variance (ANOVA)] in excess of medians for all four control groups. With IL-2, the number of responders in the active QFS group was decreased relative to control groups (Fisher’s exact test, p = 0.01) whereas the number of IFN gamma responders was increased (Fisher’s exact test, p = 0.0008). Significant correlations were observed between concentrations of IL-6 in CM, total symptom scores, and scores for other key symptoms.

Comment in: Fatigue syndromes. [QJM. 1999]

 

Source: Penttila IA, Harris RJ, Storm P, Haynes D, Worswick DA, Marmion BP. Cytokine dysregulation in the post-Q-fever fatigue syndrome. QJM. 1998 Aug;91(8):549-60. http://qjmed.oxfordjournals.org/content/91/8/549.long (Full article)

 

Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome

Abstract:

The purpose of this study was to evaluate immune function through the assessment of lymphocyte subpopulations (total T cells, major histocompatibility complex [MHC] I- and II-restricted T cells, B cells, NK cells, MHC II-restricted T-cell-derived naive and memory cells, and several MHC I-restricted T-cell activation markers) and the measurement of cytokine gene expression (interleukin 2 [IL-2], IL-4, IL-6, IL-10, IL-12, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) from peripheral blood lymphocytes.

Subjects included two groups of patients meeting published case definitions for chronic fatigue syndrome (CFS)-a group of veterans who developed their illness following their return home from participating in the Gulf War and a group of nonveterans who developed the illness sporadically. Case control comparison groups were comprised of healthy Gulf War veterans and nonveterans, respectively.

We found no significant difference for any of the immune variables in the nonveteran population. In contrast, veterans with CFS had significantly more total T cells and MHC II+ T cells and a significantly higher percentage of these lymphocyte subpopulations, as well as a significantly lower percentage of NK cells, than the respective controls.

In addition, veterans with CFS had significantly higher levels of IL-2, IL-10, IFN-gamma, and TNF-alpha than the controls. These data do not support the hypothesis of immune dysfunction in the genesis of CFS for sporadic cases of CFS but do suggest that service in the Persian Gulf is associated with an altered immune status in veterans who returned with severe fatiguing illness.

 

Source: Zhang Q, Zhou XD, Denny T, Ottenweller JE, Lange G, LaManca JJ, Lavietes MH, Pollet C, Gause WC, Natelson BH. Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome. Clin Diagn Lab Immunol. 1999 Jan;6(1):6-13. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC95652/ (Full article)

 

Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis

Abstract:

The purpose of this study was to evaluate the immune dysfunction hypothesis of chronic fatigue syndrome (CFS) by comparing immunologic data from patients with CFS with data from patients with other fatiguing illnesses–major depression and multiple sclerosis (MS)–and with data from healthy sedentary controls.

The subjects were 65 healthy sedentary controls, 71 CFS patients (41 with no axis-I diagnosis), 23 patients with mild MS, and 21 patients with major depression. Blood was sampled and assayed for the following: (1) immunologic serologic variables–circulating immune complexes (i.e., Raji cell and C1q binding), immunoglobulins A, E, G, and M, and IgG subclasses; (2) cell surface activation markers–the proportion of CD4+ cells expressing CD45RA+ and CD45RO+ and the proportion of CD8+ cells expressing CD38+, CD11b-, HLA-DR+ and CD28+; and (3) natural killer (NK) total cell count as well as the proportion of lymphocytes expressing NK cell surface markers (i.e., CD3-/CD16+ and CD56+.

Of the 18 variables studied, differences between CFS patients and controls were found only for IgG1 and IgG3. When CFS patients were stratified by the presence or absence of concurrent axis-I disease, it was the group with axis-I disorder that had the lowest IgG1 values-contrary to expectation.

When data from patients with MS and major depression were also evaluated, the subclass deficiency was no longer significant. The one group to show evidence for immune activation (i.e., an elevated proportion of CD4+ cells expressing the CD45RA+ activation marker) was the group with mild MS.

These data support neither immune dysfunction nor immune activation in CFS or in major depression, for the variables studied. The reductions in IgG subclasses may be an epiphenomenon of patient or control subject composition. In contrast, MS, even in the mild and early stages, as in the patients studied here, is associated with immune activation.

 

Source: Natelson BH, LaManca JJ, Denny TN, Vladutiu A, Oleske J, Hill N, Bergen MT, Korn L, Hay J. Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis. Am J Med. 1998 Sep 28;105(3A):43S-49S. http://www.ncbi.nlm.nih.gov/pubmed/9790481