Cytokines
Cannon JG, Angel JB, Abad LW, Vannier E, Mileno MD, Fagioli L, Wolff SM, Komaroff AL. Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome. Journal of Clinical Immunology 1997; 17(3): 253-61.
Abstract: Chronic fatigue syndrome is a condition that affects women in disproportionate numbers, and that is often exacerbated in the premenstrual period and following physical exertion. The signs and symptoms, which include fatigue, myalgia, and low-grade fever, are similar to those experienced by patients infused with cytokines such as interleukin-1. The present study was carried out to test the hypotheses that (1) cellular secretion of interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-1 receptor type II (IL-1sRII) is abnormal in female CFS patients compared to age- and activity-matched controls; (2) that these abnormalities may be evident only at certain times in the menstrual cycle; and (3) that physical exertion (stepping up and down on a platform for 15 min) may accentuate differences between these groups. Isolated peripheral blood mononuclear cells from healthy women, but not CFS patients, exhibited significant menstrual cycle-related differences in IL-1 beta secretion that were related to estradiol and progesterone levels (R2 = 0.65, P <0.01). IL-1Ra secretion for CFS patients was twofold higher than controls during the follicular phase (P="0.023)," but luteal-phase levels were similar between groups. In both phases of the menstrual cycle, IL-1sRII release was significantly higher for CFS patients compared to controls (P="0.002)." The only changes that might be attributable to exertion occurred in the control subjects during the follicular phase, who exhibited an increase in IL-1 beta secretion 48 hr after the stress (P="0.020)." These results suggest that an abnormality exists in IL-1 beta secretion in CFS patients that may be related to altered sensitivity to estradiol and progesterone. Furthermore, the increased release of IL-1Ra and sIL-1RII by cells from CFS patients is consistent with the hypothesis that CFS is associated with chronic, low-level activation of the immune system.
Chao CC, Gallagher M, Phair J, Peterson PK. Serum neopterin and interleukin-6 levels in chronic fatigue syndrome [Letter]. Journal of Infectious Diseases 1990; 162: 1412-1413.
Chao CC, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, Peterson PK. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine 1991; 3(4): 292-298.
Abstract: Chronic fatigue syndrome (CFS) is an idiopathic illness associated with a variety of immunologic abnormalities. To investigate potential pathogenetic mechanisms, we evaluated serum levels and peripheral blood mononuclear cell (PBMC) production of selected cytokines and immunoglobulins. Serum bioactive transforming growth factor beta (TGF-beta) levels were higher (P less than 0.01) in patients with CFS (290 ± 46 pg/mL) than in control subjects (104 ± 18 pg/mL), but levels of other cytokines tested were not different. Lipopolysaccharide-stimulated release of interleukin 1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha was increased (P less than 0.05) in PBMC cultures from patients with CFS versus control subjects; enhanced (P less than 0.01) IL-6 release to phytohemagglutinin was also observed. In contrast, TGF-beta release in response to lipopolysaccharide was depressed (P less than 0.01) in PBMC cultures derived from patients with CFS. No differences in IL-2 and IL-4 or immunoglobulin production were observed. The enhanced release of inflammatory cytokines by stimulated PBMC from patients with CFS suggests that these cells are primed for an increased response to immune stimuli. These data also suggest an association between abnormal regulation of TGF-beta production in vivo and in vitro with the immunologic consequence of CFS.
Cheney PR, Dorman SE. Interleukin-2 and the chronic fatigue syndrome [Letter]. Annals of Internal Medicine 1989; 110: 321.
Gupta S, Aggarwal S, See D, Starr A. Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome. Journal of Psychiatric Research 1997; 31(1): 149-56.
Abstract: It has been suggested that cytokines play a role in certain clinical manifestations of chronic fatigue syndrome (CFS). In this study adherent (monocytes) and non-adherent (lymphocytes) mononuclear cells were stimulated in the presence or absence of phytohemagglutinin (PHA) or lipopolysaccharide (LPS), respectively, and supernatants were assayed for IL-6, TNF-alpha, and IL-10 by ELISA. IL-6 was also measured at the mRNA level by polymerase chain reaction. The levels of spontaneously (unstimulated) produced TNF-alpha by non-adherent lymphocytes and spontaneously produced IL-6 by both adherent monocytes and non-adherent lymphocytes were significantly increased as compared to simultaneously studied matched controls. The abnormality of IL-6 was also observed at mRNA level. In contrast, spontaneously produced IL-10 by both adherent and non-adherent cells and by PHA-activated non-adherent cells were decreased. This preliminary study suggests that an aberrant production of cytokines in CFS may play a role in the pathogenesis and in some of the clinical manifestations of CFS.
Ho-Yeu DO, Carrington D, Armstrong AA. Myalgic encephalomyelitis and alpha-interferon [Letter]. Lancet 1988; 1: 125.
Lever AML, Lewis DM, Bannister BA, et al. Interferon production in postviral syndrome [Letter]. Lancet 1988; 2: 101.
Linde A, Andersson B, Svenson SB, Ahrne H, Carlsson M, Forsberg P, Hugo H, Karstorp A, Lenkei R, Lindwall A, et al. Serum levels of lymphokines and soluble cellular receptors in primary Epstein-Barr virus infection and in patients with chronic fatigue syndrome. Journal of Infectious Diseases 1992; 165(6): 994-1000.
Abstract: The immunopathology in primary Epstein-Barr virus (EBV) infections and in chronic fatigue syndrome was studied by examining serum levels of interleukins (IL) and of soluble T cell receptors in serum samples. Serum samples were from patients during and 6 months after primary EBV-induced infectious mononucleosis and from patients with chronic fatigue syndrome and serologic evidence of EBV reactivation. Markers for T lymphocyte activation (soluble IL-2 and CD8) and for monocyte activation (neopterin) were significantly elevated during acute infectious mononucleosis but not in patients with chronic fatigue syndrome. Interferon-alpha, IL-1 beta, and IL-6 levels were not significantly increased in any patient group but inferferon-gamma levels were significantly increased during the acute phase of infectious mononucleosis. The levels of IL-1 alpha were significantly higher than in controls both in patients with infectious mononucleosis and in those with chronic fatigue syndrome. In the latter, the lack of most markers for lymphocyte activation found in patients with infectious mononucleosis makes it less likely that EBV reactivation causes symptoms.
Lloyd A, Gandevia S, Brockman A, Hales J, Wakefield D. Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise. Clinical Infectious Diseases 1994; 18(Supp 1): S142-6.
Abstract: We have studied the relationship between the cytokine production induced in vivo by prolonged isometric exercise and the symptom complex marked by fatigue in patients with chronic fatigue syndrome (CFS). Twelve male patients and 13 matched male control subjects undertook an isometric hand-grip exercise protocol utilizing dynamometers. Subjects undertook 30 minutes of exercise, for which the target force was set at 40% of the maximal voluntary contraction and the duty cycle was 50%. Prior to, during, and for 24 hours following the exercise, blood samples were collected and assayed for the presence of cytokines, including interferon-gamma and interferon-alpha, interleukin-1 beta, and tumor necrosis factor-alpha. At those times subjects also completed the Profile of Mood States (POMS) questionnaire, which served as a measure of changes in subjective fatigue. No significant alteration in the level of any of the cytokines in the plasma of patients or control subjects was detected before, during, or after exercise. Surprisingly, the patients' levels of fatigue, depression, and confusion, as measured by the POMS, decreased in response to the exercise. These data do not confirm the presence of an immunologic process correlating with the exacerbation of fatigue after exercise experienced by patients with CFS. Limitations in the study design and in the sensitivity of the cytokine assays may have affected our results.
Lloyd AR, Hanna DA, Wakefield D. Interferon-2 and the chronic fatigue syndrome [Letter]. Lancet 1988; 1: 471.
MacDonald KL, Osterholm MT, LeDell KH, White KE, Schenck CH, Chao CC, Persing DH, Johnson RC, Barker JM, Peterson PK. A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome. American Journal of Medicine 1996; 100(5): 548-54.
Abstract: PURPOSE: To assess possible triggers and cofactors for chronic fatigue syndrome (CFS) and to compare levels of selected cytokines between cases and an appropriately matched control group. PATIENTS AND METHODS: We conducted a case-control study of 47 cases of CFS obtained through a regional CFS research program maintained at a tertiary care medical center. One age-, gender-, and neighborhood-matched control was identified for each case through systematic community telephone sampling. Standardized questionnaires were administered to cases and controls. Sera were assayed for transforming growth factor-beta (TGF-beta), interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and antibody to Borrelia burgdorferi and Babesia microti. RESULTS: Cases were more likely to have exercised regularly before illness onset than controls (67% versus 40%; matched odds ratio (MOR) = 3.4; 95% CI = 1.2 to 11.8; P = 0.02). Female cases were more likely to be nulliparous prior to onset of CFS than controls (51% versus 31%; MOR = 8.0; 95% CI = 1.03 to 170; P = 0.05). History of other major factors, including silicone-gel breast implants (one female case and one female control), pre-morbid history of depression (15% of cases, 11% of controls) and history of allergies (66% of cases, 51% of controls) were similar for cases and controls. However, cases were more likely to have a diagnosis of depression subsequent to their diagnosis of CFS compared to a similar time frame for controls (MOR = undefined; 95% CI lower bound = 2.5; P <0.001). Positive antibody titers to B burgdorferi (one case and one control) and B microti (zero cases and two controls) were also similar. CONCLUSIONS: Further investigation into the role of prior routine exercise as a cofactor for CFS is warranted. This study supports the concurrence of CFS and depression, although pre-morbid history of depression was similar for both groups.
McDonald EM, Mann AH, Thomas. Interferons as mediators of psychiatric morbidity. Lancet 1987; 2: 1175-1178.
Abstract: A significant increase in psychiatric morbidity, assessed by standard measures, was demonstrated in a group of patients receiving recombinant gamma-interferon for chronic hepatitis-B virus infection. In some cases the psychiatric symptoms were severe enough to need urgent psychiatric attention. The changes seemed most severe in patients with coexistent human immunodeficiency infection. The mental state changes are clinically reminiscent of those in the "post-viral" psychiatric symptoms.
Morte S, Castilla A, Civeira MP, Serrana M, Prieto J. Gamma-interferon and chronic fatigue syndrome [Letter]. Lancet 1988; 2: 623-4.
Morte S, Castilla A, Civeira MP, Serrano M, Prieto J. Production of interleukin-1 by peripheral blood mononuclear cells in patients with chronic fatigue syndrome. Journal of Infectious Diseases 1989; 159: 362.
Patarca R, Klimas N, Sandler D, Garcia MN, Fletcher MA. Interindividual immune status variation patterns with chronic fatigue syndrome: association with gender and the tumor necrosis factor system. Journal of Chronic Fatigue Syndrome 1996; 2(1): 13-39.
Abstract: Changes in soluble immune mediator levels in association with the chronic fatigue syndrome (CFS) usually occur within normal ranges and are apparent mainly as changes in the skewness of population distributions. The latter finding undermines the usefulness of cytokine levels as clinical tools at the individual level as has been seen in sepsis syndrome where a similar overlap occurs. Nonetheless, changes in cytokine levels at the population level can contribute to an understanding of the disease process. For example, we reported previously that significant proportions of CFS patients showed elevated serum levels of either soluble tumor necrosis factor-receptor I (STNF-RI, sCD120a) or TNF-alpha, as compared to controls. The latter results could reflect different disease processes or extremes of a common disease process. Using sera collected over a five-year period, we have now studied an extended cohort of 108 CFS patients and our results are consistent with a common graded disease process. When we assessed the effect of gender on the distributions of serum levels of immune mediators, levels of sTNF-RI,sTNF-RII (sCD120b), sIL-6R (sCD126), and sICAM-1 were found to be consistently higher among males than females and among CFS patients as compared to controls regardless of gender. Moreover, differences in soluble immune mediator levels between CFS and control individuals were more clearly defined when restricting the analysis to the female gender. These observations are consistent with endocrine influences on immunological changes.
Patarca R, Klimas NG, Lutgendorf S, Antoni M, Fletcher MA. Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome - interrelations with cellular sources and patterns of soluble immune mediator expression. Clinical Infectious Diseases 1994; 18(Supp 1): S147-53.
Abstract: Among a group of 70 individuals who met the criteria established by the Centers for Disease Control and Prevention (Atlanta) for chronic fatigue syndrome (CFS), 12%-28% had serum levels exceeding 95% of control values for tumor necrosis factor (TNF) alpha, TNF-beta, interleukin (IL) 1 alpha, IL-2, soluble IL-2 receptor (sIL-2R), or neopterin; overall, 60% of patients had elevated levels of one or more of the nine soluble immune mediators tested. Nevertheless, only the distributions for circulating levels of TNF-alpha and TNF-beta differed significantly in the two populations. In patients with CFS—but not in controls—serum levels of TNF-alpha, IL-1 alpha, IL-4, and sIL-2R correlated significantly with one another and (in the 10 cases analyzed) with relative amounts (as compared to beta-globin or beta-actin) of the only mRNAs detectable by reverse transcriptase-coupled polymerase chain reaction in peripheral-blood mononuclear cells: TNF-beta, unspliced and spliced; IL-1 beta, lymphocyte fraction; and IL-6 (in order of appearance). These findings point to polycellular activation and may be relevant to the etiology and nosology of CFS.
Straus SE, Dale JK, Peter JB, Dinarello CA. Circulating lymphokine levels in the chronic fatigue syndrome [Letter]. Journal of Infectious Diseases 1989; 160: 1085-6.