Category: Immune System

Single aetiological agent may not be feasible in CFS patients

Comment on: Cortisol deficiency may account for elevated apoptotic cell population in patients with chronic fatigue syndrome. [J Intern Med. 1999]

 

Dear Sir, I would like to thank Dr Baschetti for his very interesting letter. I hope clinicians and CFS patients will be able to benefit from its contents. We agree that chronic fatigue syndrome (CFS) is an illness with uncertain aetiology. Although it is true that no single infectious agent has been identified as a primary cause of CFS, a variety of pathogens, including HTLV-II, EBV, cytomegalovirus, herpes simplex viruses 1 and 2, and human herpes viruses 6, 7 and 8, have been identified in CFS patients [1–7]. In addition to the pathogens previously mentioned, a recent study by our laboratory has identified Mycoplasma fermentans in a statistically significant number of CFS patients over non-CFS control subjects [8]. Further investigation is necessary to determine whether these pathogens are occurring secondarily to some immunological disturbances, as some investigators believe, or whether they are involved as a primary cause of symptoms characteristic of CFS. As mentioned by Dr Baschetti, various measures of immune function have been reported to be altered in CFS subjects, thereby suggesting an association rather than demonstrating a causative link. Abnormalities that have been reported include increased circulating immune complexes, reduced CD4 and CD8 T-lymphocyte subsets, diminished natural killer cell activity, reduction in IgG subclasses, reduced mitogenic response of lymphocytes, altered cytokine production, elevated titres of antibodies to a number of viruses and abnormal production of IFN [9–15]. However, similar immune functional abnormalities have been reported in patients exposed to toxic chemicals without evidence of viral infection or reactivation [16, 17]. Moreover, the symptomatologies described in these patients overlap with CFS patients, thus making the differentiation between the two groups extremely difficult [18–21]. In these articles, the substantial overlap between chemical sensitivity, fibromyalgia and CFA was discussed. It was concluded that the latter two conditions may involve chemical sensitivity and may even be the same disorder. In fact, in a separate study strictly with CFS patients without evidence of viral reactivation but exposed to methyl tertiary-butyl ether (MTBE) and benzene, we showed that programmed cell death and cell cycle were abnormal in both groups [22]. Similarly, in our original article published in this journal, we reported elevated apoptosis and abnormal cell cycle in CFS patients without a history of exposure to toxic chemicals. The interferon-induced protein kinase RNA (PKR) was found to be elevated in these patients as well and was therefore proposed as a possible mechanism of induction of apoptosis and cell cycle abnormalities [23].

 

You can read the rest of this comment here: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.1999.00479.x/full

 

Source: Vojdani A. Single aetiological agent may not be feasible in CFS patients. J Intern Med. 1999 Apr;245(4):410-2. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.1999.00479.x/full

 

Cortisol deficiency may account for elevated apoptotic cell population in patients with chronic fatigue syndrome

Comment in: Single aetiological agent may not be feasible in CFS patients. [J Intern Med. 1999]

Comment on: Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. [J Intern Med. 1997]

 

Dear Sir, Vojdani et al. [1] report that patients with chronic fatigue syndrome (CFS) display an increased apoptotic cell population. This abnormality, according to the authors, is due to the activation of protein kinase RNA pathway, which, in turn, ‘could result from disregulated immune system or chronic viral infection’[1].The latter explanation, however, seems unlikely, because no specific virus has been identified in CFS patients, despite extensive research [2]. Special attention, therefore, should mainly be paid to the immune system of CFS patients, because its repeatedly reported abnormalities may help reveal both the aetiology of CFS and an effective treatment against it.

As Vojdani et al. [1] point out, decreased natural killer (NK) cell activity and altered cytokine production characterize CFS patients. These immunological abnormalities, however, may simply reflect the hypocortisolism of CFS patients [3], because a mere lack of steroid restraint on the immune system may well account for its derangement [3]. In fact, since NK cell activity is directly associated with the circadian rhythm of cortisol [4], the decreased NK cell activity observed in CFS patients may simply be due to their cortisol deficiency [3]. The latter, additionally, may also explain why the release of the cytokines interleukin-lβ, interleukin-6, and tumour necrosis factor-α has been found to be increased in peripheral blood mononuclear cell cultures from patients with CFS [5]. All those cytokines, in fact, have been reported to rise during hypocortisolism [6]. This suggests, therefore, that the cortisol deficiency of CFS patients may play a central role in causing both their immunological abnormalities and, presumably, their elevated apoptotic cells.

In view of the role of hypocortisolism in CFS, Vojdani and coworkers might be interested in determining whether the enhanced apoptosis found in their subjects with CFS could be reduced by giving them small daily doses of hydrocortisone and fludrocortisone. The latter, notably, already has been reported to be of great benefit to CFS patients [7]. The rationale for treating CFS patients with the two steroids that are routinely administered to Addisonian patients [8] lies primarily in the fact that no medical condition, except Addison’s disease, shares 20 features with CFS [3]. Five additional symptoms (dizziness upon standing, orthostatic tachycardia, nausea, diarrhoea, and constipation) can be found in both CFS [9] and Addison’s disease [8, 10, 11]. Rather surprisingly, however, despite the staggering similarities between CFS and Addison’s disease, as yet no published attempt has been made to treat CFS patients with both hydrocortisone and fludrocortisone.

You can read the rest of this comment here: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.1999.00478.x/full

 

Source: Baschetti R. Cortisol deficiency may account for elevated apoptotic cell population in patients with chronic fatigue syndrome. J Intern Med. 1999 Apr;245(4):409-10. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.1999.00478.x/full

 

Chronic fatigue syndrome and nickel allergy

Abstract:

50 patients with chronic fatigue syndrome (CFS) and 73 controls were patch tested with 8 metal allergens. We found an overrepresentation of allergies among the CFS patients, which was not significant. However, allergy to nickel occurred in 36% of patients in the CFS group and in 19% of subjects in the control group (p<0.05). The high frequency of nickel allergy was more noteworthy in females in the CFS group than among female controls (52% and 24%, respectively, p<0.05). Similarly, in the males the figures were 14% and 9%. We suggest that in vivo immunoactivation by ions of nickel, or metal cross-reacting with nickel, could be an etiological factor in CFS.

 

Source: Marcusson JA, Lindh G, Evengård B. Chronic fatigue syndrome and nickel allergy. Contact Dermatitis. 1999 May;40(5):269-72. http://www.ncbi.nlm.nih.gov/pubmed/10344482

 

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

 

Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during ‘natural fatigue’ but not following ‘experimental fatigue’ in patients with chronic fatigue syndrome

Abstract:

In an investigator-blinded study, adherent (monocytes) and non-adherent cells (lymphocytes) from patients with chronic fatigue syndrome (CFS) were examined on two separate occasions (when feeling ‘fatigued’ and when feeling ‘rested’) for in vitro spontaneous, phytohemagglutinin- (PHA, for lymphocytes), and lipopolysaccharide- (LPS, for monocytes) induced production of IL-6 by ELISA assay.

A group of CFS patients and controls were also subjected to exercise-induced fatigue (‘experimental fatigue’) and IL-6 production was compared, in a double-blinded manner, prior to and following induction of fatigue.

A significant increase in spontaneous, PHA- and LPS-induced IL-6 secretion by both lymphocytes and monocytes was observed in CFS patients during ‘natural fatigue’ as compared to during state. However, no such changes in IL-6 production were observed during ‘experimental fatigue’.

These data suggest a role of IL-6 in natural symptomatology and perhaps in the pathogenesis of CFS. In addition, the data demonstrate that laboratory-induced fatigue (experimental fatigue) may not be a good model to study immunological changes in CFS; immunological parameters should be studied in a longitudinal manner during the natural course of the disease.

 

Source: Gupta S, Aggarwal S, Starr A. Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during ‘natural fatigue’ but not following ‘experimental fatigue’ in patients with chronic fatigue syndrome. Int J Mol Med. 1999 Feb;3(2):209-13. http://www.ncbi.nlm.nih.gov/pubmed/9917531

 

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)

 

The in vitro immunomodulatory effects of glyconutrients on peripheral blood mononuclear cells of patients with chronic fatigue syndrome

Abstract:

In humans, eight monosaccharides are required for the synthesis of glycoproteins. Dietary supplements that supply these crucial sugars are known as glyconutrients. A glyconutrient compound was added to Peripheral Blood Mononuclear Cells (PBMC) isolated from normal controls and patients with the Chronic Fatigue Syndrome (CFS), a disease associated with immune dysregulation. The in vitro immunomodulatory effects were investigated.

Cell surface expression of the glycoproteins CD5, CD8, and CD11a were significantly lower in patients with CFS compared to normal controls. Addition of glyconutrient homogenate to PBMC from patients with CFS stimulated with phytohemagglutinin significantly increased the expression of each glycoprotein.

Furthermore, natural killer (NK) cell function was reduced in CFS patients. The glyconutrient preparation significantly enhanced NK cell activity versus human herpes virus 6 (HHV-6)-infected H9 cells in an 8 h 51Cr release assay compared to placebo for PBMC from patients with CFS (p< .01).

Finally, apoptosis was significantly higher in patients with CFS. The percentage of apoptotic cells was significantly decreased in PBMC from patients with CFS that had been incubated for 48 h with glyconutrients. Thus, glyconutrients improved abnormal immune parameters in vitro in patients with CFS.

 

Source: See DM, Cimoch P, Chou S, Chang J, Tilles J. The in vitro immunomodulatory effects of glyconutrients on peripheral blood mononuclear cells of patients with chronic fatigue syndrome. Integr Physiol Behav Sci. 1998 Jul-Sep;33(3):280-7. http://www.ncbi.nlm.nih.gov/pubmed/9829439

 

Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome

Abstract:

BACKGROUND: L-Arginine (L-Arg), one of the essential amino acids, has been reported to have an immunomodulatory effect. The precise mechanism of the L-Arg-induced natural killer (NK) cell activation remains unresolved,and the effect of L-Arg on NK cells in chronic fatigue syndrome (CFS) patients has not been estimated.

METHODS: NK cell function was evaluated in 20 subjects with CFS and compared with that in 21 healthy individuals.

RESULTS: In healthy control subjects, NK activity was significantly increased after treatment with L-Arg, an NK function enhancer, for 24 h, whereas the same treatment failed to enhance NK activity in the CFS patients. We thus focused on L-Arg metabolism, which involves nitric oxide (NO) production through NO synthase (NOS). The expression of inducible NO synthase (iNOS) transcripts in peripheral blood mononuclear cells was not significantly different between healthy control subjects and CFS patients. The L-Arg-mediated NK cell activation was abolished by addition of NG-monomethyl-L-arginine, an inhibitor for iNOS. Furthermore, incubation with S-nitroso-N-acetyl-penicillamine, an NO donor, stimulated NK activity in healthy control subjects but not in CFS patients.

CONCLUSION: These results demonstrate that the L-Arg-induced activation of NK activity is mediated by NO and that a possible dysfunction exists in the NO-mediated NK cell activation in CFS patients.

 

Source: Ogawa M, Nishiura T, Yoshimura M, Horikawa Y, Yoshida H, Okajima Y, Matsumura I, Ishikawa J, Nakao H, Tomiyama Y, Kanayama Y, Kanakura Y,Matsuzawa Y. Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome. Eur J Clin Invest. 1998 Nov;28(11):937-43. http://www.ncbi.nlm.nih.gov/pubmed/9824439

 

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