Category: Immune System

Increased neutrophil apoptosis in chronic fatigue syndrome

Abstract:

BACKGROUND/AIMS: Many patients with chronic fatigue syndrome (CFS) have symptoms that are consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection, this study examined whether this phenomenon also occurs in patients with CFS.

METHODS: Apoptosis was assessed in patients with CFS in conjunction with concentrations of the anti-inflammatory cytokine, transforming growth factor beta1 (TGFbeta1).

RESULTS: The 47 patients with CFS had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V binding, and increased expression of the death receptor, tumour necrosis factor receptor-I, on their neutrophils than did the 34 healthy controls. Patients with CFS also had raised concentrations of active TGFbeta1 (p < 0.005).

CONCLUSIONS: These findings provide new evidence that patients with CFS have an underlying detectable abnormality in their immune cells.

 

Source: Kennedy G, Spence V, Underwood C, Belch JJ. Increased neutrophil apoptosis in chronic fatigue syndrome. J Clin Pathol. 2004 Aug;57(8):891-3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770396/ (Full article)

 

Cellular and humoral immune abnormalities in Gulf War veterans

Abstract:

We examined 100 symptomatic Gulf War veterans (patients) and 100 controls for immunologic assays. The veterans and controls were compared for the percentage of T cells (CD3); B cells (CD19); helper:suppressor (CD4:CD8) ratio; natural killer (NK) cell activity; mitogenic response to phytohemagglutin (PHA) and pokeweed mitogen (PWM); level of immune complexes; myelin basic protein (MBP) and striated and smooth muscle autoantibodies; and antibodies against Epstein-Barr virus, cytomegalovirus, herpes simplex virus type 1 (HSV-1), HSV-2, human herpes Type 6 (HHV-6), and Varicella zoster virus (VZV).

The percentage of T cells in patients versus controls was not significantly different, whereas a significantly higher proportion of patients had elevated T cells compared with controls. The percentage of B cells was significantly elevated in the patients versus the controls. The NK cell (NK) activity was significantly decreased in the patients (24.8 +/- 16.5 lytic units) versus the controls (37.3 +/- 26.4 lytic units). The percentage of patients with lower than normal response to PHA and PWM was significantly different from controls. Immune complexes were significantly increased in the patients (53.1 +/- 18.6, mean +/- SD) versus controls (34.6 +/- 14.3). Autoantibody titers directed against MBP and striated or smooth muscle were significantly greater in patients versus controls.

Finally, the patients had significantly greater titers of antibodies to the viruses compared with the controls (p < 0.001). These immune alterations were detected 2-8 years after participation in the Gulf War. The immune alterations are consistent with exposure to different environmental factors. We conclude that Gulf War syndrome is a multifaceted illness with immune function alterations that may be induced by various factors and are probably associated with chronic fatigue syndrome.

 

Source: Vojdani A, Thrasher JD. Cellular and humoral immune abnormalities in Gulf War veterans. Environ Health Perspect. 2004 Jun;112(8):840-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1242010/ (Full article)

 

Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response

Abstract:

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations.

First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients.

Second, the activation of the protein kinase R enzyme, a characteristic feature in at least subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasodilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension.

Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.

 

Source: Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P. Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Med Hypotheses. 2004;62(5):759-65. http://www.ncbi.nlm.nih.gov/pubmed/15082102

 

Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?

Abstract:

Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory.

Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis.

This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition.

The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.

 

Source: Staines DR. Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry? Med Hypotheses. 2004;62(5):646-52. http://www.ncbi.nlm.nih.gov/pubmed/15082083

 

High levels of type 2 cytokine-producing cells in chronic fatigue syndrome

Abstract:

The aetiology of chronic fatigue syndrome (CFS) is not known. However, it has been suggested that CFS may be associated with underlying immune activation resulting in a Th2-type response. We measured intracellular production of interferon (IFN)-gamma and interleukin (IL)-2; type 1 cytokines), IL-4 (type 2) and IL-10 (regulatory) by both polyclonally stimulated and non-stimulated CD4 and CD8 lymphocytes from patients with CFS and control subjects by flow cytometry.

After polyclonal activation we found evidence of a significant bias towards Th2- and Tc2-type immune responses in CFS compared to controls. In contrast, levels of IFN-gamma, IL-2 and IL-10-producing cells were similar in both study groups. Non-stimulated cultures revealed significantly higher levels of T cells producing IFN-gamma or IL-4 in CFS patients. Concluding, we show evidence for an effector memory cell bias towards type 2 responsiveness in patients with CFS, as well as ongoing type 0 immune activation in unstimulated cultures of peripheral blood cells.

 

Source: Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004 Feb;135(2):294-302. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808936/ (Full article)

 

Immune modulation with a staphylococcal preparation in fibromyalgia/chronic fatigue syndrome: relation between antibody levels and clinical improvement

Abstract:

The aims of this study were to evaluate the serological response to treatment with staphylococcal vaccine in fibromyalgia/chronic fatigue syndrome patients and to explore the relationship between serological response and clinical effect.

Twenty-eight patients, half of whom served as controls, were recruited from a 6-month randomised trial in which repeated administration of the staphylococcal toxoid vaccine Staphypan Berna (Berna Biotech, Switzerland) was tested against placebo. Antibody status against extracellular toxins/enzymes, cell-wall components, and enterotoxins was evaluated at baseline and at endpoint. The clinical response to treatment was recorded in rating scales.

In the group receiving active treatment, significant serological changes were recorded, whereas no significant changes were found in controls. Treatment led to a significantly increased capacity of serum to neutralise alpha-toxin and a significant increase in serum IgG to alpha-toxin and lipase. Furthermore, the increase in these parameters combined paralleled the improvement in clinical outcome. Thus, the greater the serological response, the greater was the clinical effect.

In conclusion, this explorative study has shown that repeated administration of the Staphypan Berna vaccine in patients with fibromyalgia/chronic fatigue syndrome causes a serological response to several staphylococcal antigens, particularly to certain extracellular toxins and enzymes. The results further show that this response is related to the clinical outcome of treatment.

 

Source: Zachrisson O, Colque-Navarro P, Gottfries CG, Regland B, Möllby R. Immune modulation with a staphylococcal preparation in fibromyalgia/chronic fatigue syndrome: relation between antibody levels and clinical improvement. Eur J Clin Microbiol Infect Dis. 2004 Feb;23(2):98-105. Epub 2004 Jan 20. http://www.ncbi.nlm.nih.gov/pubmed/14735403

 

Influenza vaccination: is it appropriate in chronic fatigue syndrome?

Abstract:

Chronic fatigue syndrome (CFS) is a recognized clinical illness of unknown cause and pathophysiologic mechanisms. Immunizing patients against influenza would seem to be a prudent strategy since infection has been associated with symptom exacerbation. However, patients with CFS have demonstrated variable abnormalities in the immune system, the clinical significance of which is unclear. Anecdotal information has suggested that, due to the etiologic uncertainty surrounding CFS, many patients reject immunization, fearful of untoward effects. This article attempts to clarify the situation by reviewing immunologic findings in CFS and influenza vaccines in current use. Results from a recent survey of perceptions of patients with CFS regarding immunization revealed that 31% felt immunization was neither safe nor beneficial. This opinion was universal in those patients who had never received influenza vaccine. Among patients who had received vaccine and experienced an adverse effect, 26% felt the vaccine was safe and 28% felt it was beneficial. Among those who had received vaccine without an adverse effect, 45% believed the vaccine was safe, and 55% felt it was effective. CFS patients as a group expressed concern that influenza vaccine would alter an already dysfunctional immune system, or worsen CFS symptoms.

Significantly more patients with CFS who had never received influenza vaccine voiced this opinion than did patients who had received immunization for influenza in the past. Contrary to the opinions expressed by the sample, clinical trials in CFS have yet to find that any type of immunization has produced a deleterious effect on symptoms or functioning. Moreover, patients with CFS in a randomized, placebo-controlled, double-blind trial of influenza immunization produced an antibody titer in the protective range to inactivated trivalent influenza vaccine, although the geometric mean titer was slightly blunted compared with healthy vaccinees.

Although patients with CFS in placebo and active groups reported four times the number of post-injection adverse effects of healthy vaccinees, data re-analysis revealed that this finding was related to the overlap of common, post-influenza immunization symptoms and CFS constitutional symptoms. CFS is a poorly understood illness and some patients may believe in causal theories that lead to the rejection of disease prevention strategies such as immunization. However, influenza immunization appears to provide protective antibody levels without worsening CFS symptoms or causing excessive adverse effects. Efforts to motivate patients with CFS to obtain annual influenza immunization should take into account illness perceptions and concentrate on education based on placebo-controlled trials.

 

Source: Sleigh KM, Marra FH, Stiver HG. Influenza vaccination: is it appropriate in chronic fatigue syndrome? Am J Respir Med. 2002;1(1):3-9. http://www.ncbi.nlm.nih.gov/pubmed/14720070

 

Effect of bojungikki-tang on lipopolysaccharide-induced cytokine production from peripheral blood mononuclear cells of chronic fatigue syndrome patients

Abstract:

Bojungikki-tang (BIT) has been widely used to treat patients suffering from chronic fatigue syndrome (CFS). However, its effect has not been yet investigated experimentally. Based upon the clinical presentation of CFS, we hypothesized that cytokines may play a role in the pathogenesis of the disease. We studied the effect of BIT on lipopolysaccharide (LPS)-induced various cytokines production in peripheral blood mononuclear cells (PBMC) of CFS patients. Bojungikki-tang (1 mg/mL) significantly inhibited LPS-induced tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, transforming growth factor (TGF)-beta1 production by 63.55% +/- 0.19%, 55.06% +/- 0.27%, 48.23% +/- 0.48%, 54.09% +/- 0.76%, respectively (P < 0.05). Bojungikki-tang showed a slightly lower inhibitory effect of LPS-induced Interferon (IFN)-gamma production. These results suggest that BIT may be useful in treating fatigue associated with chronic diseases.

 

Source: Shin HY, Shin CH, Shin TY, Lee EJ, Kim HM. Effect of bojungikki-tang on lipopolysaccharide-induced cytokine production from peripheral blood mononuclear cells of chronic fatigue syndrome patients. Immunopharmacol Immunotoxicol. 2003 Nov;25(4):491-501. http://www.ncbi.nlm.nih.gov/pubmed/14686792

 

Identification of novel expressed sequences, up-regulated in the leucocytes of chronic fatigue syndrome patients

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is an increasing medical phenomenon of unknown aetiology leading to high levels of chronic morbidity. Of the many hypotheses that purport to explain this disease, immune system activation, as a central feature, has remained prominent but unsubstantiated. Supporting this, a number of important cytokines have previously been shown to be over-expressed in disease subjects. The diagnosis of CFS is highly problematic since no biological markers specific to this disease have been identified. The discovery of genes relating to this condition is an important goal in seeking to correctly categorize and understand this complex syndrome.

OBJECTIVE: The aim of this study was to screen for changes in gene expression in the lymphocytes of CFS patients.

METHODS: ‘Differential Display’ is a method for comparing mRNA populations for the induction or suppression of genes. In this technique, mRNA populations from control and test subjects can be ‘displayed’ by gel electrophoresis and screened for differing banding patterns. These differences are indicative of altered gene expression between samples, and the genes that correspond to these bands can be cloned and identified. Differential display has been used to compare expression levels between four control subjects and seven CFS patients.

RESULTS: Twelve short expressed sequence tags have been identified that were over-expressed in lymphocytes from CFS patients. Two of these correspond to cathepsin C and MAIL1 – genes known to be upregulated in activated lymphocytes. The expression level of seven of the differentially displayed sequences have been verified by quantifying relative level of these transcripts using TAQman quantitative PCR.

CONCLUSION: Taken as a whole, the identification of novel gene tags up-regulated in CFS patients adds weight to the idea that CFS is a disease characterized by subtle changes in the immune system.

 

Source: Powell R, Ren J, Lewith G, Barclay W, Holgate S, Almond J. Identification of novel expressed sequences, up-regulated in the leucocytes of chronic fatigue syndrome patients. Clin Exp Allergy. 2003 Oct;33(10):1450-6. http://www.ncbi.nlm.nih.gov/pubmed/14519154

 

Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome

Abstract:

Human parvovirus B19 infection has been associated with various clinical manifestations of a rheumatic nature such as arthritis, fatigue, and chronic fatigue syndrome (CFS), which can persist for years after the acute phase.

The authors have demonstrated recently that acute B19 infection is accompanied by raised circulating levels of IL-1b, IL-6, TNF-a, and IFN-g and that raised circulating levels of TNF-a and IFN-g persist and are accompanied by MCP-1 in those patients who develop CFS.

A resolution of clinical symptoms and cytokine dysregulation after intravenous immunoglobulin (IVIG) therapy, which is the only specific treatment for parvovirus B19 infection, also has been reported. Although CFS may be caused by various microbial and other triggers, that triggered by B19 virus is clinically indistinguishable from idiopathic CFS and exhibits similar cytokine abnormalities and may represent an accessible model for the study of CFS.

 

Source: Kerr JR, Tyrrell DA. Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome. Curr Pain Headache Rep. 2003 Oct;7(5):333-41. http://www.ncbi.nlm.nih.gov/pubmed/12946285