Category: Immune System

Role of pathological delayed-type hypersensitivity in chronic fatigue syndrome: importance of the evaluation of lymphocyte activation by flow cytometry and the measurement of urinary neopterin

Abstract:

Chronic fatigue syndrome or benign myalgic encephalomyelitis has been extensively described and investigated. Although numerous immunological abnormalities have been linked with the syndrome, none have been found to be specific.

This article describes the detection of delayed-type hypersensitive responses to certain common environmental antigens in almost fifty per cent of patients with this syndrome. Such hypersensitivity can be detected by the intradermal administration of antigens derived from commensal organisms like the yeast Candida albicans, and then monitoring for a systemic reaction over the following six to forty eight hours. This approach can be consolidated by performing lymphocyte activation tests in parallel and measuring in vitro T-cell activation by Candida albicans antigens by three-colour flow cytometry based on CD3, CD4 and either CD69 or CD25.

Another useful parameter is the kinetics of neopterin excretion in the urine over the course of the skin test. The results showed that the intensity of the DTH response correlated with the number of T-cells activated in vitro. Various factors have been implicated in the fatigue of many patients, notably lack of sleep. However, it remains difficult to establish causality in either one direction or the other. This work is in the spirit of a multifactorial approach to the group of conditions referred to as “chronic fatigue syndrome”.

 

Source: Brunet JL, Fatoohi F, Liaudet AP, Cozon GJ. Role of pathological delayed-type hypersensitivity in chronic fatigue syndrome: importance of the evaluation of lymphocyte activation by flow cytometry and the measurement of urinary neopterin. Allerg Immunol (Paris). 2002 Feb;34(2):38-44. [Article in French] http://www.ncbi.nlm.nih.gov/pubmed/11933752

 

Cellular immunity in monozygotic twins discordant for chronic fatigue syndrome

Abstract:

Studies elsewhere have suggested that immune dysfunction may be common in patients with chronic fatigue syndrome (CFS). The objective of this study was to assess the nature and extent of abnormalities in lymphocyte cell surface markers and NK cell activity in patients with CFS while controlling for genetic factors. A co-twin control study of immune system parameters was conducted for 22 pairs of monozygotic twins discordant for CFS and 9 healthy pairs of twins.

The CFS twins had greater numbers of CD62L(+) T cells in several T cell subsets, although these differences did not achieve statistical significance. Significantly greater variability was noted in twins discordant for CFS than in the concordant healthy twins for 20 of 48 variables examined. The monozygotic co-twin control design is of unique value because of its ability to control for genetic influences on CFS; however, additional studies will be required to further assess immune dysregulation in this illness.

 

Source: Sabath DE, Barcy S, Koelle DM, Zeh J, Ashton S, Buchwald D. Cellular immunity in monozygotic twins discordant for chronic fatigue syndrome. J Infect Dis. 2002 Mar 15;185(6):828-32. Epub 2002 Feb 28. http://jid.oxfordjournals.org/content/185/6/828.long (Full article)

 

Prevalence of allergen-specific IgE among patients with chronic fatigue syndrome

Abstract:

The prevalence of atopy among patients having chronic fatigue syndrome (CFS) has been reported to be as high as 80% in published surveys of patients with this syndrome. However, many of the reports relied on self-assessment by patients for the presence of atopy or solely used total immunoglobulin E (IgE) levels to assess the likelihood of atopy.

To more critically assess the presence of atopy among patients with CFS, testing was done for total IgE and allergen-specific IgE using the Pharmacia CAP system including 20 common allergens: trees (birch/oak/ash), grass (rye/blue), weeds (common/giant ragweed), molds (Penicillium/Aspergillus/Alternaria), dust mites (Dermatophagoides pteronyssinus/Dermatophagoides farinae), animal dander (cat/dog), and foods (egg white/milk/wheat/corn/peanut/shrimp).

Testing of 50 patients having documented CFS indicated that 78% had total IgE < 100 IU/mL, among whom 26% had a positive test for allergen-specific IgE of class I or greater for one or more allergens. Among the 22% of CFS patients having a total IgE > 100 IU/mL, 73% had a positive test for allergen-specific IgE for one or more allergens. The most commonly positive allergens were dust mites (24-26%), whereas molds (0-6%) and foods (0-4%) were rarely positive. The overall frequency of positive results for the presence of allergen-specific IgE among CFS patients was 36%, not significantly different from the normal prevalence of these antibodies in the general population (20-35%). This assessment of the prevalence of allergen-specific IgE antibodies in patients with CFS fails to support a potential association between CFS and atopy.

 

Source: Kowal K, Schacterele RS, Schur PH, Komaroff AL, DuBuske LM. Prevalence of allergen-specific IgE among patients with chronic fatigue syndrome. Allergy Asthma Proc. 2002 Jan-Feb;23(1):35-9. http://www.ncbi.nlm.nih.gov/pubmed/11894732

 

A biochemical analysis of people with chronic fatigue who have Irlen Syndrome: speculation concerning immune system dysfunction

Abstract:

This study investigated the biological basis of visual processing disabilities in adults with Chronic Fatigue Syndrome. The study involved 61 adults with symptoms of Chronic Fatigue Syndrome who were screened for visual processing problems (Irlen Syndrome) and divided into two groups according to the severity of symptoms of Irlen Syndrome.

Significant variations were identified in blood lipids and urine amino and organic acids of the two groups, which may be indicative of activation of the immune system due to some infective agent. It was suggested that metabolic profiling may help the development of more valid diagnostic categories and allow more investigation of immune system dysfunction as a possible causal factor in a range of learning and behaviour disorders.

 

Source: Robinson GL, McGregor NR, Roberts TK, Dunstan RH, Butt H. A biochemical analysis of people with chronic fatigue who have Irlen Syndrome: speculation concerning immune system dysfunction. Percept Mot Skills. 2001 Oct;93(2):486-504. http://www.ncbi.nlm.nih.gov/pubmed/11769907

 

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

 

Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection

Abstract:

Gene expression of key enzymes in 2 antiviral pathways (ribonuclease latent [RNase L] and RNA-regulated protein kinase [PKR]) was compared in 22 patients with chronic fatigue syndrome (CFS), 10 patients with acute gastroenteritis, and 21 healthy volunteers. Pathway activation in the group of patients with infections differed significantly from that of the other 2 groups, in whom there was no evidence of upregulation. Therefore, assay of activation is unlikely to provide the basis for a diagnostic test for CFS.

Comment in: Antiviral pathway activation in chronic fatigue syndrome and acute infection. [Clin Infect Dis. 2002]

 

Source: Gow JW, Simpson K, Behan PO, Chaudhuri A, McKay IC, Behan WM. Antiviral pathway activation in patients with chronic fatigue syndrome and acute infection. Clin Infect Dis. 2001 Dec 15;33(12):2080-1. Epub 2001 Nov 6. http://cid.oxfordjournals.org/content/33/12/2080.long (Full article)

 

A twin study of the etiology of prolonged fatigue and immune activation

Abstract:

Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors.

Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwin-crosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation.

By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49-0.69 versus 0.42-0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = -0.07 to -0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation.

PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.

 

Source: Hickie IB, Bansal AS, Kirk KM, Lloyd AR, Martin NG. A twin study of the etiology of prolonged fatigue and immune activation. Twin Res. 2001 Apr;4(2):94-102. http://www.ncbi.nlm.nih.gov/pubmed/11665341

 

IgE levels are the same in chronic fatigue syndrome (CFS) and control subjects when stratified by allergy skin test results and rhinitis types

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) has an uncertain pathogenesis. Allergies have been suggested as one cause.

OBJECTIVE: The aim of this study was to compare serum immunoglobulin (Ig)E in CFS and control subjects to determine whether IgE levels were elevated in CFS. This would be suggestive of increased atopy in CFS.

METHODS: IgE was measured by quantitative ELISA (sandwich) immunoassay in 95 CFS and 109 non-CFS control subjects. Subjects were classified by positive or negative allergy skin tests (AST) and rhinitis questionnaires (rhinitis score, RhSc) into four rhinitis types: nonallergic rhinitis (NAR with positive RhSc and negative AST); allergic rhinitis (AR with positive AST and RhSc); atopic/no rhinitis (AST positive/RhSc negative); and nonatopic/no rhinitis (both AST and RhSc negative) subjects.

RESULTS: IgE was not significantly different between control (128 +/- 18 IU/mL, mean +/- SEM) and CFS (133 +/- 43 IU/mL) groups, or between control and CFS groups classified into the four rhinitis types. IgE was significantly higher in subjects with positive AST whether or not they had positive RhSc or CFS symptoms.

CONCLUSIONS: Elevated IgE and positive AST indicate allergen sensitization, but are not necessarily indicators of symptomatic allergic diseases. There was no association between IgE levels and CFS, indicating that atopy was probably not more prevalent in CFS. Therefore, TH2-lymphocyte and IgE-mast cell mechanisms are unlikely causes of CFS.

 

Source: Repka-Ramirez MS, Naranch K, Park YJ, Velarde A, Clauw D, Baraniuk JN. IgE levels are the same in chronic fatigue syndrome (CFS) and control subjects when stratified by allergy skin test results and rhinitis types. Ann Allergy Asthma Immunol. 2001 Sep;87(3):218-21. http://www.ncbi.nlm.nih.gov/pubmed/11570618

 

Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders

Abstract:

OBJECTIVE: To identify antinuclear antibodies (ANA) specific for chronic fatigue syndrome (CFS), and in related conditions such as fibromyalgia (FM) or psychiatric disorders.

METHODS: One hundred and fourteen CFS patients and 125 primary and secondary FM patients were selected based on criteria advocated by the Centers for Disease Control and Prevention and by the American College of Rheumatology, respectively. As controls, healthy subjects and patients with either various psychiatric disorders or diffuse connective tissue diseases were included. Autoantibodies were examined by immunoblot utilizing HeLa cell extracts as the antigen.

RESULTS: Autoantibodies to a 68/48 kDa protein were present in 13.2 and 15.6% of patients with CFS and primary FM, respectively. In addition, autoantibodies to a 45 kDa protein were found in 37.1 and 21.6% of the patients with secondary FM and psychiatric disorders, respectively. Meanwhile, these two autoantibodies were not found at all in connective tissue disease patients without FM, nor in healthy subjects (P<0.05). As a group, the anti-68/48 kDa-positive CFS patients presented more frequently with hypersomnia (P<0.005), short-term amnesia (P<0.07) or difficulty in concentration (P<0.05) than those CFS patients without the antibodies.

CONCLUSIONS: The presence of the anti-68/48 kDa protein antibodies in a portion of both CFS and primary FM patients suggests the existence of a common immunological background. These antibodies may find utility as possible markers for a clinicoserological subset of CFS/FM patients with hypersomnia and cognitive complaints.

 

Source: Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka S, Akiya K. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology (Oxford). 2001 Jul;40(7):806-10. http://rheumatology.oxfordjournals.org/content/40/7/806.long (Full article)

 

Metal-specific lymphocytes: biomarkers of sensitivity in man

Abstract:

Many patients attribute their health problems to amalgam and other dental metals. In genetically susceptible indviduals, mercury and gold may function as haptens and elicit allergic and autoimmune reactions.

The frequency of metal-induced lymphocyte responses was examined in 3,162 patients in three European laboratories using MELISA(R), an optimized lymphocyte proliferation test. The patients suffered from local and systemic symptoms attributed to dental restorations. The effect of dental metal removal was studied in 111 patients with metal hypersensitivity and symptoms resembling Chronic Fatigue Syndrome (CFS).

After consultation with a dentist the patients decided to replace their metal restorations with non-metallic materials. The changes in health and in vitro lymphocyte reactivity were studied by inquiries and follow-up MELISA(R). Lymphocyte reactivity was also analyzed in 116 healthy subjects with no complaints of metal allergy.

A significant number of patients had metal-specific lymphocytes in the blood. Nickel was the most common sensitizer, followed by inorganic mercury, gold, phenylmercury, cadmium and palladium. As compared to lymphocyte responses in healthy subjects, the CFS group had significantly increased responses to several metals, especially to inorganic mercury, phenylmercury and gold.

Following dental metal removal, 83 patients (76%) reported long-term health improvement. Twenty-four patients (22%) reported unchanged health and two (2%) reported worsening of symptoms. Following dental metal replacement, the lymphocyte reactivity to metals decreased as well.

We propose that an inflammatory process induced by metals may modulate the hypothalamic-pituitary-adrenal axis (HPA axis) and trigger multiple non-specific symptoms characterizing CFS and other chronic conditions like myalgic encephalitis (ME) and multiple chemical sensitivity (MCS).

 

Source: Stejskal VD, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A, Mayer W, Bieger W, Lindh U. Metal-specific lymphocytes: biomarkers of sensitivity in man. Neuro Endocrinol Lett. 1999;20(5):289-298. http://www.ncbi.nlm.nih.gov/pubmed/11460087