Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis

Article (PDF Available)inJournal of General Virology 91(Pt 4):893-7 · December 2009with13 Reads
DOI: 10.1099/vir.0.017590-0 · Source: PubMed
Abstract
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a neuro-immune disease of uncertain pathogenesis. Human parvovirus B19 infection has been shown to occur just prior to development of the onset of CFS/ME in several cases, although B19 seroprevalence studies do not show any significant differences between CFS/ME and controls. In this study, we analysed parvovirus B19 markers in CFS/ME patients (n=200), diagnosed according to Fukuda CDC criteria, and normal blood donors (n=200). Serum from each subject was tested for anti-B19 VP2 IgM and IgG (by Biotrin ELISA), anti-B19 NS1 IgM and IgG (by immunofluorescence), and B19 DNA (by real-time PCR). CFS/ME patients and normal blood donors had a similar B19 seroprevalence (75 % versus 78 %, respectively). Eighty-three CFS patients (41.5 %) as compared with fourteen (7 %) normal blood donors tested positive for anti-B19 NS1 IgG (chi(2)=64.8; P<0.0001; odds ratio=9.42, CI 5.11-17.38). Of these 83 patients, 61 complained of chronic joint pain, while 22 did not. Parvovirus B19 DNA was detected in serum of 11 CFS patients and none of the controls by Taqman real-time PCR (chi(2)=9.35, P<0.002). Positivity for anti-B19 NS1 IgG was associated with higher expression levels of the human CFS-associated genes NHLH1 and GABPA. As NS1 antibodies are thought to indicate chronic or severe courses of B19 infection, these findings suggest that although the seroprevalence of B19 in CFS patients is similar to controls, the immune control of the virus in these patients may not be efficient.
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Antibody to parvovirus B19 nonstructural protein is
associated with chronic arthralgia in patients with
chronic fatigue syndrome/myalgic
encephalomyelitis
Jonathan R. Kerr,
1
John Gough,
1
Selwyn C. M. Richards,
2
Janice Main,
3
Derek Enlander,
4
Michelle McCreary,
5
Anthony L. Komaroff
5
and John K. Chia
6
Correspondence
Jonathan R. Kerr
jkerr@sgul.ac.uk
1
Department of Cellular & Molecular Medicine, St George’s University of London, London, UK
2
Dorset CFS Service, Poole Hospital, Dorset, UK
3
Dept of Infectious Diseases and General Medicine, Imperial College London, St Mary’s Hospital,
London, UK
4
New York ME/CFS Service, 860 Fifth Avenue, New York, USA
5
Division of General Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston,
USA
6
ID Med, Torrance, CA, USA
Received 13 October 2009
Accepted 4 December 2009
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a neuro-immune disease of
uncertain pathogenesis. Human parvovirus B19 infection has been shown to occur just prior to
development of the onset of CFS/ME in several cases, although B19 seroprevalence studies do
not show any significant differences between CFS/ME and controls. In this study, we analysed
parvovirus B19 markers in CFS/ME patients (n5200), diagnosed according to Fukuda CDC
criteria, and normal blood donors (n5200). Serum from each subject was tested for anti-B19 VP2
IgM and IgG (by Biotrin ELISA), anti-B19 NS1 IgM and IgG (by immunofluorescence), and B19
DNA (by real-time PCR). CFS/ME patients and normal blood donors had a similar B19
seroprevalence (75 % versus 78 %, respectively). Eighty-three CFS patients (41.5 %) as
compared with fourteen (7 %) normal blood donors tested positive for anti-B19 NS1 IgG
(x
2
564.8; P,0.0001; odds ratio59.42, CI 5.11–17.38). Of these 83 patients, 61 complained of
chronic joint pain, while 22 did not. Parvovirus B19 DNA was detected in serum of 11 CFS
patients and none of the controls by Taqman real-time PCR (x
2
59.35, P,0.002). Positivity for
anti-B19 NS1 IgG was associated with higher expression levels of the human CFS-associated
genes NHLH1 and GABPA. As NS1 antibodies are thought to indicate chronic or severe courses
of B19 infection, these findings suggest that although the seroprevalence of B19 in CFS patients
is similar to controls, the immune control of the virus in these patients may not be efficient.
INTRODUCTION
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/
ME) is a disease characterized by severe and debilitating
fatigue, sleep abnormalities, impaired memory and con-
centration, and musculoskeletal pain (Fukuda et al., 1994).
In the Western world, the population prevalence is
estimated to be of the order of 0.5 % (Report of the CFS/
ME Working Group, 2002; Papanicolaou et al., 2004).
Several factors have been proposed to account for the
pathogenesis of CFS; however, the most widely believed
theory is that the symptoms of this disease are mediated
by immune mechanisms which, in turn, may be somehow
induced by virus infection (Komaroff & Buchwald, 1998;
Devanur & Kerr, 2006).
Human parvovirus B19 (B19) is the aetiological agent of
the rash illness erythema infectiosum, arthralgia and
arthritis, transient aplastic crisis in patients with shortened
red cell survival, fetal death and pure red cell aplasia in
immunocompromised persons (Kerr & Modrow, 2006).
B19 infection has also been shown to occur just prior to the
onset of symptoms of CFS in several case reports and
follow-up studies (Kerr et al., 2002). However, B19
seroprevalence in CFS patients is similar to that in the
general population.
Journal of General Virology (2010), 91, 893–897 DOI 10.1099/vir.0.017590-0
017590
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2010 SGM Printed in Great Britain 893
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The B19 genome consists of a linear, single-stranded DNA
of ~5.6 kb, encoding the two capsid proteins VP1 and VP2
from the right side and the non-structural protein (NS1)
from the left side (Aste ll et al., 1997). The NS1 protein
possesses DNA-nicking and helicase activities, is cytotoxic
and trans-activates the human interleukin-6 gene (Moffatt
et al., 1996). Immunity to B19 virus is mediated by both
humoral and cellular means. Antibodies to NS1 occur in
approximately 30 % of infected individuals and may
indicate more persistent and severe courses of B19
infection (Searle et al., 1998).
The present study was undertaken in view of the paucity of
knowledge of the role of B19 infection in CFS patients and
the human immune response to it. Findings of this study
confirm that B19 seroprevalence in CFS patients is similar
to that in the normal population. However, antibodies to
the NS1 protein were elevated in frequency in CFS patients
and were associated with both chronic arthralgia and
higher expression levels of the human CFS-associated genes
NHLH1 and GABPA.
RESULTS
Subjects and clinical characterization
A total of 200 CFS/ME patients fulfilling Fukuda CDC
diagnostic criteria and 200 normal healthy blood donors
of equivalent age and gender were included in this
study. A summary of the clinical d etails of these CFS
patients is shown in Table 1. There were obvious
differences between the two groups with regard to the
frequency and severity of CFS-associated symptoms, and
of scores on clinical questionnaires (Table 1), as would
be expected.
Parvovirus B19 markers
The CFS/ME patients and normal blood donors had a
similar B19 seroprevalence (anti-B19 VP2 IgG) (75 %
versus 78 %, respective ly). Four CFS patients were found to
be positive for anti-B19 VP2 IgM; however, these pati ents
reported no symptoms which would suggest acute B19
infection against a background of CFS. Of these four IgM-
postitive patients, two were positive for B19 DNA by PCR;
however, none was positive for either anti-B19 VP2 IgG or
anti-B19 NS1 IgM. Eighty-three CFS patients (41.5 %) as
compared with fourteen (7 %) normal blood donors tested
positive for anti-B19 NS1 IgG (
x
2
564.8; P,0.0001; odds
ratio59.42, CI 5.11–17.38). Of these 83 patients, 61
complained of chronic joint pain, whi le 22 did not.
Three CFS patients were positive for anti-B19 NS1 IgM, as
compared with one of the controls. Parvovirus B19 DNA
was detected in serum of 11 CFS patients, but none of the
normal blood donors, by Taqman real-time PCR; 5 of these
11 were positive for anti-NS1 IgG antibody. The B19 DNA
viral load in positive samples ranged from 10
1
to 10
3
genome copies per ml blood.
Human CFS-associated genes
The fold-differences of expression between CFS and
normal groups for the human CFS-associated genes
NHLH1 and GABPA were 13.5 and 7, respectively, results
which confirm our previous findings (Kerr et al., 2008;
Zhang et al., 2010). Although in most CFS patients these
genes were raised above the mean level found in normal
persons, we observed significant heterogeneity in expres-
sion within the CFS group, with some patients exhibiting
very high levels and others exhibiting lower levels. The
expression levels of the two genes were strongly associated
(P50.0012) with each other in all subjects, regardless of
whether they were CFS patients or normal blood donors;
this association was statistically significant (P50.0012).
In CFS patients, positivity for anti-B19 NS1 IgG was
associated with higher expression levels of both NHLH1
(fold difference 2.4; P50.006) and GABPA (fold difference
1.6; P50.003). However, this association was not seen in
the normal controls.
DISCUSSION
This study was undertaken to clarify an apparent paradox:
acute parvovirus B19 infection may somehow induce
development of CFS in a subset of patients, yet patients
with CFS exhibit similar B19 seroprevalence to the normal
population. This study confirms that CFS patients have
similar B19 seroprevalence to normal healthy controls.
However, we found that CFS patients have a much higher
prevalence of anti-B19 NS1 antibody.
The major B19 nonstructural protein, NS1 (77 kDa), is a
multifunctional protein. It has been shown to possess site-
specific DNA-binding and helicase activities, and is
functionally active as a trans-activator of the viral p6 and
various cellular promoters (Gareus et al., 1998; Raab et al.,
2001, 2002; Vassias et al., 1998), for example, the cellular
promoters for the expression of TNF-
a and interleukin 6
(Fu et al., 2002; Moffatt et al., 1996 ). NS1 also contains a
well-conserved nucleoside-triphosp hate-binding motif,
which is essential for a variety of biologic al functions,
such as ATPase activity and cytotoxicity.
In immunocompetent patients with persistent parvovirus
B19 infections, VP1- and VP2-specific IgG antibodies are
detected in combination with NS1-specific antibodies (von
Poblotzki et al., 1995a, b; Hemauer et al., 1999, 2000; Kerr
& Cuniffe, 2000; Lehmann et al., 2002). Usually, the
synthesis of these NS1 antibodies follows anti-VP1/VP2-
IgG and starts at about 3–4 weeks after infection (Hemauer
et al., 2000; von Poblotzki et al., 1995a). NS1 antibodies
have been reported to occur in more severe and persistent
courses of B19 infection (von Poblotzki et al., 1995a, b)
and one study reports their association with chronic but
not acute arthritis attributable to B19 infection (Kerr &
Cunniffe, 2000). Therefore, their presence in 41.5 % of CFS
patients as compare d with 7 % of normal controls in the
J. R. Kerr and others
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present study may indicate a more severe or persistent
course of B19 infection in the context of CFS, whether or not
B19 virus infection was the inducing event for CFS. CFS is
recognized to be an inflammatory disease which can persist
for many years. Our findings are consistent with a previous
study which reported that 73 % of NS1 antibody-positive
CFS patients suffered arthralgia (Kerr & Cunniffe, 2000).
Of the 83 patients with antibodies to B19 NS1, 61 (73 %)
suffered from chronic arthralgia. This is similar to the results
of previous studies of B19-infected patients (Kerr & Cunniffe,
2000). This is very interesting and quite unexpected.
Parvovirus B19 DNAaemia was documented in 11 CFS
patients as compared with none of the controls. In a
previous study (Kerr et al., 2001), 4 of 5 patients with B19-
associated CFS (i.e. patients followed from the time of
detection of anti-B19 IgM whose CFS-like symptom onset
occurred comtemporaneously with detection of anti-B19
IgM, and whose symptoms persisted such that they later
fulfilled diagnostic criteria for CFS) exhibited B19
DNAaemia at follow-up. Therefore, this finding may suggest
that the disease in these 11 patients may have been somehow
induced by acute B19 infection. Such patients have
previously been shown to respond very well to intravenous
immunoglobulin (IVIG), the only specific treatment for
parvovirus B19 infection (Kerr et al., 2003). In patients with
antibodies to anti-B19 NS1, but without parvovirus B19
DNAaemia, it is possible that the parvovirus infection was
latent and reactivated at a low level.
The CFS-associated human genes NHLH1 and GABPA
were chosen for testing in the present study, as they were
the transcription factors found to have over-representation
of binding sites in most upregulated genes in a previous
study of gene expression in CFS (Kerr et al., 2008). The
helix–loop–helix (HLH) proteins are a family of putative
transcription factors, some of which have been shown to
play an important role in growth and development of a
wide variety of tissues and species. The GABP complex
contributes to the transcriptional regulation of a number of
subunits of mitochondrial enzymes, including cytochrome
c oxidase and mitochondrial transcription factor A. The
association between expression levels of NHLH1 and
GABPA is intriguing, but unexplained. Further work is
required to explain this relationship.
The relationship between NS1 antibody positivity and
higher expression levels of NHLH1 and GABPA is also
unexplained. Following the acute phase of infection, B19
virus DNA persists, possibly life-long in many tissues of the
human body. It is possible that chronic B19 antigen
Table 1. Patient information including age, sex, symptoms and questionnaire results summarizing
fatigue severity, pain, sleep, general function, and associated symptoms for CFS/ME patients and
normal blood donors
Clinical parameter CFS/ME patients
(n5200)
Normal blood donors
(n5200)
Gender (M : F) 1 : 3 1 : 3
Mean age (years) 38.4 40.9
Mean duration of disease (years : months) 3.67
NA
Symptoms/signs (no. of subjects with
each symptom)
Headache 103 10
Sore throat 109 8
Poor memory/concentration 110 11
Muscle pain 125 13
Muscle weakness 119 5
Joint pain 142 7
Post-exertional malaise 158 15
Sleep problem 151 24
Gastrointestinal problems 137 13
Fainting/dizziness 112 9
Numbness/tingling 98 2
Tender lymphadenopathy 87 0
Mean scores
Physical fatigue (Chalder) 18.34 6.29
Mental fatigue (Chalder) 10.47 5.47
McGill Pain Questionnaire 14.26 6.66
Sphere Questionnaire 12.98 3.87
SF-36 Questionnaire 44.64 88.37
Pittsburgh Sleep Quality Index 11.81 5.14
NA, Not applicable.
Parvovirus B19 infection in CFS/ME
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stimulation may be responsible for an inflammatory state
which could increase levels of these transcription factors,
although this requires confirmation.
In conclusion, we report that the prevalence of anti-NS1
antibody is significantly increased in CFS patients and is
associated with chronic joint pain and elevated levels of the
CFS-associated human genes, NHLH1 and GABPA. Further
work is required to determine how B19 virus could
upregulate these genes in the context of CFS.
METHODS
Subject enrolment, clinical characterization and blood sam-
pling.
CFS/ME patients (n5200) from three different geographical
areas in the UK and USA (New York and Boston) were diagnosed
according to Fukuda diagnostic criteria for CFS/ME (Fukuda et al.,
1994) and enrolled into the study. Patients with psychiatric disease
were excluded from the CFS/ME group using the Minnesota
International Neuropsychiatric Interview (MINI), thus ensuring that
none of our CFS/ME patients was suffering from major psychiatric
disease or abuse of alcohol or other drugs.
Healthy normal blood donors enrolled from the Dorset National
Blood Service (NBS) (n5200) were used as a comparison group.
Restrictions imposed by the NBS on those allowed to donate blood
are outlined elsewhere (Kaushik et al., 2005).
For both CFS and normal groups, individuals who smoked in the
previous year, who abused alcohol or other drugs, were currently
taking (or were within 3 months of taking) antibiotics, steroids,
cytotoxic drugs or antidepressants were excluded from the study. The
only exception to this was that these criteria were not formally applied
to the Boston patients (n515); however, we believe that these patients
also fulfilled these same criteria.
For all enrolled subjects (patients and controls), according to the
recommendations of the International CFS Study Group (Reeves
et al., 2003), severity of physical and mental fatigue was assessed using
the Chalder Fatigue Scale (Chalder et al., 1993); level of disability was
assessed using the Medical Outcomes Survey Short Form-36 (SF-36);
accompanying symptoms were characterized using the Somatic and
Psychological Health Report (SPHERE); sleep abnormalities were
assessed using the Pittsburgh Sleep Questionnaire; and assessment of
type and severity of pain was performed using the McGill Pain
Questionnaire.
Patients and controls gave informed written consent according to
guidance of the Wandsworth Research Ethics Committee (approval
number 05/Q0803/137). For the New York and Boston patients,
approval of the local Institutional Review Board was obtained. The
human experimentation guidelines of the US Department of Health
and Human Services were followed in this study.
Fifteen millilitres of blood was taken from both CFS/ME patients and
normal blood donors (as part of routine blood donation) and used to
inoculate PAXgene tubes (PreAnalytix), EDTA blood tubes and
clotted blood tubes , for extraction of total RNA, genomic DNA and
serum, respectively. Total RNA was extracted using the PAXgene
blood RNA kit (PreAnalytix), according to the instructions of the
manufacturer. RNA quality and amount were confirmed by micro-
spectrophotometry (Nanodrop). Total RNA samples used in this
study had an A
260
/A
280
ratio of 1.9–2.0. cDNA was prepared from
total RNA using random hexamers. Genomic DNA was extracted
from EDTA blood using the DNA Blood mini kit (Qiagen). All
samples were stored at 280 uC until the time of the study.
Detection of parvovirus B19 anti-VP2 antibodies. Anti-B19 VP2
IgM and IgG were detected by ELISA (Biotrin) according to the
instructions of the manufacturer.
Detection of parvovirus B19 anti-NS1 antibodies. Anti-B19 NS1
antibodies were detected by immunofluorescence using SF9 cells
infected with a recombinant Autographica california nuclear poly-
hedrosis virus (rAcNPV) with the Stu NS1 nucleotide sequence
inserted just downstream of the polyhedrin promoter; this recom-
binant virus was kindly provided by B. J. Cohen (Virus Reference
Division, Central Public Health Laboratory, Public Health Laboratory
Service, Colindale, London, UK) (Hicks et al., 1996). rAcNPV-
infected SF9 cells were spotted onto immunofluorescence slide wells
and used for the IF assay as a source of NS1 antigen. Human anti-NS1
positive control serum from a pregnant woman with B19 infection
and documented anti-NS1 antibodies was kindly provided by
S. Modrow (Institut fu
¨
r Medizinische Mikrobiologie und Hygiene,
Universita
¨
t Regensburg, Regensburg, Germany).
Serum samples were diluted 1 : 100 in sterile PBS and used to stain
both infected and uninfected SF9 cells for 30 min at 37 uCina
humidified atmosphere. After thorough washing, goat anti-human
IgG FITC conjugate (Sigma) was added at its working dilution of
1 : 32 for 30 min at 37 uC. After further washing, slides were mounted
and viewed on a fluorescence microscope with a filter of emission
waveband at 515 nm (Leitz, Switzerland). Positive control anti-NS1
serum and PBS (negative control) were used throughout. Sera
showing the characteristic pattern of positive fluorescence in infected
but not uninfected cells were designated positive.
Detection of parvovirus B19 DNA. Parvovirus B19 DNA was
detected by real-time PCR using primers specific to highly conserved
sequences within the structural and non-structural genes, respectively,
as previously described (Kerr et al., 2005). The sensitivity of both of
these PCR tests was five genome copies.
Quantification of CFS-associated human genes. QPCR (Applied
Biosystems) was used to quantify the amount of mRNA for the CFS/ME-
associated human genes NHLH1 and GABPA by the comparative
method, using custom 384-well low-density arrays and the ABI PRISM
7900HT instrument (Applied Biosystems), with GAPDH (encoding
glyceraldehyde-3-phosphate dehydrogenase) as the endogenous control
gene. Experiments were performed in triplicate using the protocol
described previously (Kaushik et al.,2005;Kerret al., 2008). Data were
displayed using SDS 2.2 software (ABI), discordant data between
replicates omitted, and results calculated. The threshold cycle (C
t
)for
each test gene in each sample was compared to that for GAPDH to
calculate a
DC
t
value. DC
t
values were then normalized to the calibrator
sample to give the
DDC
t
values. Relative quantities (RQ) (2
{DDC
t
)of
each mRNA were then calculated. Samples showing a difference between
minimum and maximum RQ values of ¢100 (indicating poor replicate
concordance) were excluded. The t-test was used to compare mean RQ
values between groups. A P-value of ¡0.05 was taken to be significant.
Statistical testing. The x
2
test was used to test the significance of
associations of B19 markers in CFS/ME patients and controls, CFS-
associated symptoms and CFS-associated human genes. The t-test was
used to determine the significance of association between expression
levels of the two CFS-associated human genes, NHLH1 and GABPA.
ACKNOWLEDGEMENTS
This work was supported by grants from ME Research UK and Sir
Joseph Hotung (salary of J. R. K.). Informed consent was obtained from
normal blood donors and CFS/ME patients. None of the authors has a
commercial or other association which might pose a conflict of interest.
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    • "ME often appears after a severe viral or bacterial infection. Human herpesvirus 6 (HHV-6) [16–19], Epstein-Barr virus (EBV)[19–29], enteroviruses [30–32], parvovirus B19 [32,33], Chlamydia pneumoniae [34,35] and Mycoplasma spp. [36–40] have been implicated in, but not proven to be the single cause of, ME. "
    [Show abstract] [Hide abstract] ABSTRACT: Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.
    Full-text · Article · Nov 2013
    • "The potential role of pathogens in the CFS field has boosted research in the immunological sides of the illness91011. Indeed, the link between the immune system and CFS has been explored since the early 90's [12], and is supported by the coincidence of the onset of symptoms with viral in- fections [13], the persistence of several infections in CFS individuals [10,14151617, the beneficial effect of treatment of human herpesvirus 6 and Epstein-Bar virus infection in CFS symptoms [18] and the reported role of autoimmun- ity [19,20] Moreover, other features of ME/CFS, such as mild inflammation, oxidative/nitrosative stress, mitochondrial dysfunction and the presence of autoimmunne re- sponses [4] may alter immune function and phenotype. However, the characterization of the immune status of CFS individuals has frequently yield contradictory results. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Chronic Fatigue Syndrome (CFS) is a debilitating neuro-immune disorder of unknown etiology diagnosed by an array of clinical manifestations. Although several immunological abnormalities have been described in CFS, their heterogeneity has limited diagnostic applicability. Methods Immunological features of CFS were screened in 22 CFS diagnosed individuals fulfilling Fukuda criteria and 30 control healthy individuals. Peripheral blood T, B and NK cell function and phenotype were analyzed by flow cytometry in both groups. Results CFS diagnosed individuals showed similar absolute numbers of T, B and NK cells, with minor differences in the percentage of CD4+ and CD8+ T cells. B cells showed similar subset frequencies and proliferative responses between groups. Conversely, significant differences were observed in T cell subsets. CFS individuals showed increased levels of T regulatory cells (CD25+/FOXP3+) CD4 T cells, and lower proliferative responses in vitro and in vivo. Moreover, CD8 T cells from the CFS group showed significantly lower activation and frequency of effector memory cells. No clear signs of T-cell immunosenescence were observed. NK cells from CFS individuals displayed higher expression of NKp46 and CD69 but lower expression of CD25 in all NK subsets defined. Overall, T cell and NK cell features clearly clustered CFS individuals. Conclusions Our findings suggest that alterations in T-cell phenotype and proliferative response along with the specific signature of NK cell phenotype may be useful to identify CFS individuals. The striking down modulation of T cell mediated immunity may help to understand intercurrent viral infections in CFS.
    Full-text · Article · Mar 2013
    • "Moreover, the number and severity of symptoms, including neurological symptoms, is correlated with the existence of concurrent infections [186,187]. Gene expression data show latent viral or bacterial infections in ME/CFS, for example, Epstein-Barr virus, enteroviruses and C. burnetii188189190. Other infections that are associated with this disorder are, among others, human herpesvirus (HHV) 6 and 7, cytomegalovirus, enteroviruses , Borna disease virus, Chlamydia pneumoniae and Borrelia burgdorferi [182]. "
    [Show abstract] [Hide abstract] ABSTRACT: It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions.
    Full-text · Article · Mar 2013
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