Current Rheumatology Reports
 Vol. 9, #6, pp 482-487
 December 2007

 http://www.current-reports.com/archives.cfm

 Chronic Fatigue Syndrome: Inflammation, Immune Function, and 
 Neuroendocrine Interactions

 Nancy G. Klimas, MD, and Anne O'Brien Koneru, MSN

 Corresponding author
 Nancy G. Klimas, MD, University of Miami Miller School of Medicine, 1201 
 NW 16th Street, VA Medical Center, 200 BMRC, 6th Floor, Miami, FL 33125, USA.
 E-mail: nancy.klimas@va.gov

 Investigations into the underlying cause of chronic fatigue syndrome have
 advanced the field considerably in the past year. Gene microarray data 
 have led to a better understanding of pathogenesis. Recent research has 
 evaluated
 genetic signatures, described biologic subgroups, and suggested potential
 targeted treatments. Acute viral infection studies found that initial
 infection severity was the single best predictor of persistent fatigue.
 Genomic studies showed that persistent cases express Epstein Barr
 virus-specific genes and demonstrate abnormalities of mitochondrial 
 function.
 Studies of immune dysfunction extended observations of natural killer
 cytotoxic cell dysfunction of the cytotoxic T cell through quantitative
 evaluation of intracellular perforins and granzymes. Other research has
 focused on a subgroup of patients with reactivated viral infection. These
 advances should result in targeted therapies that impact immune function,
 hypothalamic-pituitary-adrenal axis regulation, and persistent viral
 reactivation.


 Introduction

 Chronic fatigue syndrome (CFS) is an illness characterized by unexplained
 fatigue lasting 6 months or more. The condition is not alleviated with 
 rest and is accompanied by at least four of eight case-defining symptoms 
 including sore throat, tender lymphadenopathy, impaired memory or concentration,
 myalgia, arthralgia, unrefreshing sleep, postexertional malaise, and
 headaches [1]. A diagnosis of CFS is made by excluding all other 
 conditions that would cause similar symptoms. The study and clinical management of 
 CFS is complicated by the lack of accepted biomarkers or pathogenomic signs 
 for the illness.

 CFS is characterized by a multifactorial pathogenesis. Endocrine,
 neuroendocrine, psychosocial, and immunologic factors mediate the 
 physiologic response to CFS and the course of the illness. Although a consensus 
 regarding the pathophysiology and etiology of CFS has yet to be developed, a large 
 body of research supports a link between immune dysregulation and CFS.

 A number of symptoms of CFS are linked to inflammatory processes (eg,
 lymphadenopathy, sore throat, myalgia, arthralgia), which has led many
 researchers to hypothesize that immune dysfunction causes the illness. CFS
 has been found to be associated with increased immune activation and
 inflammatory cytokine levels, with subgroups demonstrating viral 
 reactivation and decreased cytotoxicity, alterations in lymphocyte function, 
 activation, and subset distributions [2,3,4*,5**]. In addition, our expanded
 understanding of the genomics of CFS has reinforced the evidence that the
 illness is rooted in a biologic pathogenesis that involves cellular
 dysfunction and interactions between the physiologic stress response and
 inflammation. Progress in genetic research has provided new avenues for
 future study of immunomodulating therapies.


 Immune Activation

> Chronic immune activation has long been thought to be a component of CFS. 
> In
> patients with CFS, T lymphocytes appear to be chronically activated. CD8
> cells in CFS patients typically demonstrate an increase in activation 
> markers
> (CD38, HLA-DR) and a reduction in CD8 suppressor cells. Levels of CD26, an
> ectoenzyme known to increase with cell activation, are also elevated in
> patients with CFS. CD26 is associated with the adenosine deaminase on T 
> cells
> and plays a critical role in the immune response. Abnormal expression is 
> also
> commonly seen in autoimmune diseases, HIV-related diseases, and cancer.
> Compared with controls, CFS patients also show significantly higher levels 
> of
> CD26+ lymphocytes [4*].
>
> The homeostasis between the cell-mediated or T helper (Th) 1 immune 
> response
> and the humoral or Th2 immune response is disrupted in CFS. Th1 functions
> primarily by destroying infected human cells, whereas Th2 functions 
> through
> antibody production. Increased antibody production contributes to 
> elevations
> in immune complexes, increased levels of antinuclear antibody production, 
> and
> the increased prevalence of allergies among CFS patients [4*]. Some
> researchers have theorized that if infections can lead to an aberrant 
> shift
> to an unremitting Th2 dominant response, then perhaps vaccines can cause 
> the
> same reaction, because immunizations are designed to induce a persistent
> immunity to antigens. Although further investigation is needed, a recent
> study provides evidence that vaccines do not lead to CFS symptoms [6].
>
>
> Functional Immune Defects
>
> Essential fatty acids, zinc levels, T cells, and inflammation
>
> In a series of articles by Maes et al. [7-9] cellular levels of various
> minerals and fatty acids were correlated with immune dysfunction. Maes et 
> al.
> [7] documented significantly lower serum zinc levels in patients with CFS
> compared with controls and found evidence that low levels of serum zinc 
> are
> related to increased signs of inflammation and defects in the early T-cell
> activation pathways. The results of this study showed a negative 
> correlation
> between serum zinc, the severity of CFS symptoms, and the subjective
> experience of infection. Serum zinc was also found to be negatively
> correlated to increases in the 2 protein fraction. Levels of serum zinc
> showed a positive correlation with decreases in the expression of a T-cell
> activation marker (CD69) on CD3 and CD8 T cells. Zinc is a strong
> antioxidant, and diminished levels in CFS support findings that the 
> illness
> is accompanied by increased oxidative stress [7].
>
> They also documented a significant positive relationship between lowered
> serum zinc levels, the omega 3/omega 6 ratio, and lowered 
> mitogen-stimulated
> CD69 expression on CD3+, CD3+CD4+, and CD3+CD8+ T cells indicating 
> abnormal
> early T-cell activation. Omega 3/omega 6 and eicosapentaenoic acid/
> arachidonic acid ratios were significantly reduced in patients with CFS, 
> with
> a significant increase in proportionate omega 6 levels. Lowered levels of
> omega 3 or elevated levels of omega 6 contribute to inflammation and may
> contribute to CFS symptoms [8].
>
> In a later study the Maes group [9] found an immunoglobulin (Ig) M-related
> immune response in CFS patients directed against disrupted lipid membrane
> components, by-products of lipid membrane elements, by-products of lipid
> peroxidation, S-farnesyl-L-cysteine and nitric oxide-modified amino acids.
> These neoepitopes normally go undetected by the immune system but appear 
> to
> become immunogenic after undergoing oxidative and nitrosative damages. 
> This
> study found a significant positive correlation between serum IgM levels
> directed at fatty acids and the severity of illness [9].
>
> The role of long-chain polyunsaturated fatty acids (PUFA) biosynthesis in 
> the
> pathophysiology of CFS is an important area of research. A large body of
> evidence links CFS to a persistent viral infection. Additional evidence
> suggests that such an infection may play a role in adversely affecting 
> cell
> membrane structure and the functioning and production of eicosanoids by
> affecting the biosynthesis of PUFAs. In light of this finding, treatment 
> with
> long-chain PUFAs may be an area of future promise [10].
>
>
> Estrogen and immune modulation
>
> Grans et al. [11*] showed reduced levels of estrogen receptor B mRNA in a
> cohort of patients with CFS. Estrogen is an important steroid hormone that
> plays a critical physiologic role in various processes including sexual
> development and the reproductive cycle. CFS prevalence rates are estimated 
> to
> be two to four times higher in women. A number of autoimmune diseases
> including rheumatoid arthritis and multiple sclerosis also 
> disproportionately
> affect females and are thought to have a hormone-related pathogenesis.
> Estrogen is a potential immunomodulator that functions by binding to the 
> two
> estrogen receptors, ERalpha and ERbeta. These two receptors have unique 
> and
> overlapping roles. Grans et al. [11*] found that among a study sample of 
> 30
> patients with CFS, lower levels of ERbeta cx mRNA were found in patients 
> with
> a shorter course of illness. These results should be viewed as preliminary
> due to the small sample size in this study. However, the role of ER wt
> protein levels and cellular effects are interesting candidates for future
> study.
>
>
> Inflammatory cytokines
>
> Suboptimal functioning of the hypothalamic-pituitary-adrenal (HPA) axis in
> CFS has been well documented [12,13]. Hypofunctioning of the HPA axis 
> could
> lead to an exaggerated stress response and a subsequently excessive 
> release
> of proinflammatory cytokines. Long-term stress increases levels of
> glucocorticoids and catecholamines, which over time suppress immune 
> function.
>
> A recent study investigated potential immunologic changes in severely
> fatigued adolescent girls with symptoms similar to patients with CFS and 
> with
> a symptom constellation of sickness behavior [14]. The immunologic changes
> under investigation were the levels of mitogen-induced T-cell 
> proliferation
> and T-cell mitogen- or lipopolysaccharide (LPS)-induced pro- and
> anti-inflammatory cytokine production. Among the three cohorts studied
> (severely fatigued adolescent girls, CFS patients, and nonfatigued
> individuals), the severely fatigued participants reported higher levels of
> depression, anxiety, fatigue, reduced sleep quality, somatic and 
> CFS-related
> symptoms. In addition, seasonal variations in cytokine and leukocyte 
> subset
> distributions were observed among the severely fatigued individuals. No
> immunologic differences were seen between nonfatigued and fatigued
> individuals. However, CFS patients exhibited a distinct immune profile
> compared with severely fatigued and nonfatigued individuals. These 
> patients
> displayed increased anti-inflammatory cytokines (interleukin [IL]-10,
> decreased interferon (IFN)-gamma/IL-10 ratio) and reductions in
> proinflammatory cytokines (IL-6, tumor necrosis factor-alpha).
>
>
> Viral reactivation
>
> Some of the most robust data exploring the link between immune 
> dysregulation
> and CFS has been garnered through the investigation of postinfective 
> states.
> Since the illness was first described, researchers have been interested in
> the potential role of reactivated viruses, especially after the discovery 
> of
> human herpes virus (HHV)-6 in the blood sample of a CFS patient [15]. CFS
> often has an acute postviral onset, and two longitudinal studies observed
> postinfectious chronic fatigue following Epstein-Barr virus (EBV) 
> infection
> [5**,16].
>
> In a recent study Hickie et al. [5**] demonstrated that CFS is a fairly
> common sequel of several types of viral and nonviral infections including
> EBV, Q fever, and Ross River virus. The investigators conducted a 
> prospective
> observational study in one rural township in Australia, which confirmed 
> the
> presence of a postinfective fatigue syndrome linked to these three
> infections. Among 253 patients, 12% experienced a postinfective fatigue 
> that
> was present 6 months after acute infection. The best predictor of 
> prolonged
> fatigue was the severity of the acute infection. Premorbid mood disorders 
> and
> other potential psychiatric risks were not predictive of risk for 
> prolonged
> fatigue. This work confirms previous findings that the severity of the 
> acute
> illness rather than the infective pathogen appeared to be the critical
> determinant of postinfective fatigue syndrome [16].
>
> Chapenko et al. [17] recently found a significantly higher prevalence of
> persistent/latent HHV-6 infections and dual HHV-6 and HHV-7 infections 
> among
> patients with CFS. The study compared levels and characteristics of viral
> infection using nested polymerase chain reaction, restriction endonuclease
> analysis, and flow cytometry in 17 patients with CFS, 12 patients with
> unexplained chronic fatigue, and 20 healthy controls. Researchers found
> active HHV-6 and dual HHV-6 and HHV-7 infections only in CFS patients, and
> these infections were present in 40% of those tested. Based on these
> findings, the researchers concluded that HHV-6 and HHV-7 may be involved 
> in
> the pathogenesis of CFS and that reactivation of both viruses could cause
> changes in circulating lymphocytes and a state of chronic immune 
> activation
> [17].
>
> Petersen et al. [18*] recently published prevalence figures for fatigue
> post-EBV infection. Their study found an immediate link between EBV 
> infection
> and fatigue, but also found that the median duration of fatigue was 8 
> weeks
> and the majority of the patients recovered within 1 year. Only one of the 
> 10
> patients studied had an additional record of fatigue. Based on these
> findings, the authors concluded that acute fatigue after EBV infection and
> CFS may share some risk factors but most likely do not share the same
> etiology [18*].
>
> Enteroviral infections can cause acute respiratory and gastrointestinal
> infections with tropisms for the heart, muscles, and central nervous 
> system.
> Enteroviruses have been evaluated in several studies, with early data from
> Gow et al. [19] initially suggesting muscle infection; however, the same
> group failed to find levels higher than those in controls in later 
> studies.
> Maes et al. [20] found elevated serum levels of IgA and IgM against the 
> LPS
> of gram-negative enterobacteria in a group of CFS patients, indicating
> increased gut permeability and an anti-LPS immune response. Researchers 
> noted
> that the intestinal barrier may be weakened by factors that have been 
> shown
> to trigger CFS such as psychologic stress, strenuous exercise, allergies,
> surgery, and trauma. These same factors may induce inflammation, immune
> activation, and oxidative stress. Inflammation may then increase the
> permeability of the gastrointestinal barrier, and they suggested this may
> lead to autoimmunity or increased inflammation in patients with an 
> existing
> fatigue syndrome. Based on these findings, the authors suggested that
> patients with CFS and other forms of chronic fatigue should be assessed 
> for
> the presence of increased gut permeability through the measurement of 
> IgA/IgM
> against the LPS of gram-negative bacteria. The authors also recommend 
> using
> certain antioxidants to treat patients with increased gut permeability 
> [20].
>
> A recent study evaluated the presence of chronic enterovirus infections in
> patients with CFS experiencing chronic gastrointestinal complaints [21**].
> The study took stomach biopsy specimens from 165 patients with CFS; 82% of
> CFS patients tested positive for the presence of viral capsid protein 1
> within parietal cells compared with only 20% of controls. In addition,
> enterovirus RNA and noncytopathic viruses were also detected in a 
> subsample
> of subjects tested. Based on these results, investigators concluded that a
> significant subset of CFS patients may have a chronic, noncytolytic,
> potentially disseminated enteroviral infection, which could be diagnosed
> through stomach biopsy. The investigators noted the tropism with brain and
> muscle and suggested that the neuroinflammation seen in neuroimaging 
> studies
> of a subgroup of CFS patients may result from enteroviral infection.
>
>
> Genomics and Proteomics
>
> Gene expression microarray data has become a highly productive tool in 
> better
> understanding CFS research. A group of research studies supported by the 
> US
> Centers for Disease Control and Prevention led to a series of 14 articles
> published in a dedicated issue of Pharmacogenomics in April 2006. These
> publications were the result of a multidisciplinary endeavor among an
> international cadre of 20 molecular biologists, epidemiologists,
> mathematicians, engineers, and other scientists, who independently 
> analyzed
> genomic, laboratory, and clinical data collected from 227 study 
> participants.
> During a 2-day hospital stay, the study participants underwent a
> comprehensive battery of tests that included measurements of cognitive
> function, sleep physiology, autonomic nervous system function, and blood
> analyses of the sequencing and expression of over 20,000 genes. 
> Mitochondrial
> and ion channel regulatory genes were dysregulated. Microarray data also
> showed upregulation of proinflammatory cytokine pathways, and subgroup
> analyses linked different patterns of endocrine, immune, and metabolic
> dysregulation that identified as many as six subgroups of CFS. Although 
> the
> investigators could not identify a definitive genetic marker for CFS, they
> were able to identify 28 single nucleotide polymorphisms to predict with 
> 76%
> accuracy whether an individual had CFS.
>
> These investigators also found that patients with CFS and control patients
> demonstrated different levels of gene expression for genes affecting the 
> HPA
> axis and the sympathetic nervous system. Genes that modulate physiologic
> response to chemical messengers like hormones released as part of a normal
> stress response were altered in the CFS group. These data from gene arrays
> and single nucleotide polymorphisms are consistent with the studies of 
> Jerjes
> et al. [22**] and others that have shown an enhanced sensitivity of the 
> HPA
> axis to negative feedback in CFS, as demonstrated using the prednisolone
> suppression test. Abnormal stress responses in patients with CFS and the 
> link
> between the deregulation of immune function and abnormalities in HPA axis
> activity have been investigated in several studies. Anther study, 
> published
> this year by Rajeevan et al. [23] identified sequence variations in the
> glucocorticoid receptor gene (NR3C1) in patients with CFS. NR3C1 is a key
> effector of the HPA axis. The study demonstrated that NR3C1 is a potential
> mediator of CFS, and further study into variations in this area may 
> broaden
> our understanding of how CFS manifests [23].
>
> Recent studies using microarray technology have suggested that infectious
> agents may trigger and perpetuate CFS symptoms. A study by Vernon et al.
> [24**] found evidence of mitochondrial dysfunction in cases of 
> postinfective
> fatigue caused by EBV. The investigators compared subjects with acute
> mononucleosis who developed postinfective fatigue of more than 6 months'
> duration to HLA-matched subjects who recovered within 3 months. The gene
> expression profiles of subjects who displayed a postinfective fatigue
> response lasting more than 6 months differed from those of the controls. 
> Six
> genes known to be activated during EBV infection were differentially
> displayed in the postinfective fatigue cases. A number of these
> differentially expressed genes are known to affect mitochondrial 
> functions,
> including fatty acid metabolism and the cell cycle [24**].
>
>
> Immunology Dysregulation and Treatment Modalities
>
> Immune dysregulation has been described by many groups, with evidence of
> cellular dysfunction and chronic immune activation described in early
> articles on CFS [25,26]. Studies of the mechanisms of immune dysfunction
> attempt to discover targets for immune-based therapies. Research into
> treatments that target humoral immune response and viral loads are 
> important
> areas of investigation.
>
>
> Natural killer cell and cytotoxic T-cell dysfunction: interferon beta use
>
> Natural killer cells are versatile lymphocytes, which - in healthy
> individuals - can destroy infected cells. Patients with CFS often have
> reduced natural killer cell cytotoxic activity [27,28,29*]. Maher et al. 
> [4*]
> found that the natural killer cells of patients with CFS had abnormally 
> low
> levels of perforin, which natural killer cells use to penetrate infected
> cells and inject cytotoxic granzymes. Perforin plays a critical role in
> immune surveillance and immunomodulation; therefore, a decrease in 
> perforin
> levels may play a role in the pathogenesis of CFS. This study was the 
> first
> to examine cytotoxic T cells in CFS. The authors describe a decrease in
> perforin and granzyme content of the cytotoxic T cells equal to that seen 
> in
> natural killer cells. The clinical implications are consistent with an 
> immune
> system that may allow viral reactivation and raises a concern for tumor
> surveillance as well.
>
> Some researchers have proposed that natural killer cell activity (NKCA) 
> could
> be used as an immunological sub-group marker in CFS. Siegel et al. [29*]
> found that relative to CFS patients with normal NKCA, patients with low 
> NKCA
> levels reported more cognitive dysfunction, more daytime impairment, and 
> less
> vigor. These patients also scored lower on objective measures of cognitive
> function relative to patients with normal NKCA levels. Immunomodulatory
> therapies that target natural killer cell and cytotoxic T-cell function 
> would
> seem reasonable, using functional and quantitative flow to identify the
> appropriate subgroup [30*].
>
> One such therapy is postulated by Kerr et al. [30*]. IFN-beta, a licensed
> treatment for multiple sclerosis, may hold some hope for patients with 
> CFS.
> To date, no trials have tested the efficacy of IFN-beta on patients with 
> CFS,
> but the theoretical support for such a trial is compelling. Much like CFS,
> the pathogenesis of fatigue in multiple sclerosis is thought to be 
> cytokine
> mediated. IFN-beta is known to regulate humoral immune responses and 
> response
> to viral infection. IFN-beta increases the activity of natural killer 
> cells
> and the expres- sion of human leukocyte class 1 antigens while blocking 
> the
> expression of human leukocyte class 2 antigens. In addition, it can
> selectively inhibit the expression of several genes implicated in genomic
> studies of patients with CFS. Based on gene expression data, studies are
> planned to explore CFS treatment with IFN-beta. A clinical trial of 
> IFN-beta
> is expected to begin at St. George's University in London.
>
>
> Antiviral treatments
>
> At the 2007 International Association of Chronic Fatigue Syndrome meeting,
> investigators presented two phase 1 studies of valganciclovir in CFS 
> patients
> with evidence of HHV-6 or EBV infection. Kogelnik et al. [31*] found 
> evidence
> of clinical improvement in 20 of 23 subjects with acute onset CFS and high
> EBV and/or HHV-6 antibody titers. Lerner et al. [32*] presented data from 
> an
> open-label phase 1 trial supporting EBV reactivation affecting cardiac
> function in profoundly ill CFS patients. The study, which was a follow-up 
> to
> his previously published study of 19 CFS patients with cardiac wall 
> motility
> abnormalities, showed a favorable clinical response from most of the 60
> patients to 6 months of oral valganciclovir. Both investigators cautioned
> that the drug had a significant risk of bone marrow suppression and renal
> toxicity, and phase 2 placebo control studies are underway.
>
> In an open-label study of folinic acid, authors reported a high incidence 
> of
> chronic reactivated EBV infection accompanied by B-cell immunodeficiency 
> in
> patients with CFS. A significant proportion of these patients experienced 
> a
> marked improvement in symptoms after treatment with folinic acid [33].
>
> A retrospective study measuring the response of patients with CFS to
> azithromycin found that 58 of the 99 participants reported a decrease in
> symptom severity [34]. The responders improved to an estimated maximum of 
> 80%
> of their premorbid level. Those patients who responded to the treatment 
> had
> lower levels of plasma acetylcarnitine. The investigators theorize that 
> the
> efficacy of the azithromycin could be attributed to the modulating effect 
> on
> the chronically primed immune glia-cells in the brain or in the activated
> immune system of the patients with CFS.
>
>
> Conclusions
>
> The preponderance of available research confirms that immune dysregulation 
> is
> a primary characteristic of CFS. New research has further elucidated our
> understanding of the genomics of the illness and the role of viral 
> infection
> and reactivation in the pathogenesis. Advances in the field should result 
> in
> targeted therapies to impact immune function, HPA axis regulation, and
> persistent viral reactivation in CFS patients. Future research 
> investigating
> these important areas may lead to promising new discoveries and options 
> for
> treating CFS.
>
>
> Acknowledgment
>
> The authors have no potential conflicts, financial or otherwise.
>
>
> References and Recommended Reading
>
> Papers of particular interest, published recently, have been highlighted 
> as:
> *  Of importance
> ** Of major importance
>
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      Described the results of a study investigating the risk factors and
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 21.** Chia JK, Chia AY: Chronic fatigue syndrome is associated
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      The first study to look at enterovirus in CFS. Researchers found
      enterovirus viral capsid protein 1, RNA, and noncytopathic viruses
      in the stomach biopsy specimens in the majority of CFS patients
      with chronic gastrointestinal complaints.
 22.** Jerjes WK, Taylor NF, Wood PJ, Cleare AJ: Enhanced
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      Described alterations in negative feedback control of HPA axis in
      patients with CFS using dexamethasone suppression test.
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      post-infective fatigue after acute infection with Epstein Barr
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      Described alterations in gene transcripts among patients with
      postinfective fatigue following acute infection with EBV. Found
      that the patients who developed the postinfective fatigue syndrome
      had gene expression profiles that indicated an altered host response
      during episode of acute mononucleosis when compared with those
      patients who recovered without event.
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 26.   Landay AL, Jessop C, Lennette ET, Levy JA: Chronic
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 27.   Maher K, Klimas N, Fletcher MA: Immunology. In
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