T Helper 17 and IL17f implicated in ME, CFS and Leaky Gut

Discussion in 'Fibromyalgia Main Forum' started by tansy, Sep 20, 2008.

  1. tansy

    tansy New Member

    Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue
    syndrome patients
    Kristine Metzger(a), Marc Fremont(a,*), Chris Roelant(a), Kenny De Meirleir(b)
    a Protea Biopharma, Z.1-Researchpark 100, 1731 Zellik, Belgium
    b Vrije Universiteit Brussel, Department of Human Physiology and Medicine,
    Pleinlaan 2, 1051 Brussels, Belgium
    * Corresponding author. Fax +32 2 481 5311.

    Article history: Received 25 August 2008


    Chronic fatigue syndrome (CFS) is characterized by immune dysfunctions
    including chronic immune activation, inflammation, and alteration of cytokine
    profiles. T helper 17 (Th17) cells belong to a recently identified subset of
    T helper cells, with crucial regulatory function in inflammatory and
    autoimmune processes.

    Th17 cells are implicated in allergic inflammation,
    intestinal diseases, central nervous system inflammation, disorders that may
    all contribute to the pathophysiology of CFS. IL-17F is one of the
    pro-inflammatory cytokines secreted by Th17 cells. We investigated the
    association between CFS and the frequency of rs763780, a C/T genetic
    polymorphism leading to His161Arg substitution in the IL-17F protein. The
    His161Arg variant (C allele) antagonizes the pro-inflammatory effects of the
    wild-type IL-17F.

    A significantly lower frequency of the C allele was
    observed in the CFS population, suggesting that the His161Arg variant may
    confer protection against the disease. These results suggest a role of Th17
    cells in the pathogenesis of CFS.

    Keywords: Chronic fatigue syndrome - CFS - Th17 cells - IL-17F - Polymorphism
    - Intestinal dysfunction


    Chronic fatigue syndrome (CFS)/myalgic encephalomyelitis is defined by a
    severe and debilitating fatigue associated with a variety of symptoms
    including musculoskeletal pain, sore throat, tender lymph nodes, sleep
    abnormalities, neurocognitive problems [1].

    The pathogenesis of CFS is still
    poorly understood, but is likely to be multifactorial; viral infections,
    stress, neuroendocrine dysfunctions, exposure to toxins have all been
    proposed as contributing factors to the onset and maintenance of the disease

    A large body of evidence supports the implication of chronic immune
    activation and other immunological dysfunctions in CFS. Decreased NK cell
    activity [3] and dysregulation of interferon pathways [4] have been observed
    in CFS patients.

    Increased oxidative stress levels have been detected, which
    is consistent with a chronic inflammatory situation [5]. Decreased NK cell
    activity, increased allergic and autoimmune manifestations in CFS suggest a
    Th2-oriented cytokine pattern [6], a hypothesis supported by the observations
    that IFN-gamma production is decreased, whereas IL-4 production is increased
    in CFS patients [7-9].

    Genetic predispositions may contribute to alterations
    of cytokine profiles in CFS patients: a first study of cytokine gene
    polymorphisms found an association between CFS and the frequency of TNF-857
    and IFN-gamma 874 rare alleles [10].

    Another class of cytokines may be relevant in the context of CFS: those
    associated with T helper 17 (Th17) cell function. Th17 cells have recently
    been identified as a new subset of T helper cells, in addition to the
    traditional Th1 and Th2 subsets.

    Differentiation of Th17 cells from naïve
    CD4+ T cells requires the coordinate action of the pro-inflammatory cytokine
    IL-6 (produced by activated macrophages/dendritic cells), and of the
    immunosuppressive cytokine TGF-beta. Differentiated Th17 cells produce
    IL-17A, IL-17F, IL-22, which appear to mediate host response to specific
    infections (extra-cellular bacteria), and to play crucial regulatory
    functions in inflammatory and autoimmune processes [11-14].

    A common variant
    of IL-17F, His161Arg, has been characterized; this variant lacks the ability
    to activate cytokine production in target cells, and confers protection
    against the pro-inflammatory effects of wild-type IL-17F [15]. The Arg/His
    amino acid substitution is determined by a T/C polymorphism in the IL-17F
    gene (rs763780).

    Th17 cells have been implicated in pathologies that share certain symptoms
    with CFS: inflammatory bowel disease, rheumatoid arthritis, allergic
    inflammation [16-18].

    To investigate the role of Th17 cells, and more
    specifically of the cytokine IL-17F, in the pathogenesis of CFS, we studied
    the association between CFS and the frequency of the IL-17F His161Arg
    variant. The rs763780 polymorphism was analyzed in 89 CFS patients, compared
    with 56 healthy controls.

    Subjects and methods

    Eighty-nine CFS patients (40 p/m 12 year old) were enrolled in the study. All
    were diagnosed for CFS according to the clinical criteria kolom5 of Fukuda et
    al. [1]. Fifty-six aged-matched controls (37 p/m 12 year old) were also
    recruited. Seventy-nine percent of the patients, and 70% of the controls,
    were females. All subjects were of European origin.

    Genomic DNA was extracted from whole blood using the Blood and Tissue DNA
    extraction kit, Qiagen (Venlo, Netherlands). Analysis of the rs763780
    polymorphism was performed with the SNPlexTM genotyping technology, Applied
    Biosystems (Foster City, CA, USA). Genotyping analyses were performed by
    DNAvision S.A. (Charleroi, Belgium), using ISO17025-accredited procedures.

    Results and discussion

    We found a significantly lower prevalence of the His161Arg variant in the CFS
    population, compared to the control population. Eight out of 89 patients
    have a CT genotype (8.9%), versus 14 out of 56 controls (25%). None of the
    CFS patients have the CC genotype, versus 2 out of 56 controls (3.6%). In
    total, 28.5% of the controls have a CC or CT genotype versus only 8.9% of the
    patients (OR=4.05, p=0.0018).

    The observed lower frequency suggests an involvement of IL-17F, and more
    generally of Th17 cells, in the pathophysiology of CFS.

    The His161Arg variant
    antagonizes the pro-inflammatory effects of wild-type IL-17F, and thereby
    exerts a protective effect against asthma [15]. Similarly, we can make the
    hypothesis that the development and/or maintenance of CFS involves an
    increased production of IL-17F, and that expression of the inactive variant
    confers protection against the disease.

    Increased IL-17F production has been observed in various inflammatory
    situations [11,15]. Interestingly, it also occurs in the context of
    intestinal disease, such as Crohn's disease or ulcerative colitis [19].
    Intestinal dysfunction is a common symptom in CFS.

    Alterations of the
    intestinal microbial flora have been reported [20]; such alterations can lead
    to intestinal mucosal dysfunction, increased intestinal permeability (leaky
    gut), that will finally cause an immune response to the LPS of gram-negative
    enterobacteria [21,22].

    Exposure of immune cells to LPS could therefore be
    the clue to the chronic immune activation observed in CFS patients.

    Considering this hypothesis, it is particularly noteworthy that in addition
    to IL-6 and TGB-b, optimal Th17 cell induction requires the action of
    Toll-like receptor (TLR)-activated peripheral blood mononuclear cells
    (PBMCs). TLR-activated monocytes may contribute to Th17 cell induction by
    cell-cell contact, through ligation of the T-cell receptor [23];
    alternatively, TLR-activated PBMCs may secrete a specific set of cytokines
    that will potentiate Th17 induction [24].

    In this last report, it was shown
    that TLR-4 (receptor for LPS), as well as TLR-7/8, evoked the most robust
    induction of Th17, whereas stimulation of TLR-1, -2, -3 or -9 was not

    Th17 cell induction could therefore be the link between exposure to
    enterobacterial LPS and the symptoms of chronic inflammation associated with
    CFS. Interestingly, Th17 and Th1 responses are mutually exclusive, since
    IFN-gamma suppresses IL-17 and vice-versa [11]. Th17 induction is therefore
    consistent with a decreased production of Th1 cytokines, as seen in CFS.

    proinflammatory effects of Th17-secreted cytokines are also consistent with
    other specific dysfunctions observed in CFS patients: IL-17 and IL-22 can
    disrupt the blood-brain barrier; Th17 lymphocytes transmigrate across the
    blood-brain barrier endothelial cells and promote inflammation of the central
    nervous system [25].

    Blood-brain barrier permeability and CNS inflammation is
    thought to be a key aspect in the pathogenesis of CFS [26].

    The implication of Th17 cell activation in the pathogenesis of CFS would be
    a significant progress in the understanding of the disease, opening new
    therapeutic perspectives. Confirmation of our results on a larger number of
    samples is therefore warranted.

    Further genetic studies will also look at
    other IL-17F-related genes, such as IL-23R. IL-17F is indeed specifically
    produced by IL-23R-expressing Th17 cells; IL-23R is also polymorphic and some
    variants of this receptor predispose to inflammatory bowel disease [16,19].

    An association between CFS and polymorphisms of the IL-23R gene, or other
    functionally related genes, would provide additional support for the
    implication of intestinal dysfunction and IL-17 axis in the pathogenesis of


    This work was supported by Grant IWT-070559 from the Instituut voor de
    Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen
    (IWT). We thank Dr. Patricia Lienard and Roser Sens Espel, from DNAvision
    S.A., for their help in designing the genotyping experiment.


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  2. meditationlotus

    meditationlotus New Member

    so much. This is good info. I have been dealing with so much inflammation.

    I have heard good things about grape seed extract in modulating the immune system from Jammin Health. I'm going to try it as well as staying away from food allergens.

    Thanks again