I de neste blogginnleggene skal vi se litt på funnene som er blitt gjort i immunsystemet til ME-pasientene med tanke på blant annet B og T- celler/lymfocytter, bakgrunn for fenomenet IRIS og stille det spørsmål om det er immunresponsreaksjonene som medfører vedvarende sykdomsaktivitet og blant annet økt risiko for utvikling av autoimmun sykdom. I del en fikk vi ett innblikk i fenotyper og hvilke ulike funn det er gjort på lymfoyttene T, B og NK celler, hovedsakelig fra en oversiktsartikkel av Klimas fra 2000. Denne delen ser vi på funksjonen til immuncellene og på cytokiner mm. Teksten beskriver godt en god del av symptomaktivitet og er relevant når en kommer til ulike behandlingstilnærmelser. Kort sagt – skal en behandle ME-pasienter må behandleren ha god oversikt over immun-profilen til pasienten, slik at det ikke skjer utilsiktet feilbehandling, og hvor en setter inn forbedrende tiltak.
IMMUNE CELL FUNCTION
T and B Lymphocytes
Depressed responses to phytohemagglutinin (PHA) and pokeweed mitogen (PWM), an indication of dysfunction in cellular immunity, were found in the CFS patients studied by most teams while Mawle and coworkers found no change. Gupta and coworkers found that the lymphocyte DNA synthesis in response to PHA, PWM and concanavalin A was normal in CFS patinets, but the response to soluble antigens (mumps, E. coli) was significantly reduced.
Roberts and colleagues found that PWM lymphoproliferative response is associated with Rh status among healthy controls but not among CFS patients and recommended to control future studies for Rh status. In terms of the functional implications of decreased lymphoproliferative activities in CFS, Hassan and coworkers reported that PHA proliferative responses were lower in patients with poor emotional and mental health scores, and the anti-CD3/anti-CD28 response was low in those with low general health perception scores.
T-cell dysfunction in CFS patients has been suggested to result from decreased surface expression of CD3, an important component of the T-cell receptor complex and Barker and coworkers found no significant increase in the mean proliferation of peripheral blood cells when stimulated with anti-CD3 antibody.
In terms of B-cell function, spontaneous and mitogen-induced immunoglobulin synthesis is also affected as discussed later. Despite these deficits in B-cell function, stimulation with allergens provides differential lymphocyte responsiveness. Greater in vitro lymphocyte responses to specific allergens, greater baseline levels of lymphocyte incorporation of tritiated thymidine, and an increased number of immunoglobulin E-bearing B and T lymphocytes have been reported. Elevation in levels of certain cytokines, such as IL 4, IL-5 and IL-6 may underlie the latter effects as discussed later.
In a sample of 65 CFS patients, we observed that decreased lymphoproliferative responses to PHA and PWM were associated with increased cognitive difficulties and greater SIP physicial illness burden.
[Apoptose – programmert celledød]
Another area of research in CFS is that of apoptosis, the process of programmed cell death, which is regulated by several genes including Bax and Bcl-2. The Bcl-2 protein forms a heterodimer with Bax that inhibits apoptosis, whereas the Bax-Bax homodimer promotes it.
A report by Hassan and coworkers on surface and intracellular immunologic and apoptotic markers and functional lymphocyte assays after stimulation with anti-CD3/anti-CD28 antibodies or PHA in 44 CFS patients revealed increased expression of the apoptosis repressor ratio of bcl-2/bax in both CD4 and CD8.
However, recent evidence indicates that induction of apoptosis might be mediated in a dysregulated immune system, such as that present in CFS, by the upregulation of growth inhibitory cytokines. In this respect, Vojdani and colleagues found an increased apoptotic cell population in CFS individuals as compared to healthy controls.
The increased apoptotic subpopulation in CFS individuals was accompanied by an abnormal cell arrest in the S phase and the G2/M boundary of the cell cycle as compared to the control group. In addition, CFS individuals exhibited enhanced mRNA and protein levels of the IFN-induced protein kinase RNA (PKR) product as compared to healthy controls.
In 50% of the CFS samples treated with 2-aminopurine (a potent inhibitor of PKR) the apoptotic population was reduced by more then 50%.
PKR-mediated apoptosis may thus contribute to the pathogenesis and the fatigue symptomatology associated with CFS.
See and colleagues found that addition of a glyconutrient compound (dietary supplement that supplies the crucial eight monosaccharides required for synthesis of glycoproteins) to peripheral blood cells of CFS patients in vitro significantly decreased the percentage of apoptotic cells (all three parameters were deficient at baseline).
In contrast to the studies described above, Swanink and coworkers found no obvious difference in apoptosis in leukocyte cultures from CFS patients.
Natural Killer Cells – NK-celler
Several studies revealed impaired NK cell function in CFS patients as assessed by cytotoxic activity against K562 cells and a decreased number of CD56+CD3- lymphocytes.
A study by Levine and coworkers on NK cell activity in a family with members who had developed CFS as adults, as compared to those who had not, documented low NK cell activity in 6/8 cases and in 4/12 unaffected family members. Two of the offspring of the CFS cases had pediatric malignancies. Based on these observations, the authors suggested that the low NK cell activity in this family may be a result of a genetically determined immunologic abnormality predisposing to CFS and cancer.
Gold and colleagues were the only group to find elevated NK cell activity among the CFS patients they studied while Mawle and colleagues found no change in NK cell function.
The changes in NK cell cytotoxic activity found by most groups could be related to several findings:
 CD56+CD3- cells are the lymphoid subset with highest NK cell activity; and a decrease in their representation is expected to lower the value for the NK cell activity per effector cells;
 The reduction in CD4+CD45+ T cells described previously may also result in decreased induction of suppressor/cytotoxic T cells; and
 Reduced NK cell activity may be associated with deficiencies in the production of IL-2 and interferon(IFN)- gamma by T cells or in the ability of NK cells to respond to these lymphokines.
In the terms of the latter possibility, Buchwald and Komaroff found that stimulation with IL-2 failed to result in improvement of cytolytic activity in many patients with CFS.
Poor NK cell function may also be related to the finding of an impaired ability of lymphocytes from CFS patients to produce IFN-gamma in response to mitogenic stimuli. Although one study reported elevated IFN-gamma production and another demonstrated normal production, the inability of lymphocytes from CFS patients to produce IFN-gamma found by Klimas , Kibler and Visser and their associates might represent a cellular exhaustion as a consequence of persistent viral stimulus.
The latter postulate is supported by Morag and Straus and their colleagues’ finding of elevated levels of leukocyte 2’5′-oligoadenylate synthetase, an IFN-inducible enzyme, in lymphocytes of CFS patients.
Furthermore, the lack of IFN-gamma production in CFS patients may be responsible for the impaired activation of immunoregulatory circuits, which in turn facilitates the reactivation and progression of viral infections.
In this respect, Lusso and associates described the prevention of intercellular spread of EBV mediated by the IFN released as a consequence of cellular response, and Borysiewicz and co-workers described normal NK cell activity but reduced EBV-specific cytotoxic T-cell activity in their CFS patients. Reactivation/replication of a latent virus (such as Epstein Barr virus) secondary to decreased NK cell activity has also been proposed to modulate the immune system to induce CFS.
More recent research has provided alternative explanations for the decreased NK cell activity observed in CFS.
A study by Ogawa and coworkers revealed a possible dysfunction in the nitric oxide (NO)-mediated NK cell activation in CFS patients based on the observations that 24 hours treatment of NK cells with L-Arginine (L-Arg), one of the essential amino acids, enhanced NK cell activity in controls but not CFS patients.
Although the expression of inducible NO synthase (iNOS) (the enzyme involved in the synthesis of NO from L-Arg) transcripts in peripheral blood mononuclear cells was not significantly different between healthy control subjects and CFS patients, and incubation with S-nitroso-N-acetyl penicillamine, an NO donor, stimulated NK cell activity in healthy control subjects but not in CFS patients.
See and coworkers (1998) reported that addition in vitro of a glyconutrient compound (dietary supplement that supplies the crucial eight monosaccharides required for synthesis of glycoproteins) to peripheral blood cells from CFS patients significantly enhanced natural killer cell activity, increased the expression of the glycoproteins CD5, CD8 and CD11a, and decreased the percentage of apoptotic cells, parameters which were all deficient at baseline.
«NK cytotoxic activity in CFS/ME has received much attention while only one study has examined CD8+T cell cytotoxic activity. Most studies found significant decreases in NK activity and one study found decreased CD8+T cell cytotoxic activity in a CFS/ME population compared with a control group.
These findings are confirmed in our study. In a previous study as well as this study in a larger population we have found that NK cytotoxic activity and CD56bright NK phenotypes are decreased in CFS/ME patients.
These atypical cytotoxic responses may be linked to compromised granule-mediated cell death pathways involving apoptotic mediators, perforin and granzymes. Perforin forms pore-like structures to facilitate the entry of granzymes into the target cell, and granzymes activate several apoptosis pathways that ensure effective killing of the target cell.
Perforin and granzymes have been shown to be decreased in both NK and CD8+T cells in CFS/ME. In contrast both granzyme A and granzyme K were significantly reduced while perforin levels were elevated in both the NK and CD8+T cells of CFS/ME patients. Reduced cytotoxic activity may therefore be an important component of the immune dysregulation seen in CFS/ME. (Klimas 2011)»
Prieto and coauthors found significant monocyte dysfunction in patients with CFS, such as reduced display of vimentin, phagocytosis index, and surface expression of HLA-DR. These deficits responded to naloxone treatment, which suggests that increased interaction of endogenous opioids with monocyte receptors might account for the monocyte dysfunction.
Gupta and coworkers found that monocytes from CFS patients display an increased density of ICAM-1 and LFA-1, but showed decreased enhancing response to recombinant IFN-gamma in vitro. In contrast to the latter studies, Barker and coworkers did not find abnormalities in superoxide anion production and phagocytosis in CFS patients.
Moreover, lack of a consistent elevation of neopterin, a macrophage activation marker (see later discussion), suggests that monocytes do not appear to account for the imbalances in IL-1 described below.
Conti and colleagues provided evidence for eosinophil activation in CFS by demonstrating elevated serum levels of eosinophil cationic protein (ECP). In the CFS population they studied, the prevalence of RAST positivity to one or more allergens was 77%, while no control showed positive RAST. Twelve of the 14 CFS patients with increased ECP serum levels were RAST-positive. However, CFS RAST-positive patients had no significantly higher ECP serum levels than CFS RAST-negative patients.
It remains to be determined whether eosinophil activation has a pathogenetic role in CFS or whether a common immunologic background may exist for both atopy and CFS.
[Allergi og andre typer av hypersensitivitet]
Although a higher prevalence of allergy and delayed type hypersensitivity can be detected in CFS patients, a trial with antihistamine treatment did not provide significant improvement and other authors such as Mawle and coworkers found no significant difference in the incidence of delayed type hypersensitivity and allergic responses among CFS patients.
Baraniuk and coworkers found that 30% of CFS patients had positive skin tests suggesting the potential for allergic rhinitis complaints, and 46% had non allergic rhinitis and suggested that while atopy may coexist in some CFS subjects, it is unlikely that it plays a causal role in CFS pathogenesis.
Borish and coworkers proposed that in at least a large subgroup of subjects with CFS with allergies, the concomitant influences of immune activation brought on by allergic inflammation in an individual with the appropriate psychologic profile may interact to produce the symptoms of CFS, and Borok suggested that food intolerance, in a genetically predisposed group of people, causes symptoms akin to both the major and minor criteria of CFS and it should be screened for to avoid confusion.
Although the controversy of atopy and CFS continues, it may be possible that these two conditions share some common denominators that are worth pursuing particularly in light of the proposed Th2 cytokine predominant pattern.
CYTOKINES AND OTHER SOLUBLE IMMUNE MEDIATORS
Stimulated lymphoid cells either express or induce the expression in other cells of a heterogeneous group of soluble mediators that exhibit either effector or regulatory functions. These soluble mediators include cytokines, hormones, and neurotransmitters, which in turn affect immune function and may underlie many of the pathological manifestations seen in CFS.
The studies of cytokines in CFS have been done in the peripheral blood compartment and a recent review by Vollmer-Conna and coworkers on the immunopathogenesis of CFS concludes that neuropsychiatric symptoms in CFS patients may be more closely related to disordered cytokine production by glial cells within the CNS than to circulating cytokines.
The hypothesis that expression of proinflammatory cytokines within the CNS plays a role in the pathogenesis of immunologically-mediated fatigue is underscored by the study by Sheng and coworkers who, using two strains of mice with differential patterns of cytokine expression in response to an injection challenge with Corynebacterium parvum, demonstrated that elevated IL-1 and TNF cytokine mRNA expression in the central nervous system corresponded to development of fatigue.
Injection of antibodies specific to either IL-1 or TNF did not alter immunologically induced fatigue, suggesting a lack of involvement of these cytokines produced outside of the CNS.
We will nonetheless describe the potential implications of the cytokine imbalances detected in peripheral blood to physiological and psychological functions.
Bildet viser hvilke cytokiner/chemokiner som er opp og nedregulert i ME-pasienter (wpi-studie – Nevada cohort). Mange med statistisk signifikans og noen som avviker fra kontroller og sannsynligvis har klinisk betydning. Denne studien viser en tendens, men avviker for eksempel på IL-5 fra Klimas datafra 2011.
Bildet viser en oversikt over hvilke cytokiner som tilhører T-hjelper celler. Noe som er hjelpsomt når vi snakker om Th1 vs Th2 dominans og når den skifter som følge av mulig behandling eller som en naturlig del av både tilfriskning og progresjon/forverring av sykdommen. Dette er noe en kan objektivt måle, men vitenskapelige årsaksforklaringer er som vi vet fremdeles uklare, og det gjelder ikke bare for sykdommen ME. Th2 dominans betyr i praksis at en uttrykker cytokiner som IL-4 istedet for IL-2 og mulig undertrykking av IFN-gamma. mRNA er genutrykket, altså utsondringsaktivitet fra genet som produserer cytokinet.
The decreased NK cell cytotoxic and lymphoproliferative activities and increased allergic and autoimmune manifestations in CFS would be compatible with the hypothesis that the immune system of affected individuals is biased towards a Th2 type, or humoral immunity oriented cytokine pattern.
The factors that could lead to a Th2 shift and to mood changes associated with immunoendocrine changes among CFS patients are unknown. Vaccines and stressful stimuli have been shown to lead to long-term, non-specific shifts in cytokine balance. Therapeutic regimens that induce a systemic Th1 bias are being tested including repeated stimulation with bacterial antigens or poly (I)-poly (C12U) and ex vivo activation of lymph node cells.
Interleukin-1 (IL-1) and soluble IL-1 receptors
IL-1 is the term for two distinct cytokines – IL-1a and IL-1b – that share the same cell-surface receptors and biological activities.
One study of CFS patients found elevated levels of serum IL-1 alpha but not of plasma IL-1 beta in 17% of patients studied. When the cohort was examined as to severity of symptoms, it was noted that the top quartile in terms of disability had the highest level of IL-1.
Curiously, use of reverse transcriptase-coupled polymerase chain reaction (RT-PCR) revealed IL-1b but not IL-1a messenger RNA (mRNA) in peripheral blood mononuclear cells (PBMCs) of several CFS patients with highly elevated levels of IL-1a. RT-PCR of fractionated cell populations showed that lymphocytes accounted for the IL-1b mRNA detected in PBMCs. No IL-1 mRNA was apparent in control subjects. That IL-1a mRNA was not detectable by RT-PCR in either PBMCs or granulocytes suggests that serum IL-1a in CFS patients is probably derived from a source other than peripheral blood cells.
Other potential sources are tissue macrophages, endothelial cells, lymph node cells, fibroblasts, central nervous system microglia, astrocytes, and dermal dendritic cells.
Linde and coworkers found significantly higer levels of IL-1 alpha in CFS and mononucleosis patients but Lloyd, Peakman and Rasmussen and their coworkers found no difference.
Five studies, in addition to one described above by Patarca and colleagues found no difference in the levels of IL-1 beta in CFS patients.
The signs and symptoms of CFS, which include fatigue, myalgia, and low-grade fever, are similar to those experienced by patients infused with cytokines such as interleukin-1.
Elevated serum levels of IL-1a found in a significant number of CFS patients could underlie several of the clinical symptoms. IL-1 can gain access to the brain through the preoptic nucleus of the hypothalamus, where it induces fever and the release of adrenocorticotropin hormone (ACTH)-releasing factor, which in turn would lead to release of ACTH and cortisol.
The observation that cortisol levels tend to be low in CFS patients regardless of IL-1a levels suggests a role of a defective hypothalamic feedback loop in the pathogenesis of CFS.
The presence of such a defect has been documented in Lewis rats, which are particularly susceptible to the induction of a variety of inflammatory and autoimmune diseases and exhibit reduced levels of ACTH-releasing hormone, ACTH and cortisol in response to IL-1.
Besides its effects on the HPA axis, IL-1 has other effects on the pituitary; it has been shown to augment release of prolactin and growth hormone and to inhibit release of thyrotropin and luteinizing hormone. The growth hormone deficiency state associated with CFS may also be a reflection of the defect in hypothalamic feedback loop which renders it inadequately responsive to IL-1.
IL-1 and tumor necrosis factor (TNF) provoke slow-wave sleep when placed in the lateral ventricles of experimental animals. The inordinate fatigue, lassitude, and excessive sleepiness associated with CFS could well be a consequence of the direct action of these cytokines on neurons.
Neurotoxic effects due to chronic overexpression of IL-1a and/or b of S100 – a small (10KDa), soluble calcium-binding protein that is synthesized and released by astroglia – have been proposed to underlie progressive neurological degeneration in Alzheimer’s disease.
IL-1 induces prostaglandin (PGE2, PGI2) synthesis by endothelial and smooth muscle cells.
These substances are potent vasodilators, and IL-1 administration in animals and humans produces significant hypotension. IL-1 has a natriuretic effect and may affect plasma volume. Gulick and colleagues showed that IL-1 and TNF inhibit b-adrenergic agonist-mediated cardiac myocyte contractility in cultures and intracellular accumulation of cyclic adenosine monophosphate.
Cytokine imbalances may, therefore, also underlie the cardiovascular manifestations of CFS.
Chronic fatigue syndrome is a condition that affects women in disproportionate numbers, and that is often exacerbated in the premenstrual period and following physical exertion.
Cannon and coworkers found that isolated peripheral blood mononuclear cells from healthy women, but not CFS patients, exhibited significant menstrual cycle-related differences in IL-1 beta secretion that were related to estradiol and progesterone levels. IL 1Ra secretion for CFS patients was twofold higher than controls during the follicular phase, but luteal-phase levels were similar between groups. In both phases of the menstrual cycle, IL-1sRII release was significantly higher for CFS patients compared to controls. The only changes that might be attributable to exertion occurred in the control subjects during the follicular phase, who exhibited an increase in IL-1 beta secretion 48 hr after the stress.
These results suggest that an abnormality exists in IL-1 beta secretion in CFS patients that may be related to altered sensitivity to estradiol and progesterone.
Furthermore, the increased release of IL-1Ra and sIL-1RII by cells from CFS patients is consistent with the hypothesis that CFS is associated with chronic, low-level activation of the immune system.
In contrast to the studies described above, Swanink and coworkers found no obvious difference in the levels of circulating cytokines, and ex vivo production of IL-1 alpha and IL-1 receptor antagonist. Although endotoxin-stimulated ex vivo production of tumor necrosis factor-alpha and IL-beta was significantly lower in CFS, none of the immunologic test results correlated with fatigue severity or psychologic well-being scores. Swanink and coworkers concluded that these immunologic tests cannot be used as diagnostic tools in individual CFS patients.
Tumor necrosis factors (TNFs) and soluble TNF-receptors
TNF-alpha and TNF-beta are cytokines produced on lymphoid cell activation. Twenty eight percent of CFS patients studied by Patarca and colleagues had elevations in serum levels of TNF-alpha and TNFbeta usually with elevation in serum levels of IL-1 or sIL 2R.
TNF- alpha expression in CFS patients is also evident at the mRNA level, which suggests de novo synthesis rather than release of a preformed inducible surface TNF-alpha protein upon activation of monocytes and CD4+ T cells.
The levels of spontaneously (unstimulated) produced TNF-alpha by non-adherent lymphocytes were also significantly increased as compared to simultaneously studied matched controls by Gupta and colleagues.
TNF-alpha may be associated with CNS pathology because it has been associated with demyelination and may also lead to loss of appetite. A study by Dreisbach and coworkers suggests that TNF-alpha may be involved in the pathogenesis of post-dialysis fatigue.
In contrast to the studies discussed above, Lloyd et al. found no difference in the levels of TNF-alpha or -beta in CFS patients and Rasmussen et al. and Peakman et al. found no differences in the levels of TNF-alpha and -beta, respectively.
The latter discrepancies are likely due to the fact that TNF levels decrease precipitously if the serum or plasma is not frozen within 30 minutes from collection.
TNF-alpha’s proinflammatory effects may be mediated by induction of gene expression for neutrophil activating protein-1 and macrophage inflammatory proteins resulting in neutrophil migration and degranulation.
Thus, it is reasonable that TNF elevations may also be associated with markers of macrophage activation such as serum neopterin (see below).
Among patients studied in our laboratory, we found that illness burden scores were significantly positively correlated with elevated TNF-alpha serum levels.
CFS patients have higher levels of sTNF-RI or sCD120a and sTNF-RII or sCD120b. Levels of sTNF-Rs are negatively correlated with NK cell cytotoxic and lymphoproliferative activities in CFS, an observation that is consistent with the activities of these soluble mediators.
Interleukin-2 (IL-2) and soluble IL-2 receptor
IL-2, formerly termed “T-cell growth factor,” is a glycosylated protein produced by T lymphocytes after mitogenic or antigenic stimulation. IL-2 acts as a growth factor and promoted proliferation of T cell and, under particular conditions, of B cells and macrophages.
Although serum IL-2 levels were found to be elevated in CFS patients compared with control individuals in one study, decreased levels were reported in two other studies and no difference was reported in three studies. Rasmussen and coworkers reported a higher production of IL-2 by stimulated peripheral blood cells from CFS patients as compared to controls. Cheney and coworkers found no obvious relation between IL-2 serum levels and severity or duration of illness in CFS.
Elevated levels of sIL-2R, a marker of lymphoid cell activation, have been found in a number of pathological conditions including viral infections, autoimmune diseases, and lymphoproliferative and hematological malignancies. Twelve percent of CFS patients studied by Patarca and coworkers had elevated levels of sIL-2R. The latter observation is consistent with the increased proportion of activated T cells and the reduced levels of IL-2 or decreased NK cell cytotoxic activity found in several studies of CFS patients discussed above. Linde and coworkers found no elevation in sIL-2R levels in CFS patients.
Visser and colleagues reported that although CD4 T cells from CFS patients produce less interferongamma than cells from controls, IL-4 production and cell proliferation are comparable.
With CD4 T cells from CFS patients (compared with cells from controls), a 10- to 20-fold lower desamethasone (DEX) concentration was needed to achieve 50% inhibition of IL-4 production and proliferation, indicating an increased sensitivity to DEX in CFS patients.
In contrast to IL-4, interferon-gamma production in patients and controls was equally sensitive to DEX. A differential sensitivity of cytokines or CD4 T cell subsets to glucocorticoids might explain an altered immunologic function in CFS patients.
IL-4 acts as a growth factor for various types of lymphoid cells, including B, T, and cytotoxic T cells,and has been shown to be involved in immunoglobulin isotype selection in vivo.
Activated T cells are the major source of IL-4 production, but mast cells can also produce it, and IL-4 has been associated with allergic and autoimmune reactions.
It is also noteworthy that many of the effects of IL-4 are antagonized by IFN-gamma, and the decreased production of the latter may underlie a predominance of IL-4 over IFN-gamma effects.
Interleukin-6 (IL-6) and soluble IL-6 receptor
The levels of spontaneously produced IL-6 by both adherent monocytes and non-adherent lymphocytes were significantly increased in CFS patients as compared to controls. The abnormality of IL-6 was also observed at mRNA level. In terms of circulating IL-6, Buchwald and coworkers found that IL-6 was elevated among febrile CFS patients compared to those without this finding and therefore considered it an epiphenomenon possibly secondary to infection.
Chao and coworkers also found elevated levels of IL-6 in CFS patients, but five other groups found no difference.
Most of the cell types that produce IL-6 so in response to stimuli such as IL-1 and TNF, among others. Excessive IL-6 production has been associated with polyclonal B-cell activation, resulting in hypegammaglogulinemia and auto antibody production.
As is the case with IL-4, IL-6 may contribute to activation of CD5-bearing B cells, leading to autoimmune manifestations. IL-6 also synergizes with IL-1 in inflammatory reactions and may exacerbate many of the features described previously for IL-1.
Study of cytokine production by stimulated peripheral blood mononuclear cells from patients with a closely related syndrome to CFS, the post-Q-fever fatigue syndrome (QFS) (inappropriate fatigue, myalgia and arthralgia, night sweats, changes in mood and sleep patterns following about 20% of laboratory-proven, acute primary Q-fever cases), showed an accentuated release of IL-6 which was significantly in excess of medians for all four control groups (resolving QFS, acute primary Q-fever without subsequent QFS, healthy Q-fever vaccinees and healthy controls).
Levels of induced IL-6 significantly correlated with total symptom scores and scores for other key symptoms. CFS patients have higher levels of sIL-6R (24) and sIL-6R enhances the effects of IL-6.
A study by Gupta and coworkers revealed that spontaneously produced IL-10 by both adherent monocytes and non-adherent lymphocytes and by PHA-activated non-adherent monocytes were decreased.
IL-10 is part of the Th2-type response.
The IFNs comprise a multigenic family with pleiotropic properties and diverse cellular origin. Data from six studies indicate that circulating IFNs are present in 3% or less of patients studied.
Peripheral blood cells from children affected by postviral fatigue syndrome produced more IFN-alpha than those from controls. In line with latter observation, Vojdani and colleagues found elevated IFN-alpha levels in CFS patients but Linde and Straus and their coworkers found no difference.
Fatigue occurs in more than 70% of patients treated with IFN-alpha and it may be associated with the development of immune-mediated endocrine diseases, in particular hypothryoidism and hypothalamic-pituitary-adrenal axisrelated hormonal deficiencies, in these patients. IFN-alpha therapy-associated fatigue is often the dominant dose-limiting side effect, worsening with continued therapy, and accompanied by significant depression.
Decreases in mental information processing speeds, verbal memory, and executive functions have also been reported at therapeutic doses of IFN-alpha. Although the direct cause of IFN-alpha-induced fatigue is unknown, it is possible that neuromuscular fatigue, similar to that observed in patients with postpolio syndrome, may also be one component of this syndrome.
The induction of proinflammatory cytokines observed in patients treated with IFN-alpha is consistent with a possible mechanism of neuromuscular pathology that could manifest as fatigue. A study by Davis and colleagues also revealed that IFN-alpha/beta is at least partially responsible for the early fatigue induced by polyI:C during prolonged treadmill running in mice.
IFN-gamma is an immunoregulatory substance, enhancing both cellular antigen presentation to lymphocytes and NK cell cytotoxicity and causing inhibition of suppressor T lymphocyte activity.
Two groups have found impaired IFN-gamma production on mitogenic stimulation of peripheral blood mononuclear cells from CFS patients and one group found increased production.
In contrast with the findings on lymphocyte activation, four groups reported no difference in the levels of circulating IFN-gamma. These results are in favor of the Th2 shift descibed previously, a shift that is not apparent at the level of circulating cytokines.
Tumor growth factor-beta (TGF-beta)
A study by Bennett and coworkers found that patients with CFS had significantly higher levels of bioactive TGF-beta levels compared to healthy controls and to patients with various diseases known to be associated with immunologic abnormalities and/or pathologic fatigue: major depression, systemic lupus erythematosis (SLE), and multiple sclerosis (MS) of both the relapsing/remitting (R/R) and the chronic progressive (CP) types.
A total of three studies supports the finding of elevated levels of TGF-beta among CFS patients.
Three studies found elevated levels of beta-2 microglobulin in patients with CFS and one study found no difference. Beta-2 microglobulin is a marker of immune activation.
Neopterin is a metabolite produced during the utilization of guanosine triphosphate, and increased production of neopterin is associated with macrophage activation by IFN gamma.
Neopterin is a presumed primate homolog of nitric oxide, which activated guanylate cyclase and is involved in neurotransmission, vasodilation, neurotoxicity, inhibition of platelet aggregation, the antiproliferative action of cytokines, and reduction of oxidative stress.
Neopterin derivatives belong to the cytotoxic arsenal of the activated human macrophage and, in high doses, enhance oxidative stress through enhancemente of radicalmediated effector functions and programmed cell death by TNF alpha, while having an opposite effect at low doses.
Buchwald and Chao and their coworkers found elevated levels of neopterin in CFS patients, while Linde and Patarca and their coworkers found no difference. A report of nine CFS cases showed significantly elevated serum neopterin levels in association with high Cognitive Difficulty Scale (CDS) scores and neopterin levels have been shown to correlate with levels of many other mediators that have been found to be dysregulated in CFS including members of the TNF family.
In terms of neurotoxicity, serum neopterin and tryptophan concentrations correlate among cancer and AIDS patients, an observation which can be accounted for by activity of indoleamine 2,3-dioxygenase, a tryptophandegrading enzyme. The latter enzyme also converts L-tryptophan to L kynurenine, kynurenic acid and quinolinic acid (QUIN).
QUIN is a neurotoxic metabolite that accumulates within the central nervous system following immune activation and is also a sensitive marker for the presence of immune activation within the CNS. Direct conversion of L-tryptophan into QUIN by brain tissue occurs in conditions of CNS inflammation, but not by normal brain tissue.
Macrophage infiltrates, and perhaps microglia, are important sources of QUIN, an observation which is consistent with the results of inoculation of poliovirus directly into the spinal cord of rhesus macaques, resulting in increased CSF levels of both QUIN and neopterin. Elevated serum levels of neopterin correlate with the presence of brain lesions and with neurologic and psychiatric symptoms in patients with AIDS dementia complex.
It is worth noting in this context that Buchwald and colleagues found subcortical lesions consistent with edema and demyelination by magnetic resonance scans in 78% of CFS patients as compared to 20% of controls.
Soluble CD8 (sCD8)
Linde and coworkers found no elevation of sCD8 in CFS patients.
Soluble ICAM-1 (sICAM-1)
Patarca and coworkers found higher levels of sICAM-1 in CFS patients, an observation which is consistent with the higher expresion of ICAM-1 in monocytes of CFS patients reported by Gupta and coworkers.
Spontaneous and mitogen-induced immunoglobulin synthesis is depressed in 10% of patients with CFS. The latter decrease may be a result of an increased T-cell suppression of immunoglobulin synthesis, because a similar effect is obtained in vitro when using normal allogeneic B cells.
This inhibitory effect may also account for the reported difficulty in establishing spontaneous outgrowth of EBV-transformed B-cell lines from cells from CFS patients. The depletion of the CD4+CD45RA+ lymphocyte subset in the studies by Klimas et al. and Franco and colleagues may be associated with alteration in B-cell regulation.
In twelve studies, CFS patients were found to have decreased amounts of immunoglobulins of the G, A, M, or D classes, in five studies no difference was found and in one study IgG levels were elevated while IgA levels were normal. IgG subclass deficiency, particularly of the opsonins IgG1 or IgG3, can be demonstrated in a substantial percentage of CFS patients, and for a subset of these, immunoglobulin replacement therapy may be beneficial albeit controversial. Bennett and coworkers also failed to find immunoglobulin subclass deficiencies in CFS patients.
Konstantinov and colleagues found that approximately 52% of sera from CFS patients react with nuclear envelope antigens.
Some sera immunoprecipitated nuclear envelope protein lamin B1, an observation which underscores an autoimmune component in CFS. von Mikecz and colleagues found a high frequency (83%) of autoantibodies to insoluble cellular antigens (vimentin and lamin B1) in CFS, a unique feature which might help to distinguish CFS from other rheumatic autoimmune diseases.
Another finding that underscores a possible autoimmune etiology is the significant association between CFS and the presence of HLA-DQ3 reported by Keller and colleagues.
The presence of rheumatoid factor, antinuclear antibodies, antithyroid antibodies, anti-smooth-muscle antibodies, antigliadin, cold agglutinins, cryoglobulins, and false serological positivity for syphilis have also been reported.
No circulating antimuscle and anti-CNS antibodies were found in 10 CFS patients and Rasmussen and coworkers found no significant differences in the number of positive tests for autoantibodies in CFS patients.
Circulating immune complexes
Elevated levels of immune complexes have been reported in four studies while the studies by Natelson and Mawle and their coworkers revealed no abnormality in the level of circulating immune complexes (i.e., Raji cell and C1q binding).
Depressed levels of complement have also been reported in 0% to 25% of patients. Buchwald and coworkers found elevated levels of C-reactive protein among CFS patients.
Kilder og referanser:
Brenu, E. et al (2011) Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis
Patarca, R. et al. (2000). Review: Immunology of Chronic Fatigue Syndrome Patarca2000ImmuneReviewFull
Klimas et al. (1990) Immunologic Abnormalities in Chronic Fatigue Syndrome immundysfunksjon_Klimas_publ_1990
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