Immunsystemet til ME pasienter: immunceller og cytokiner – en intro del 1

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 de nye ME kriteriene kan vi lese blant annet dette (1): En initial infeksjon kan muligens skade deler av CNS og immunsystemet, noe som medfører en alvorlig deregulering av immunforsvaret og unormal infeksjonsrespons. Vitenskapelige artikler beskriver redusert natural killer cell (NK-celle) signalering og funksjon, unormale veksthormonprofiler, nedsatt aktivitet av nøytrofile granulocytter og Th1, med en dreining mot en Th2-profil. Kronisk immunaktivering, økning av inflammatoriske cytokiner, proinflammatoriske alleler, kjemokiner og T-lymfocytter og dysregulering av den antivirale ribonuklease L-pathway (RNase L).

Immunolog Dr. Nancy Klimas har en årrekke forsket på ME-pasienters immunsystem og vi skal i dette innlegget vise til blant annet hennes publikasjoner om funn som er gjort. Som det fremgår av sammenstilling av ulike forskeres funn så varierer de og årsaken kan være flere, som ulik bruk av kriterier, studiedeltakere, når prøvene er tatt, variasjon over året, faser av og varighet av sykdommen, samt utvikling av sykdommen, aktiv infeksjon, ulike undergrupper, ulike labs og utstyr mm.  Likevel, som uavhengige studier viser så er det flere som viser en tendens med at de finner det samme. Teksten er ikke oversatt (så bruk oppgitte referanser for lesning) og gjør oppmerksom på at dette er komplisert og innfløkt stoff. Vil nok anta at du minst må ha studert immunsystem i 50 år og fremdeles ikke er utlært og stadig nytt med ny teknologi. Sånn bare for å ha sagt det!

Utdrag fra publikasjonene til Klimas (referanse oppgitt fra hvilken publikasjon det gjelder):

Population based studies have suggested a link between infections, neurological and neuroimmune dysfunctions and clinical manifestations of CFS/ME. Immunity has been widely investigated in patients with CFS/ME but the results of these studies are inconsistent, reporting different lymphocyte cell numbers and cytokine distributions in patients with CFS/ME.

Nonetheless, findings on immunoglobulins, complement markers and activation molecules in CFS/ME, may demonstrate a underlying infringement in immune function. Decreased function of lymphocytes, in particular Natural Killer (NK) cell cytotoxic activity in CFS/ME patients compared to healthy controls, seems to be a consistent finding.

The functional capacity of other immune cells, such as T cells, and the contribution of other molecules in the pathophysiological mechanism of CFS/ME, remains to be determined. In particular, the role of subsets of CD4+T and the CD8+T cell populations has not been fully studied in CFS/ME.

Importantly, recent data on cytokine distribution in CFS/ME patients point towards an increase in pro inflammatory cytokines suggesting the presence of an underlying viral prevalence in these patients and this can be detrimental to the immune inflammatory processes. (2).

Bildet viser hvilke cytokiner/chemokiner som er opp og nedregulert i ME-pasienter (wpi-studie). 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 data (2).

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.

Ett abstrakt fra en oversikt over funn i publikasjon fra 2000 (3):

Navnene er ulike forskere og publikasjoner.

A review of the literature on the immunology of CFS reveals that people who have Chronic Fatigue Syndrome (CFS) have two basic problems with immune function that have been documented by most research groups:

immune activation, as demonstrated by elevation of activated T lymphocytes, including cytotoxic T cells, as well as elevations of circulating cytokines; and poor cellular function, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3.

These findings have a waxing and waning temporal pattern which is consistent with episodic immune dysfunction (with predominance of so called T-helper type 2 and proinflammatory cytokines and low NKCC and lymphoproliferation) that can be associated as cause or effect of the physiological and psychological function derangement and/or activation of latent viruses or other pathogens.

The interplay of these factors can account for the perpetuation of disease with remission/exacerbation cycles. Therapeutic intervention aimed at induction of a more favorable cytokine expression pattern and immune status is discussed.

 IMMUNE CELL PHENOTYPIC DISTRIBUTIONS (3):

Analysis of the complex interactions underlying immune responses was greatly facilitated by the development of monoclonal antibodies to various surface proteins on lymphoid cells, which defined functionally distinct subsets. Such analysis has also demonstrated that each type of lymphoid cell is genetically programmed to carry out defined immunological functions that are predictable on the basis of surface phenotype.

Surface-marker phenotyping of peripheral blood lymphoid cells has also allowed insight into the cellular basis of immune dysfunction associated with pathologies of the central nervous system with diverse causes, including viral, autoimmune, and genetic, among others.

Several reports also documented alterations in the distribution of various lymphoid cell subsets among CFS patients. Certain discrepancies in the findings from different study groups can be attributed to group nonequivalences on diverse parameters such as demographic variables (gender, age, socioeconomic status), medical status variables predating onset of disease, medication use, concomitant substance abuse, nutritional status, and the effects of time of sample collection.

T Lymphocytes

CD4+ T cells (helper-inducer cells) are the principal source of “help” for antibody production by B cells in response to T-cell-dependent antigenic stimulation, as well as inducers of cytotoxic and suppressor T-cell function (CD8+ cells).

Discrepant results have been reported in reference to CD4 and CD8 cell counts in CFS patients. Straus and colleagues reported a statistically higher percentage of CD4+ lymphocytes with normal numbers of CD8+ cells and CD4/CD8 ratio.

Jones  and colleagues, Borysiewicz, Gupta, Landay, Lloyd and Tirelli  and their coworkers found normal percentages of CD4+ and CD8+ cells as well as a normal CD4/CD8 ratio.

Lloyd and coauthors found decreased numbers of both CD4+ and CD8+ cells. Buchwald and Komaroff found reduced numbers of CD8+ cells and higher-than normal CD4/CD8 ratios, and Klimas and colleagues found that most CFS subjects studied had a normal number of CD4+ cells and an elevated number of CD8+ cells that resulted in a decrease in the CD4/CD8 ratio.

Decreased CD4/CD8 ratios in 2% to 100% of patients have been demonstrated by other investigators.

These conflicting results may be associated with the fluctuation in clinical manifestations of these patients or with other factors mentioned previously. In fact, several researchers have detected fluctuations in several immunological parameters and in the severity of symptoms in longitudinal follow-up investigations of patients with CFS.

Moreover, Mawle and coworkers found that although only marginal differences in cytokine responses and in cell surface markers were apparent in the total CFS population they studied, when the patients were subgrouped by type of disease onset (gradual or sudden) or by how well they were feeling on the day of testing, more pronounced differences were seen.

It is also worth noting that although Peakman and coworkers did not find significant differences in the percentage levels of total CD3+, CD4+ , CD8+, and activated, naïve and memory T-cell subsets between CFS subjects and controls, they cryopreserved the cells before flow cytometric analysis and cryopreservation can differentially affect the representation of T-cell subsets.

A study by Sandman and colleagues found that elevated CD4+ and CD8+ cell counts in CFS patients were related to decreases in priming of memory, speed of memory scanning and increases in errors on a memory fragility test. However the latter study did not control for depression severity, and it is not clear whether the finding is related to co-morbid depression or to CFS itself.

Klimas and co-workers found a decreased proportion of CD4+CD45RA+ cells, which are associated with suppressor/cytotoxic cell induction but Natelson and coworkers  found no significant change in the proportions of CD4+CD45RA+ and CD4+CD45RO+ cells in CFS patients.

Franco and coinvestigators also described a decrease in the number of CD4+CD45RA+ lymphocytes in two patients with severe, chronic, active Epstein-Barr virus (EBV) infection; one of the two patients showed a persistent diminished number of cells despite clinical improvement with interleukin-2 (IL-2) treatment.

Several publications have associated alterations in the latter subset with a number of clinical entities, particularly autoimmune diseases.

Increased numbers of T cells expressing the activation marker CD26, probably as a result of CD8+ activation, have also been reported in CFS patients.

In this respect, an increased proportion of CD8+ cells expressing the activation marker human leukocyte antigen (HLA) DR  have been reported in CFS patients, whereas normal proportions of CD4+ T-cells co-expressing the HLA-DR marker or the IL-2 receptor (CD25) were found in one study , normal proportions of CD8+ CD38+, CD8+CD11b-, CD8+HLA-DR+ and CD8+CD28+ were found in another study, and normal proportions of CD8+HLADR+ and CD8+CD38+ were found by Swanink and coworkers.

In contraposition to the latter findings, Hassan and colleagues found significantly decreased expression of CD28 on CD8 cells and Barker, Landay  and Swanink  and their coworkers found significantly decreased expression of CD11b on CD8 cells.

Higher expression of CD38 on CD8 cells was found by Barker, Landay and Peakman and their coworkers.

It is worth noting that relatively higher proportions of HLA-DR+ T cells have been reported in a number of autoimmune disorders, and that Hassan and coworkers  found that CFS patients with increased HLA-DR expression had significantly lower Short Form-36 health questionnaire (SF-36) total scores, worse body pains, and poorer general health perception and physical functioning scores.

The increased expression of class II antigens and the reduced expression of the costimulatory receptor CD28, which is a marker of terminally differentiated cells, lend further support to the concept of immunoactivation of T lymphocytes in CFS and may be consistent with the notion of a viral etiopathogenesis in the illness.

We studied the association between CFS physicial symptoms, illness burden and lymphocyte activation markers in 27 newly-recruited CFS patients. Elevations in T-helper/inducer cells were associated with a greater frequency and severity of tender lymph nodes, greater severity of memory and concentration difficulties and headaches.

Greater numbers of activated T cells (CD2+CD3+CD26+) were associated with a greater frequency of tender lymph nodes and cognitive difficulties while more activated cytotoxic/suppressor cells (CD8+CD38+HLA-DR+) were associated with greater severity of tender lymph nodes, fatigue and sleep problems.

Conversely, lower percentages of regulatory cells such as CD3+CD8+ were associated with a greater number of cognitive difficulties, greater Sickness Impact profile(SIP)-Total, SIP Physical Impairment, and an increased frequency and severity of memory problems, increased frequency of headaches, and increased severity of fatigue.

Thus, among CFS patients the degree of cellular immune activation is associated with the severity of CFS-related physical symptoms, cognitive complaints, and perceived illness burden.

B Lymphocytes

Gupta, Klimas, Landay, Lloyd  and Barker and their colleagues found normal levels of CD20+ resting B cells, whereas other teams reported both increased and decreased level. The proportion of CD5-bearing B cells was found to be increased in two studies or decreased in one study. B cells bearing the cell marker CD5 have been associated with autoimmunity.

Natural Killer Cells

Klimas , Morrison, Peakman  and Tirelli  and their associates found increased numbers of NK cells, whereas Barker, Landay, Lloyd  and Natelson  and their coworkers found normal numbers and Masuda  and Gupta and their coworkers found decreased numbers of NK cells.

Despite the discrepancy in total numbers of NK cells measured by different groups, Caligiuri and Morrison and their coworkers found an increased proportion of CD56+CD3+ T cells, which may account for the decreased natural killer (NK) cell cytotoxic activity seen in several studies of CFS patients.

Morrison and coworkers also found a decreased percentage of CD56+Fcgamma receptor+ NK cells, which suggests a reduced capacity for antibody-dependent cellular toxicity.

Neutrophils (kom: er ikke en lymfocytt, men tilhører akutt-respons delen av immuncellene)

Previously described relationships in healthy women between basal circulating neutrophil numbers and plasma progesterone concentrations and between exercise-induced neutrophilia and urinary cortisol and plasma creatine kinase concentrations were not observed in CFS women, observations which suggest that normal endocrine influences on the circulating neutrophil pool may be disrupted in CFS patients.

Oppsummering:

Som det fremkommer i ulike studier er det altså variasjon i funnene og som nevnt i innledningen har det flere årsaker.

Likevel gir dette ett innblikk i at det er immundysfunksjon i ME-pasienter, og i del to av introen skal vi se på hva som er funnet når det gjelder funksjonen til immuncellene i ME-pasienter. Det er jo selvfølgelig relevant når det kommer til å ha ett optimalt fungerende immunforsvar, noe som beklageligvis ser ut til å ikke være tilfellet i ME-syke.

Der tar vi også med delen om cytokiner og chemokiner, immuncellenes signal og kommunikasjonssystem, som ikke akkurat spiller på vår side og gir en rekke symptomer.

Om noen trudde at avvik i immunsystemet kommer bivirkningsfritt, vel tenk om igjen.

På generelt grunnlag så kan en si at når det gjelder ME-sykes immunprofiler og immunsystem, så er det individuelle forskjeller med tanke på at noen produserer mengder av immunceller, mens andre har mangler. Derfor får en også ett helt ME-spekter, altså subgrupper. Sykdomsmønster og symptomkriterier er likevel nokså lik.

Det alle har til felles om du er rammet av sykdommen ME er manglende evne for mitokondriene til å effektivt produsere fine og gode ATP pakker av flere årsaker og fremdeles uklare årsaker. Konsekvensen er dyrkjøpt for oss pasienter, fordi det ender opp i energisvikt. Ved fysisk aktivitet produserer mitokondriene melkesyre i stedet – litt for mye og litt for kjapt!

Så kroppen prioriterer hardt og brutalt for oss – den energien som produseres går til opprettholdelse av immunsystemet og indre vitale organer, som ja jobber som f… for å oppnå «steady-state»….

Kilder og referanser:

1 ICC Internasjonale konsensuskriterier for Myalgisk Encefalopati (G93.3)

2 Brenu, E. et al (2011) Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis

3 Patarca, R. et al. (2000). Review: Immunology of Chronic Fatigue Syndrome Patarca2000ImmuneReviewFull

WPI studie: signifikant endret cytokin/chemokin mønster i ME/CFS pasienter

—–

Cytokiner og chemokiner – proteiner som signaliserer hva en stamcelle skal bli og pluss litt til

Komplementsystemet og inflammasjoner

Klimas et al. (1990) Immunologic Abnormalities in Chronic Fatigue Syndrome immundysfunksjon_Klimas_publ_1990

Lettlest om immunsystemet: ME-blogg innlegg «oversikt over immunsystemet»

En kommentar om “Immunsystemet til ME pasienter: immunceller og cytokiner – en intro del 1

  1. Tilbaketråkk: Immunsystemet til ME pasienter: immunceller og cytokiner – en intro del 2 « ToTo NeuroImmunologisk Kurativ Behandling

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