Research abstract:
Patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and multiple sclerosis (MS) suffer from debilitating fatigue which is not alleviated by rest.
In addition to the fatigue-related symptoms suffered by patients with CFS/ME and MS, dysfunction of the immune system and, in particular, reduced natural killer (NK) cell cytotoxic activity has also been reported in CFS/ME and MS.
The purpose of this pilot study was to compare NK cellular mechanisms in patients with CFS/ME and MS to investigate potential dysfunctions in the NK cell activity pathway.
Flow cytometry protocols assessed CD56dimCD16+ and CD56brightCD16+/- NK cell expression of adhesion molecules, NK activating and inhibiting receptors, NK cell maturation and lytic proteins.
All participants in this study were female and included 14 patients with CFS/ME, nine patients with MS and 19 non-fatigued controls.
The patient groups and the non-fatigued controls were not taking any immunosuppressive or immune-enhancing medications.
In the MS cohort, KIR2DL5 was significantly increased on CD56brightCD16+/- NK cells and expression of CD94 was significantly increased on CD56dimCD16+ NK cells in comparison with the controls.
Co-expression of CD57 and perforin was significantly increased on CD56dimCD16+ NK cells from patients with CFS/ME compared to the MS and non-fatigued control participants.
The results from this pilot study suggest that NK cells from patients with CFS/ME and MS may have undergone increased differentiation in response to external stimuli which may affect different mechanisms in the NK cell cytotoxic activity pathway.
Introduction:
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with disabling levels of fatigue.
Patients suffer from a state of permanent exhaustion which is also accompanied by a myriad of symptoms associated with autonomic, neurological, endocrine
and immune systems [1, 2].
Symptom severity may vary on a daily or weekly basis and is not alleviated by rest [3, 4].
Persistent fatigue is a characteristic of CFS/ME and approximately 65-95% of patients with multiple sclerosis (MS) also experience unremitting fatigue [5, 6].
Exacerbation of symptoms following physical or cognitive activity has been described in both CFS/ME and MS, as have memory and cognitive difficulties, gastrointestinal disturbances and irregular sleep patterns [5].
The symptoms suffered by patients with CFS/ME and MS may present as a relapsing-remitting course, and both CFS/ME and MS share a significant female preponderance [7, 8].
Approximately six females are affected to every one male for CFS/ME and 2.3–3.5 females to every one male for MS [7, 9].
Dysfunction of the immune system may contribute to the pathogenesis of CFS/ME and MS.
In particular, reduced natural killer (NK) cell cytotoxic activity is a consistent finding in CFS/ME and relapsing-remitting patients with MS [10-12].
CD56dimCD16+ NK cells elicit cytotoxic activity to remove target cells infected by viruses, bacteria orcells that have been malignantly transformed [13].
NK cell cytotoxic activity is a tightly regulated process which consists of a number of ordered steps including adhesion to the target cell, NK cell activation by surface receptors and release of lytic proteins to induce apoptosis of the target cell [14-16].
Whilst the consequences of reduced NK cell activity may be attributed to the persistence of viral infections reported in some patients with CFS/ME, contrasting evidence in MS suggests that the activity of NK cells can either exacerbate or attenuate disease activity [3, 7, 17].
The opposing effects of NK cells reported in patients with MS may be mediated by the different subsets of NK cells eliciting either cytotoxic or cytokine effector functions [18].
Reduced cytotoxic activity of peripheral NK cells from patients with MS has been correlated with clinical exacerbations of disease activity [12].
This finding has been replicated in the experimental autoimmune encephalomyelitis (EAE) mouse model where depletion of NK cells was associated with increased disease activity [19].
It has also been suggested that NK cells have an immunoregulatory role that promotes the remission state in relapsing-remitting MS [12, 20].
Through cytotoxic activity and the production of type 2 cytokines such as IL-5 and IL-13, NK cells may lyse and suppress T helper 1 autoimmune cells which mediate the inflammatory process in the CNS of patients with MS [20, 21].
The potential immunoregulatory role of NK cells in MS maintaining the remission state highlights the importance of optimal NK cell effector function.
As reduced NK cell cytotoxic activity has previously been reported in both CFS/ME and MS, the aim of this pilot study was to investigate cellular mechanisms required for NK cell effector function.
Adhesion molecules, surface receptors and lytic proteins were measured to determine whether mechanisms which may contribute to reduced NK cell cytotoxic activity are similar or different in female patients with CFS/ME and MS.
Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis, by Huth TK, Brenu EW, Ramos, Nguyen T, Broadley S, Staines D, Marshall-Gradisnik S in Scand J Immunol. 2016 Jan; 83(1):44-51.
