Published in Frontiers in Immunology | Primary Immunodeficiencies, 26 June, 2017.
Unperturbed Cytotoxic Lymphocyte Phenotype and Function in ME/CFS Patients
Jakob Theorell, Indre Bileviciute-Ljungar, Bianca Tesi, Heinrich Schlums, Mette Sophie Johnsgaard, Babak Asadi-Azarbaijani, Elin Bolle Strand and Yenan T. Bryceson.
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear.
Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, the discovery of adaptive natural killer (NK) cell subsets associated with certain viral infections, and compelling links between stress, adrenaline, and cytotoxic lymphocyte function, we reassessed the role of cytotoxic lymphocytes in ME/CFS.
Forty-eight patients from two independent cohorts fulfilling the Canada 2003 criteria for ME/CFS were evaluated with respect to cytotoxic lymphocyte phenotype and function. Results were compared to values from matched healthy controls.
Reproducible differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, or cytokine production.
One patient expressed low levels of perforin, explained by homozygosity for the PRF1 p.A91V variant. However, overall, this variant was present in a heterozygous state at the expected population frequency among ME/CFS patients.
No single patient displayed any pathological patterns of cellular responses. Increased expansions of adaptive NK cells or deviant cytotoxic lymphocyte adrenaline-mediated inhibition were not observed. In addition, supervised dimensionality reduction analyses of the full, multidimensional datasets did not reveal any reproducible patient/control discriminators.
In summary, employing sensitive assays and analyses for quantification of cytotoxic lymphocyte differentiation and function, cytotoxicity lymphocyte aberrances were not found among ME/CFS patients. These assessments of cytotoxic lymphocytes therefore do not provide useful biomarkers for the diagnosis of ME/CFS.
Comment from Dr Charles Shepherd, ME Association, Hon. Medical Adviser:
This is my report on this new immune system research based on a presentation at the 2017 Invest in ME Research conference. The full version of my report will appear in the August issue of ME Essential magazine:
Dr Theorell’s research is focussed on people who have what are called immunodeficiency syndromes (i.e. their immune systems are not functioning effectively). In relation to ME/CFS, he has been looking at a specific part of the immune system orchestra called cytotoxic lymphocytes.
These are cells that combat intracellular infections with dysfunctional abnormalities being reported in previous research studies.
He started off by describing the way in which NK (natural killer) cells act by recognising infected target cells, locking onto these target cells, and then releasing what are called pro-inflammatory cytokines.
Several research studies have looked at the function and phenotype of cytotoxic lymphocytes in ME/CFS, but their role remains uncertain.
This study involved 48 people with ME/CFS (meeting Fukuda and Canadian criteria) in two independent cohorts from Oslo and Stockholm plus matched controls. The phenotype and function of lymphocytes in frozen and thawed PBMCs (peripheral blood mononuclear cells) was evaluated using flow cytometry and compared to cells from age and sex matched controls.
There were no consistent differences found between people with ME/CFS and healthy controls in the wide range of functional tests involving cytotoxic lymphocytes – e.g. cell numbers, activation status, target cell killing capacity and cytokine release. In addition, no clear subgroups were identified.
These results do not therefore point to a role for defects in lymphocyte cytotoxicity in ME/CFS. Neither do they support the use of NK cell function as a biomarker for ME/CFS.