Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.

A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease

“…An increase in proton leak would usually correspond to decreased mitochondrial efficiency, as observed in two other studies by Missailidis et al [12,22,23,36]. Missailidis et al showed that respiratory function parameters can be part of an effective method to distinguish between ME/CFS/SEID and HC participant cells, however these findings require further validation in a larger cohort [23]. It is difficult to make reliable conclusions based on the glycolytic activity and respiratory function described in these featured studies, further research is required.…”

“…Interestingly, two papers reported decreased proton leak with decreased mitochondrial efficiency parameters in ME/CFS/SEID patients [12,19]. An increase in proton leak would usually correspond to decreased mitochondrial efficiency, as observed in two other studies by Missailidis et al [12,22,23,36]. Missailidis et al showed that respiratory function parameters can be part of an effective method to distinguish between ME/CFS/SEID and HC participant cells, however these findings require further validation in a larger cohort [23].…”

“…The Missailidis et al study also found no difference in mitochondrial mass, genome copy number, glycolytic rates, or steady state ATP levels between ME/CFS/SEID patients and HC participants [22]. These findings were validated in an associated study that found cells belonging to ME/CFS/SEID patients can be differentiated from HC participant cells based on respiratory function parameters [23].…”

“…As fatigue is a key diagnostic symptom for ME/CFS/SEID, energy metabolism may be a significant pathomechanistic factor. Mitochondrial function is an important aspect of energy metabolism and has been the focus of recent study [ 5 – 23 ].…”

“…Mitochondria are also fundamental for immune processes such as inflammasome activation and general intracellular calcium signaling [25,26]. Due to their physiological importance, mitochondria are implicated in a wide variety of pathological conditions including ME/ CFS/SEID [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”