Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients

Abstract

BACKGROUNDThe etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME.METHODMessenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years).RESULTSThe expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls.CONCLUSIONSIn severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness.

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival

“…Interestingly, a recent study of gene expression in NK cells of CFS patients showed upregulation of RIPK3 [84], in line with the present data (Additional file 3: Table S3); this gene encodes a kinase that plays a vital role in inflammasomes and IL-1β signaling. However, a previous analysis of cytokine levels in the present material did not relieve any differences in CFS patients as compared to healthy controls [15].…”

Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

“…Following cytotoxic granule delivery to the immune synapse, the formation of perforin pores and granzyme-induced cell apoptosis are highly dependent on Ca 2+ (Orrenius et al, 2003 ; Voskoboinik et al, 2005 ). Previous studies have reported impaired Ca 2+ signalling in NK cells from CFS/ME patients demonstrated through changes to ERK1/2 and mitogen-activated protein kinase (MAPK) pathways (Chacko et al, 2016 ; Huth et al, 2016b ). CFS/ME patients have significantly decreased ERK1/2 following incubation with K562 cells (Huth et al, 2016b ).…”

Intermittent and graded exercise effects on NK cell degranulation markers LAMP‐1/LAMP‐2 and CD8+CD38+ in chronic fatigue syndrome/myalgic encephalomyelitis

“…Several studies have found that the mitogen‐activated protein kinase (MAPK/MEK1/2) pathway, including the extracellular signal‐regulated kinases (ERK1/2) and p38 signaling molecules, was impaired in CFS/ME and furthermore, that NK cells were significantly lower in cytoplasmic calcium than non‐CFS/ME, thus reducing intracellular signaling capacity through the ZAP‐70/Lck/phosphoinositide 3‐kinase (PI3K) pathway (Chacko et al. ; Huth et al. ; Nguyen et al.…”

“…); and (2) increased tyrosine kinase phosphorylation, calcium flux/signaling within the PI3K pathway, as the release of cytotoxic granules is calcium‐dependent (Chacko et al. ; Maher et al. ).…”

“…Furthermore, there is a critical threshold for signaling of MAPK and ERK for NK cells to produce an effector cell response, therefore increased phosphorylation and calcium flux may well enhance such responses (Chacko et al. ). There is ample evidence that both aerobic exercise and resistance training increases AMP‐activated protein kinase (AMPK), MAPK/ERK and p38 phosphorylation, and calcium/calmodulin signaling cascades in skeletal muscle cells (Egan et al.…”