We have shown that there are a greater proportion of apoptotic cells among neutrophils isolated from patients with CFS and that these cells are significantly less viable when compared with those from healthy subjects. The same neutrophils expressed more TNFRI death receptor molecules and had increased binding of annexin V, indicative of phosphatidylserine exposure.
Apoptosis is triggered by signals initiated both by external stimuli and internal sensors. The death receptor mediated pathway, also known as the extrinsic pathway, starts with the binding of TNF family ligands to the death receptor TNFR1. This results in the recruitment of an adaptor protein, TNFR associated death domain, which in turn recruits another adaptor molecule, the Fas associated death domain. The Fas associated death domain then recruits procapase 8 or procaspase 10 to form a death inducing signal complex. During the formation of the death inducing signal complex, procaspase forms are cleaved and converted, with the release of activated caspase 8 or caspase 10, which directly convert other procaspases to their active forms, thereby initiating apoptosis. However, there is crosstalk between the extrinsic and intrinsic (mitochondrial dependent) pathways, and cleavage of the proapoptotic protein, Bid, by caspase 8 can occur. This cleavage can result in the release of cytochrome C and the triggering of further apoptotic mechanisms.12,13
In our study, we have shown that the neutrophils of patients with CFS have increased expression of TNFR1 and we can only surmise that the accelerated apoptosis of these cells is a consequence of extrinsic factors affecting apoptotic pathways.
“The data presented here are consistent with the fact that many patients with chronic fatigue syndrome have an underlying, detectable abnormality in the behaviour of their immune cells, consistent with an activated inflammatory process”
In addition, we found that the concentrations of activated TGFβ1 were significantly raised in the PPP of patients with CFS. An increase in activated TGFβ1 in conjunction with neutrophil apoptosis is an important process in the downregulation of cytokines and eicosanoid production during the chronic inflammatory process.4
TGFβ1 is also crucial in the apoptotic process because it curbs leucocyte adhesion and transmigration,14
and this impairment of the transmigratory process of neutrophils may independently promote apoptosis. Neutrophils that transmigrate across the endothelium lose TNF receptors and this loss of receptor density is necessary for the survival of the neutrophil.15
The fact that neutrophils from patients with CFS have increased surface expression of TNFRI is a further indication that such cells are more susceptible to apoptosis.
The neutrophils of patients with CFS have an increased rate of apoptosis and this may impact on the innate immune system of these patients, given that neutrophils are the major effector cells of this system. The control of apoptosis is complex, and the increased rate of apoptosis in patients with CFS may be a consequence of several factors. Accelerated apoptosis is indicative of a persistent or reactivating viral infection or a toxic state, reprogramming of apoptotic pathways by an infectious or toxic agent, or quicker neutrophil turnover, secondary to an abnormal host response to noxious stimuli.
With the advent of gene profiling the search is on for causative agents in CFS.1
The data presented here are consistent with the fact that many patients with CFS have an underlying, detectable abnormality in the behaviour of their immune cells, consistent with an activated inflammatory process.
Take home messages
- Patients with chronic fatigue syndrome (CFS) had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V binding, and increased expression of the death receptor, tumour necrosis factor receptor I, on their neutrophils than healthy controls
- Patients with CFS also had raised concentrations of active transforming growth factor β1
- Thus, patients with CFS appear to have an underlying abnormality in their immune cells