Abstract
Complement activation resulting in significant increases of C4a split product may be a marker of postexertional malaise in individuals with chronic fatigue syndrome (CFS). This study focused on identification of the transcriptional control that may contribute to the increased C4a in CFS subjects after exercise. We used quantitative reverse-transcription polymerase chain reaction to evaluate differential expression of genes in the classical and lectin pathways in peripheral blood mononuclear cells (PBMCs). Calibrated expression values were normalized to the internal reference gene peptidylpropyl isomerase B (PPIB), the external reference gene ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (rbcL), or the geometric mean (GM) of the genes ribosomal protein, large, P0 (RPLP0) and phosphoglycerate kinase 1 (PGK1). All nine genes tested, except mannose-binding lectin 2 (MBL2), were expressed in PBMCs. At 1 hour postexercise, C4, mannan-binding lectin serine protease 2 (MASP2) and ficolin 1 (FCN1) transcripts were detected at higher levels (> or = 2-fold) in at least 50% (4 of 8) of CFS subjects and were detected in 88% (7 of 8) CFS subjects when subjects with overexpression of either C4 or MASP2 were combined. Only an increase in the MASP2 transcript was statistically significant (PPIB, P = 0.001; GM, P = 0.047; rbcL, P = 0.045). This result may be due to the significant but transient downregulation of MASP2 in control subjects (PPIB, P = 0.023; rbcL, P = 0.027). By 6 hours postexercise, MASP2 expression was similar in both groups. In conclusion, lectin pathway responded to exercise differentially in CFS than in control subjects. MASP2 down-regulation may act as an antiinflammatory acute-phase response in healthy subjects, whereas its elevated level may account for increased C4a and inflammation-mediated postexertional malaise in CFS subjects.
Highlights
Chronic fatigue syndrome (CFS) is a medically-unexplained illness identified by self-reported symptoms and exclusionary conditions
A microarray study that included probes for 3800 genes and used total RNA from peripheral blood mononuclear cells (PBMCs) of these subjects identified differences in complement activation between CFS and control subjects following exercise [10]. These results demonstrate that complement activation may be a marker of CFS-associated postexertional malaise, and that exercise-induced complement activation, that which leads to the increased level of C4a split product, may be regulated at the transcriptional level
This study used a subset of subjects from a previous case-control study that identified a significant increase of C4a split product at 6 h postexercise in CFS subjects [9]
Summary
Chronic fatigue syndrome (CFS) is a medically-unexplained illness identified by self-reported symptoms and exclusionary conditions. Discovery of biomarkers may have been impeded by the fact that the unique biologic changes responsible for production of the original illness may no longer be present in most prevalent cases of CFS identified by various clinical case definitions [1,2]. A consistently observed casedefining symptom in CFS subjects, is the exacerbation of symptoms following exercise (postexertional malaise), as opposed to the relief from symptoms following exercise in patients with other fatigue-associated conditions such as depression, rheumatoid arthritis, systemic lupus erthymatosus, and multiple sclerosis [3,4,5,6].
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