Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome

Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported. In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4+ and CD8+ T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication. Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.

Epitopes of Microbial and Human Heat Shock Protein 60 and Their Recognition in Myalgic Encephalomyelitis.

Abstract Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM)…

High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients

43 Patients and 36 controls from Belgium and Norway were included in the study. Gut flora composition differed between people from different geographical origins. Significant alterations of gut microbiota composition were observed in patients.

This is relevant because 70% of all immune cells are located in the gastro-intestinal tract. Increased intestinal permeability may explain the systemic inflammatory situation in CFS.
Excess d-lactic acid production could contribute to mitochondrial dysfunction, but also to neurocognitive impairments in patients, since d-lactic acidosis is known to affect CNS function.

The predominance of women among patients, the fact that disease symptoms change upon e.g. puberty, pregnancy and menopause, has long suggested an involvement of hormones in ME/CFS. ER β, the preferred receptor of equol, is down-regulated in patients.
Disruption of estrogen signaling is consistent with some dysfunctions observed in ME/CFS. It could be related, for instance, with immune dysregulation since isoflavones, and more specifically equol, induce expression of antioxidant enzymes, and exert an anti-inflammatory action. Another potentially relevant aspect of phytoestrogens and their metabolites is their capacity to regulate vitamin D receptor activity, and vitamin D synthesis. The vitamin D system is critical for maintenance of gut mucosal immunity.Vitamin D has also been shown to modulate some processes that are critical for prevention of mucosal inflammation. One of the things not known yet is if the altered gut microbiota are cause or result of CFS.

Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome

Very long and technical article. 22 patients and 30 healthy controls were tested for certain cells that are part of the immune system. They found an unaffected B-cell compartment, a biased NK-cell phenotype and a poorly responsive T-cell compartment as the main immune features of ME/CFS affected individuals. The striking down modulation of T cell mediated immunity may help to understand intercurrent viral infections in CFS.

In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation.

Positive autoimmune reactions against serotonin were significantly higher in CFIDS patients than controls.

Patients with serotonin( 5-HT ) autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.