Investigations of B cell phenotype and metabolic function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Fane Kojo Fosu Mensah. PhD thesis University College London, Division of Medicine, Sep 2019
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition characterized by multiple systemic symptoms including fatigue, postexertional malaise and cognitive impairment, lasting for at least 6 months.
Immune system dysfunction triggered by infection or other insult is generally assumed to be a major causal factor that contributes to changes in energy metabolism leading to the pathophysiology of ME/CFS.
B cells became of interest after reported clinical improvement following B cell depletion-therapy with rituximab (anti-CD20). A possible but undefined role for B cells was, therefore, proposed.
The initial aim of this thesis was to explore subtle alterations in B cell subsets in ME/CFS patients which could be used as a diagnostic and prognostic marker for the disease. Further, the dynamic nature of B cells was utilised as a model to observe changes in energy demand and for performing comprehensive metabolomic profiling of activated and maturating B cells under culture conditions.
Results for HC and ME/CFS patients could, therefore, be compared under similar conditions of stress. Flow-cytometric analysis of CD19+B cells revealed increased frequencies and expression of the heat-stable antigen CD24 in ME/CFS patients, as well as an increased memory B cell subset (CD21+CD38-). Retention of CD24 was linked to unresponsiveness to proliferative and pro-apoptotic signals and phosphorylation of AMPK (pAMPK). PAMPK was found to be largely confined to IgD+IgM+ memory B cells.
Metabolic analysis of cell culture supernatant using 1H-NMR spectroscopy revealed significant correlations between CD24+B cell frequencies and the usage of glucose and the production of lactate.
Novel findings described in this thesis, therefore, established a link between CD24 positivity of B cells and energy metabolism. Immunophenotype and metabolite profiles of cultured B cells from HC and ME/CFS patients were also revealed to respond with different dynamics to interventions, thereby providing a potential platform for more focused research and diagnosis.