Metabolic Analysis of B-Cell Maturation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

A project summary as written by Geraldine Cambridge, Fane Mensah, and Chris Armstrong:

Many viral and other infectious agents have been reported to cause or trigger the symptoms described by patients with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The variety of pathogens associated with ME/CFS however suggests that a single agent is not responsible and that chronic changes to the normal functioning of immune and other body cells caused by stressors such as infections more likely underly this disease.

ME/CFS patients suffer from a wide range of physical, neurocognitive and autonomic symptoms. It is perhaps therefore not surprising that in the limited biomedical studies so far performed, there appears to be a lack of consistency in results. Understanding the underlying disease-associated physiological and biochemical pathways in ME/CFS patients would therefore allow a more evidence-based approach leading to rapid diagnosis and to potential therapies. At present there are no biomarkers which could link the changes in function of the immune, neurological and other tissues to the many different disease manifestations of ME/CFS.

There is however some concensus amongst researchers that differences from healthy controls exist in both the functioning of the immune system and also in energy metabolism in ME/CFS. Focus on the possible involvement of certain immune cells (B-cells) in ME/CFS has recently been boosted after both investigator and patient-reported improvement in symptoms following removal of B-cells using rituximab. Response to rituximab-based therapy in autoimmunity is usually associated with the presence of disease-associated antibodies which are the products of B cells following maturation. Changes in energy metabolism, including the reduced use of oxygen during aerobic respiration following exercise, reduced antioxidant levels and increases in signals of oxidative damage by reactive oxygen species have also been described by several groups of investigators. All of these relate more or less directly to the function of the mitochondria (‘power-houses’) in cells. A technique called ‘metabolic profiling’ is a powerful tool which can provide detailed information about the biochemical signals and patterns related to mitochondrial function. This technique can be used to analyse mitochondrial related ‘signals’ in blood, urine and also in cultured cells.

The aim of this study is to investigate potential biochemical pathways that may be implicated in the development and chronicity of symptoms in ME/CFS patients and HC. We will be focusing on studying the metabolic functioning of mitochondria from B cells as there is evidence that changes in metabolism will affect the way these cells mature into antibody producing cells.

Researchers at University College London were the pioneers of rituximab-based therapy and have an established reputation in B cell research in autoimmune diseases and ME/CFS. Metabolic profiling by Dr Armstrong (University of Melbourne) has provided evidence for chronic immune activation impacting mitochondrial function in ME/CFS patients. The current application is therefore a unique collaboration between two committed young researchers under the supervision of experienced supervisors in different centers of excellence.