2017 Ramsay Award Program Team 1

October 31, 2017

Biomarkers for initiation (infection) and metabolic derangement in ME/CFS

A project summary as written by Drs. Blomberg, Bergquist, Gottfries, and Zachrisson:

Our working hypothesis of ME/CFS pathogenesis is that a person predisposed for ME through genetics and previous antigen exposure is infected with a microbe prone to elicit ME. These microbial antigens have epitopes which cross-react with self-epitopes. An (auto)immune response to this microbe which bypasses tolerance mechanisms is elicited. The cross-reactive immune response, e.g. autoantibodies, is directed against molecules involved in energy metabolism, hormonal regulation and, possibly, specific portions of the brain. In short, “infection elicited autoimmunometabolic dysfunction”.

The role of infection may either be a “hit and run” phenomenon, or a chronic infection (“stay and fight”). We investigate the hit and run alternative by serology, looking for microbial antibodies, which allows retrospective detection of past infections of an ME/CFS patient. This approach also has the potential of revealing microbial antigens which cross-react with self-epitopes, a plausible origin of autoimmunity. The group of professor Jonas Blomberg already detected antibodies to a mitochondrial antigen, heat shock protein 60, which occurs both in microbes and human cells. We will continue this line of investigation, looking for more evidence of collusion between anti-microbe and anti-self in ME. Depending on financial means we will also look for evidence of chronic infection (“stay and fight”), the other form of human-microbe Interaction. We will then develop and use sensitive broadly targeted PCRs for viruses, bacteria and protozoa in the blood of ME/CFS patients.

Autoantibodies directed against energy-producing organelles like mitochondria are a plausible cause of PEM {Post Exertional Malaise), the cardinal symptom of ME/CFS. Recent research findings indicate a block of transition from anaerobic {also known as glycolysis) to aerobic energy production in

ME/CFS. The block manifests itself by an increase of metabolites before the block {e.g. lactate), and a decrease of metabolites after the block (e.g. succinate and alternative pathways like lipids and some amino acids). The nature of this block can be better understood by further studies on energy metabolites. Professor Jonas Bergquist has a unique set of quantitative methods for them. The purpose is to corroborate previous findings, and to reveal details of the metabolomic disturbance in ME/CFS.

We are fortunate to collaborate with the most experienced ME/CFS clinic in Sweden, the Gottfries clinic, in Mรถlndal. Prof. Carl-Gerhard Gottfries and Dr. Olov Zachrisson provided us with a collection of 198 blood samples from anonymous ME/CFS patients and controls. Their extensive clinical experience of ME/CFS is a guarantee for the clinical relevance of our research. Appropriate ethical permissions are at hand. The ME/CFS patients were diagnosed using the stringent Canadian criteria.

The laboratories of Jonas Bergquist and Jonas Blomberg in Uppsala are uniquely suited for a collaborative effort to better understand the pathogenesis of ME/CFS, and to develop biomarkers for the disease.