We are very excited to have just posted the full preprint of our new ME/CFS immune profiling paper on BioRxiv, which will continue to be updated following reviewer comment and peer-review. In this detailed study, we analyzed the immunological differences between ME/CFS patients and healthy controls within a large cohort and found several major differences in T cell subset frequencies and functions between the two groups.
ME/CFS is a complex and heterogeneous chronic condition that is highly debilitating and often characterized by persistent, unexplained fatigue not alleviated by rest, muscle and joint pain, sleep problems, and post-exertional malaise (PEM). There is no clear diagnostic test for the disease, so diagnosis is based largely on clinical symptoms. It’s thought that around 90% of people with ME/CFS have not been diagnosed, and up to 2.5 million Americans suffer from it, with many more suffering worldwide. This costs the US economy an estimated $17 to $24 billion annually in medical bills and lost income.
Previous studies have suggested differences in several immune system components between healthy controls and ME/CFS patients. In the present study, we have extended the interrogation of the immune system of ME/CFS patients, mostly focusing on a key subset called T cells, which are like the generals and regulators of an immune response. Overall, we did not find differences in the overall numbers of monocytes, B cells, or T cells, but the ratio of two major subsets of T cells, namely the CD4+ to CD8+ T cell ratio, was increased in ME/CFS patients compared to healthy controls. This CD4+ to CD8+ ratio is known to change due to normal aging, and interestingly, when the study groups were split by age into those younger than 50 years and those older than 50 years, this difference in the CD4+ to CD8+ ratio was seen only in the subjects who were younger than 50 years of age, suggesting an accelerated aging phenotype in people with ME/CFS.
There was also a major difference seen between healthy controls and ME/CFS patients in the Th17 cell subset, which is involved in responding to bacteria and is also a culprit in several autoimmune and chronic inflammatory conditions. These cells are also resident in mucosal tissues, and play a major role in the immune response to both bacterial infections and to the microbiota (the trillions of bacteria that live in our bodies). The frequency of these cells was significantly higher in ME/CFS patients compared to healthy controls, yet their functionality was decreased in ME/CFS patients. We will write a separate article on this topic as it is more complex than this summary. However, we think this suggests a chronic activation of Th17 cells in ME/CFS which induces an “exhausted” state where the cells are more dysfunctional due to their chronic stimulation.
There was also a major difference seen in the mucosal-associated invariant T (MAIT) cells in ME/CFS patients compared to healthy controls. MAIT cells selectively respond to a broad range of bacteria, which we will discuss in more detail in a separate article. While the MAIT cell frequency did not differ between ME/CFS and controls, the functionality of these cells was profoundly different between the two groups and included a reduced production of cytokines. It is possible that these changes in Th17 and MAIT cells are associated with differences in the composition of the microbiota of the ME/CFS patients, and that a disruption in the microbiota causes chronic activation of these subsets and an exhausted state in ME/CFS patients. Interestingly, we also noted that regulatory T cells (Tregs) were increased in ME/CFS patients compared to controls. Tregs function to suppress excessive chronic immune responses, so this is consistent with our finding that there appears to be chronic activation of major T cell subsets in ME/CFS patients.
Finally and importantly, we utilized these immune profiling parameters in a machine learning classifier and were able to correctly identify ME/CFS patients from healthy controls with high sensitivity and accuracy. As patients often wait years to receive an ME/CFS diagnosis since there are currently no clear diagnostic tools to identify the disease, the development of an immune profile classier could aid as a biomarker to diagnose the disease.