Dr. Dmitri Pchejetski, a researcher at the University of East Anglia Medical School (United Kingdom), has developed a new blood-based assay, the EpiSwitch CFS test, that may prove very effective for diagnosing people with ME/CFS.
The EpiSwitch assay works by assessing how chromosomal DNA is packaged in human cells and how this packaging associates with active or silent genes. If unraveled and lined up end-to-end, chromosomal DNA in a single human cell would be about six-and-a-half-feet long. To fit inside a nucleus, chromosomes must be carefully coiled and packaged. Genes in too tightly coiled DNA are usually silent. To be active, genes must be in somewhat relaxed DNA and, in many cases, must also contact other regions of DNA that are far away. In other words, these normally distant regions must come close to contact and activate the genes. These patterns of chromosomal packaging and contacts are the basis for the EpiSwitch test. For example, Dr. Pchejetski’s team uncovered chromosomal contact patterns uniquely associated with diseases like amyotrophic lateral sclerosis, rheumatoid arthritis, severe COVID-19, and several types of cancer. Incredibly, some patterns can even reveal which patients will respond to certain treatments. For example, EpiSwitch tests are commercially available for diagnosing prostate cancer (Prostate Screening EpiSwitch test) and for predicting which patients with cancer will respond to immune checkpoint inhibitors (EpiSwitch Checkpoint inhibitor Response Test).
Here, the researchers tested the EpiSwitch approach for diagnosing people with ME/CFS. Comparing samples from 47 people with severe ME/CFS with those from 61 healthy people, the team found 200 distinguishing chromosomal contact biomarkers. When applied to a carefully selected group of participants, the ensuing model was highly sensitive—given 100 people with ME/CFS, it would correctly categorize 92. It was highly specific—given 100 healthy people, it would correctly categorize 98. And it was highly accurate—of 100 people (either with ME/CFS or without), it would correctly categorize 96.
These results also give important clues about what goes wrong in ME/CFS and about ways to help people with the disease. For example, the chromosomal contact patterns suggest that people with ME/CFS have serious problems with cell signaling. These include problems signaling among immune cells (especially through IL-2); signaling to regulate inflammation (especially through TNF-α and NF-κB) or to regulate the innate immune response (through toll like receptors); and signaling to regulate gene expression in response to changed environments (through JAK/STAT). However, many of these signaling problems are shared by people with other autoimmune and inflammatory diseases, like allergic disease, Alzheimer’s, cancer, lupus, and multiple sclerosis. Thus, a critical next step will be to investigate whether the EpiSwitch test can distinguish people with ME/CFS from people with these other diseases.
Still, these results suggest people with ME/CFS may benefit from treatments that address key signaling pathways. For example, the researchers found ME/CFS-associated chromosomal contact patterns that dysregulate IL-2 expression. For patients with these patterns, immunomodulators like Copaxone, rituximab, and rapamycin may reduce IL-2 levels and reverse IL-2–associated cognitive decline, fatigue, and neuroinflammation.
This study appears in the Journal of Translational Medicine.