Long term patients show evidence of downregulated immune system
What was the study?
Researchers used 100 blood samples from the Solve ME/CFS Biobank of patients who were long-term patients of expert clinicians and met the Fukuda and/or Canadian Consensus case definitions. These blood samples were compared in a blinded method with 79 healthy control samples from people who were matched on criteria such as age, sex, location, race and BMI. They measured 34 plasma cytokines, chemokines and growth factors. The analysis included comparisons of the midpoints of the ME/CFS group and controls, cluster analysis, as well as techniques aiming to create a model able to predict ME patients.
What were the results?
There were 3 clusters found. The cluster of Interleukin-16 (IL-16), IL-7 and VEGF-A was both significantly downregulated and tightly correlated with each other. This seems to be the most interesting finding.
Out of the 34 measures only 5 had decreased levels in ME/CFS patients compared to healthy controls, to the extent that this is unlikely to be down to chance. These were IL-16, IL-7, VEGF-A, CXCL9, CX3CL1. The analyte CCL24 was significantly increased.
The pattern in ME/CFS was unique compared to patients who had various liver related fatigue disorders and healthy controls.
Attempts to create a predictive model from the results had low sensitivity though (41-46%), which may be to do with underlying diversity in ME/CFS.
What does all this mean?
Cytokines: there are lots of different cytokines and they are complex to understand. The quickest explanation is that they are messenger molecules passing information around the body. They are a bit like hormones in this way, but they are usually communicating in response to something external and lead to inflammatory or immune responses. When reading cytokine studies it is important to remember that with so many cytokines it is common to find some pattern, and results can change quickly within individuals. In a smaller sample than this, if just a couple of people were fighting a cold then this could change the overall results.
IL-16: this is a pro-inflammatory cytokine and the reduction shown may indicate immunodeficiency. In mice studies low IL-16 is correlated with impaired development of B cells. Most studies into human disease seem to show increases in IL-16 not a decrease (asthma, rheumatoid arthritis, Lupus, MS). The other condition which shows a decrease is HIV and IL-16 may repress HIV-1 replication (Indinavir used in HIV patients increases circulating IL-16). IL-16 has a developmental role in the human immune system. It is also related to neuronal development and may account for brainfog symptoms.
IL-7: this interleukin is indispensable for the creation and survival of immune cells (T cells, B cells, NK cells). Lowered IL-7 can compromise the immune response. It is associated with cognitive decline in aging and may mimic the process of aging if reduced early.
VEGF-A: stimulates new blood vessel and muscle growth. It may have some relationship with post-exertional malaise as it is increased after exercise. It is also a neuroprotector in the Periphery and Central Nervous Systems.
Were there any problems?
All studies have limitations. This seems to be the first study to describe algorithms with defined sensitivities and specificities in predicting ME/CFS patients, so although the sensitivity was quite low this could be something useful to follow up.
This study compared ME/CFS results to those of healthy controls and patients with various chronic liver diseases and declared the ME/CFS pattern to be unique. Liver disease seems quite specific though, compared to the many conditions which have overlapping symptoms with ME/CFS, and further comparison is necessary with different diseases.
The paper mentions relevance for diagnosis. However, this study used long-term patients and the Hornig et al (2015) study showed that early on patients have an upregulated immune system which is different from the downregulated pattern shown long term in this study and that one. For a diagnostic test to be useful hopefully it would be used before someone had been ill for 3 years.
Is it important?
It may be important in to discover a relevance of IL-16 in ME/CFS. It is the first study to measure this and it could be a component of a ME/CFS biomarker.
This study relates to the Hornig et al (2015) study which found different immune signatures in short term and long term patients. The general trend of downregulated immune response in long-term ME/CFS is repeated but the specifics aren’t all the same. A couple of the measures in this study were not in that one, and there are a number of measures in both with different results.
Reductions in circulating IL-7 and VEGF-A have been found in previous studies, so this is adding weight to their relevance to ME/CFS.