Natural killer cells (blue) attacking an unwanted intruder (yellow)

Natural killer cells (blue) attacking an unwanted intruder (yellow)

The immune system of ME/CFS patients has been the target of medical research for many years, and the abnormalities identified have included low natural killer cells, and increases in various types of ‘cytokines’, such as interleukins and interferons, which regulate the immune system (see a review). Some of these immune abnormalities are also shared with cancer patients (read more). Most recently, researchers at Columbia University have discovered “distinct immune signatures” in the blood in ME/CFS patients, as well as immune changes in the central nervous system, supporting the idea that the illness may reflect an infectious ‘hit-and-run’ event.

There is still much more to learn, of course, and one of the most pressing questions is how immunological measurements, which may change over time, relate to the severity of illness. Scientists at Griffith University in Queensland, Australia have been examining these aspects for several years, and their latest report compares groups of innate and adaptive immune cells in both moderately affected (mobile) and severely affected (housebound) ME/CFS patients. They used a number of outcome measures to gauge the severity of illness, including the classic Bell Disability Scale, and flow cytometry to measure a range of cell types and immune parameters at baseline and after 6 months.

The scientists found some changes in immune cells and their receptors over time, particularly in some natural killer cell receptors which were raised in all three groups over the 6 month period. However, a key finding was that, compared with the other two groups, people with severe ME/CFS had significant changes in four main immune categories: invariant natural killer T (iNKT) cell phenotypes (see a model); markers on CD8+ T cells (white blood cells involved in the destruction of other cells); natural killer cell receptors; and gamma delta T cells (γδ T cells) types 1 and 2 which have a complex role in immunity (Table).

Findings in severely affected ME/CFS patients at the 6-month point
iNKT cell phenotypes Increased versus controls
CD8+ T cell markers Increased versus moderately ill patients
Natural killer cell receptors Decreased versus moderately ill patients and controls
γδ T2 cells Increased versus moderately ill patients and controls
γδ T1 cells Decreased versus moderately ill patients and controls

Natural killer cell receptors have a particular importance in ME/CFS because one of the most consistent abnormalities reported in patients over the past 20 years has been that natural killer cells are lower and/or have a lower activity than in healthy people (see review). In fact, some people have suggested ‘low natural killer cell disease’ as an alternative name for this illness. Natural killer cells have a key role in the targeted killing of tumour cells and virus infected cells, so a reduction in their number implies a reduced ability to destroy other unwanted cells. The reduction in natural killer cell ‘expression’ in ME/CFS patients in this study may be due to the reduced natural killer cell activity, whereas the enhancement in iNKT cell phenotypes maybe a regulatory response to compensate for it.

One likely explanation for most of the differences in immune cells or receptors in severe ME/CFS is immune activation in response to a physiological challenge, whether within the body or from the external environment (i.e. an infection). This could explain the raised naïve CD8+ T cell numbers, and other findings, such as γδ T cells alterations; as the authors point out, “γδ T cells are sentinel cells with cytotoxic properties… this may suggest an activation as an immune response to bacterial infection, wound repair, antigen presentation or immunoregulation”.

This research highlights the importance of taking severity of illness (disablement & mobility, but also length of time ill, quality of life, etc.) and its changes over time into account, particularly in biochemical investigations. In mildly or moderately affected patients, this can be simply done by using various outcome measures which assess disability. However, the 10–25% of patients who have severe ME/CFS and are home-bound need to be included too, as their trial results may be very different from more mobile patients and contain unexpected and important findings. The scientific literature on ME and CFS contains around 6,800 publications, but vanishingly few have included data on severely affected patients, who are “ignored and invisible” by science as well as by society. This needs to change, particularly as valuable information may well be lost by their exclusion.


Further reading
Longitudinal analysis of immune abnormalities in varying severities of chronic fatigue syndrome/myalgic encephalomyelitis patients. Hardcastle SL, et al. J Transl Med, 2015 Sep 14; 13: 299. Read more (full text).
Evidence for the presence of immune dysfunction in chronic fatigue syndrome. Natelson BH, et al. Clin Diagn Lab Immunol, 2002 Jul; 9(4): 747–752. (read more).
Severely affected ME/CFS patients – a geographically defined study. An ME Research UK-funded study in Newcastle (read more).
Severe ME – what do we know? An ME Research UK overview (read more)