The Role of Adaptive and Innate Immune Cells in Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis
30 Fukuda diagnosed CFS patients and 25 controls were studied. Their disease duration was kind of short at over 2 years, which might imply (based on Lipkin's unpublished findings) that they were a CFS subgroup, the under 3 year group.
Numbers of classes of immune cells were normal, but numbers of subtypes were not normal for dendritic cells and B cells. pDCs were decreased (I think they mean plasmacytoid dendritic cells), and immature B cells were decreased, with memory B cells increased.
This finding of low immature B cells is interesting, and contradicts earlier findings of more immature B cells. I wonder if this is related to the putative 3 year transition stage between short term and long term patients?
An increase in memory cells might mean the body is fighting something. This implies pathogens or toxins, autoimmune or autoinflammatory processes.
This profile of B cells is consistent with an autoimmune disease.
Plasmacytoid cells release interferons (mainly alpha and beta interferon), so a decrease might mean reduced resistance to viruses. HIV infection decreases their numbers, so its possible a range of B cell infections can do this.
Regulatory T cell numbers were high including one subtype. This might mean the body is trying to suppress the immune response especially in autoimmune disease. Their capacity for producing adenosine is also higher.
Adenosine can cause vasodilation (and therefore might be implicated in orthostatic intolerance), bronchospasm (one of my symptoms), with possible effects on phosphodiesterases. This last is interesting, because it might make proper sleep very very difficult, something I have blogged on. However it might also make people sleepy and possibly help initiate sleep. So if its high it might be that you can kind of get to sleep but not sleep very well. More importantly for us the more adenosine you have the more tired you will be. Caffeine can counteract adenosine function, but I think resveratrol might too (by implication, not proven science). These two agents might even improve blood flow, again by implication not proven science. However the adenosine might have antiinflammatory effects, so blocking it might increase inflammation.
Natural killer cell function was down when tested. This is in line with many other studies. However numbers of interferon gamma NK cells were increased. Interferon gamma targets viral and intracellular pathogens, and cancer cells. I wonder if this explains why with lower NK function we do not appear to have higher incidence of cancer except for lymphomas, which are either B or T cell cancers?
At a chemical level they found increased interferon gamma with the NK cells, supporting the finding that interferon gamma producing NK cells were increased.
Granzyme B was significantly decreased. This enzyme cuts proteins and is used to target virally infected cells and induce cell death. A decrease in this might mean we cannot clear viral infections properly.
Various factors were found to positively and negatively correlate with each other. This is complex to explain (and would require more research from me than I have time for) so I will just comment on the negative correlation between Tregs and NK cell cytotoxic function. This might imply, together with other research, that our high Tregs might be suppressing our NK cells. Which begs the question, why are our Tregs high? Is this autoimmune or autoinflammatory?
There is also something wrong with the binding of antigens to neutrophils. I don't know enough about this to be sure, but its likely that it means neutropils cannot properly bind to cells that should be targeted by the immune system. Since neutrophils can be up to 80% of our white blood cells this is concerning. Neutrophils are involved in chronic inflammatory conditions, but I am unsure just what this finding implies.
Neutophil function is discussed here:
http://medicine.cf.ac.uk/molecular-...ing/neutrophil-resources/neutrophil-function/
http://medicine.cf.ac.uk/molecular-...ing/neutrophil-resources/neutrophil-function/
Be warned the article in the link is a little technical. What I think the low antigen binding in CFS might mean is that yet again our immune system cannot kill problem cells effectively.
Having most of our innate immune system less functional, and our adaptive immune system possibly dysfunctional in various ways, might imply we have major problems in our immune system. What a surprise!
The paper sums it up this way:
The results from the present study suggest that the mechanism for CFS/ME may involve decreases in NK cell activity, NK lytic proteins, pDCs, IFN-gamma, HNA2 antigens and memory B cells, concurrent with increases in immature B cells, NK cell degranulation, TNF-alpha and NK cell specific IFN-gamma.
They are not specific about results, but alterations in platelets and sedimentation rates are implied to be increases in patients. So we might have an increased tendency to blood clotting and failure in microcirculation, which fits with much earlier findings in CFS of problems with blood flow and increased clotting that were treated with heparin.
I find it fascinating how this study might explain so many of our problems, from chronic infection and chronic inflammation, to excessive tiredness and disrupted sleep. As usual this just begs more research, but how is this done with limited funding?
The paper ends with this:
In summary, the findings from this present study confirm a substantial breakdown in immune tolerance and inflammatory mechanisms in patients with CFS/ME. This likely involves significant impairments in the NK cell function, over-reactive Tregs, impaired DCs, neutrophils, dysregulation in cytokine levels and abnormal production of adenosine. Collectively these defects are overwhelming and further confirmatory studies may be required owing to the multifactorial and heterogeneous nature of the disorder. Importantly, it may necessary to confirm the levels of circulating IFN-Is in CFS/ME patients and the exact profile of memory B cells and immature B cells that are disproportional in CFS/ME.
