T-cells and metabolomics

[anciendaze]

Researchers at Japan's RIKEN have found that activation of some kinds of T-cells changes their metabolism. This also causes shifts in availability of certain amino acids outside those cells, as they take up more. This is direct evidence, at least in mice, of a link between some forms of persistent immune activation and metabolomic changes. Does this match the kinds of metabolomic changes seen by Dr. Naviaux in human ME/CFS patients? Stay tuned.

 

[A.B.]

Does this match the kinds of metabolomic changes seen by Dr. Naviaux in human ME/CFS patients? Stay tuned.

My first reaction: probably not, because T cells are too few in comparison to the other cells in the body to have a large impact on metabolomics.

However they seem to be reporting exactly that.

Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system

 

[Marky90]

When we dug deep into my t-cells there were genetic activations not seen in many, but cause/relevance unknown ofc..

 

[alex3619]

My first reaction: probably not, because T cells are too few in comparison to the other cells in the body to have a large impact on metabolomics.

However they seem to be reporting exactly that.

Its not about numbers in themselves, its about the signalling, and how far those signals travel.

 

[halcyon]

Full paper looks interesting, not sure I can get through it presently.
Abstract:

T cells reorganize their metabolic profiles after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. Here we report that augmented T cell responses in Pdcd1−/− mice, which lack the inhibitory receptor PD-1, induced a metabolic serum signature characterized by depletion of amino acids. We found that the depletion of amino acids in serum was due to the accumulation of amino acids in activated Pdcd1−/− T cells in the lymph nodes. A systemic decrease in tryptophan and tyrosine led to substantial deficiency in the neurotransmitters serotonin and dopamine in the brain, which resulted in behavioral changes dominated by anxiety-like behavior and exacerbated fear responses. Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system.

I've been thinking lately that what we will find in ME is that severity is related to ability to counter-regulate T cell activation. Those who are more severe perhaps have less PD-1 activity, and thus more inflammatory immune activation, more autoimmunity (which is a consequence of this as can be seen by human and animal experiments with blocking PD-1), etc.

 

[halcyon]

Here we investigated whether the metabolic readjustments within activated T cells following activation of the immune system affected systemic metabolism. Using Pdcd1−/− mice as a model of systemic activation of T cells, we found that concentrations of free amino acids in the serum of Pdcd1−/− mice decreased as a consequence of the accumulation of amino acids in activated T cells in the lymph nodes (LNs). This systemic drop in amino-acid availability downstream of strong activation of the immune system affected biochemical pathways that depend on free amino acids as precursor metabolites. Specifically, reduced availability of tryptophan and tyrosine in the brain of Pdcd1−/− mice affected the synthesis of monoamine neurotransmitters, which resulted in increased anxiety-like behavior and fear responses. Thus, sustained activation of T cells can affect emotional behavior through systemic metabolic alteration.

Seems like what Chris Armstrong et al. have been finding, diversion of amino acids away from normal metabolism and lower levels thus found in serum.

 

[anciendaze]

My first reaction: probably not, because T cells are too few in comparison to the other cells in the body to have a large impact on metabolomics.

However they seem to be reporting exactly that.

You have to realize that a great deal of signalling involves cascades of signalling cells and molecules. I'm guessing that cytotoxic T-cells are near the beginning, because killing target cells has powerful and long-lasting effects, an extreme kind of amplification. I'm also thinking that the changes in use of amino acids within cells will have significant effects on the cascade of signals involved in purinergic signalling.

We tend to think of molecules like ATP as simply fuel produced by mitochondria, and consumed by other organelles. In fact these molecules also have very powerful actions in signalling activity of nearby cells, triggering changes that would not take place simply because there was a metabolic disturbance elsewhere in the body. We are seeing evidence here that specific subpopulations of immune cells are undergoing big changes in activity. These should result in substantial changes in the signals going to other cells near them.

Take a look at the paper I linked in another post, about the gut microbiome and autoimmunity. In that case we see cytotoxic T-cells destroying dendritic cells in the gut to suppress inflammatory response in the gut. This is not all that unusual for immune cells. Different populations of immune cells fight it out to achieve a specific response while limiting damage from autoimmunity. When this fails you get damage like type 1 diabetes or unsuppressed inflammation in the gut, two things you would not normally consider related.

Dendritic cells are near the root of this signalling cascade, even though their textbook description as merely "antigen-presenting cells" makes them sound like minor passive components of immune response.

We now know they are much more active, e.g. picking up information on pathogens from maternal cells when an infant's naive immune system needs a quick-start guide to a new environment. Once they have acquired antigens in the gut, they relocate to lymph nodes, where they pass the information to both B-cells and T-cells. I'm still a little vague on how they behave in the pancreas and other organs, but I'm assuming this is also a very active operation.

We have also learned that they keep antigens in a separate compartment, allowing actual HIV virions in maternal milk or immune cells to infect other immune cells even though the dendritic cell, which carried the virion, itself remains uninfected.

Signals near the beginning of a cascade are necessarily weak and hard to find, because they have not yet been amplified by other cells in the immune system. A great deal of our understanding will change as research continues, but we are finally close to the root of many pathological processes.

 

[FMMM1]

Researchers at Japan's RIKEN have found that activation of some kinds of T-cells changes their metabolism. This also causes shifts in availability of certain amino acids outside those cells, as they take up more. This is direct evidence, at least in mice, of a link between some forms of persistent immune activation and metabolomic changes. Does this match the kinds of metabolomic changes seen by Dr. Naviaux in human ME/CFS patients? Stay tuned.

Based on about 2 minutes of looking at the review of the paper this looks interesting. As you say it seems to link to previous published research [Chris Armstrong - University of Melbourne & Naviaux & (from memory) a metabolmics study by Japanese researchers]. It would be interesting to see what Armstrong and others think of this. Possibly it's a potential mechanism explaining the low amino acids they observed in plasma (from memory).

The review of the paper also mentions that the researchers found that the symptoms could be remedied using a diet rich in essential amino acids. If this finding was replicated in people with ME/CFS then it would appear to be very significant. I think the question of supplementing with amino acids turned up on Chris Armstrong's webinar last christmas (2016).

How does this/does this link to Fluge and Mella's findings re "impaired pyruvate dehydrogenase function"?

Is this linked to Fluge and Mella's, and Ron Davis's, finding that something in the blood causes a change in cell metabolism in ME/CFS.

 

[anciendaze]

We still don't have the full biochemical connection we need to explain the disease, but that is not surprising considering the complexity of the biochemistry involved.

Pyruvate dehydrogenase provides a lead-in to the Krebs cycle. Note that this is only active on the aerobic path of glycolysis. Damage to this pathway forces energy production onto the anaerobic pathway of glycolysis, leaving excess lactates. This conforms to patient experience and laboratory measurements of impaired aerobic energy production. There is still a lot of detail to fill in, as you see in figures of the Krebs cycle itself, which is only part of one branch of energy production using glycolysis. Also notice the difference in effectiveness of the two pathways in producing ATP.

Beyond the chemistry we need to understand this at the level of organs, because complete impairment over the entire body would likely be fatal. All survivors must have something less, and patient reports make it clear the problem varies over time. These are factors that make medical research more difficult, but no longer impossible.

 

[nandixon]

How does this/does this link to Fluge and Mella's findings re "impaired pyruvate dehydrogenase function"?

I just posted something about this on the Fluge & Mella thread

 

[Murph]

The review of the paper also mentions that the researchers found that the symptoms could be remedied using a diet rich in essential amino acids. If this finding was replicated in people with ME/CFS then it would appear to be very significant. I think the question of supplementing with amino acids turned up on Chris Armstrong's webinar last christmas (2016)..

My doctor, Don Lewis, is a collaborator with Armstrong and Mcgregor. Last December he prescribed to me hydrolysed whey protein isolate, which is a highly refined source of amino acids. It has substantially reduced the frequency and severity of my PEM. I do a lot more now, including playing a game of futsal each week. I take a lot of it - about 120g/day.

I still have me/cfs and I still get PEM if I go outside my envelope. And whey alone is not enough. I take a mix of supplements and medication. But it has been a real help in expanding my envelope. @gregh286 has also seen benefits from amino acids, as have a few people I've discussed it with on Reddit.

 

[Murph]

The more I look at this the more exciting it is. A screw-up in t cells can change your whole metabolism? That sure sounds relevant. The details below aren't exactly what Naviaux found, but the general direction of it (lower levels of some amino acids in serum) is the same.

"
We performed metabolomic profiling of serum from Pdcd1−/− mice, focusing particularly on small, water-soluble molecules that can bridge diverse tissues via the circulation. Partial least-squares discri- minant analysis (PLS-DA) of metabolites indicated that Pdcd1−/− mice had a systemic metabolome profile different from that of wild-type mice (Fig. 1a), with the most significantly decreased abundance in compounds involved in energy production, such as components of the tricarboxylic acid (TCA) cycle and amino-acid metabolism (Fig. 1b and Supplementary Table 1).

Most proteinogenic amino acids, including the essential amino acids (methionine (Met), threonine (Thr), histidine (His), lysine (Lys), tryptophan (Trp), phenylalanine (Phe), leucine (Leu), isoleucine (Ile) and valine (Val)) were 10–30% less abundant in Pdcd1−/− mice than in wild-type non-littermate mice (Fig. 1c) or wild-type littermates (Fig. 1d).

The reduction in abundance of the aromatic amino acids Trp, tyrosine (Tyr) and Phe in Pdcd1−/− mice relative to that in wild-type mice was already sig- nificant by 2 months of age (Fig. 1e), and it further decreased by 4–6 months of age and persisted throughout a 1-year monitoring period, unlike results obtained for branched-chain amino acids (Leu, Ile and Val), which were similar in abundance in Pdcd1−/− mice to their base- line amounts in wild-type mice at 2 months of age (Fig. 1e).

 

[FMMM1]

Thanks for all of the above.

A brief thought. Jonathan Edwards (if I recall correctly) recently said that he thought that ME/CFS was not primarily a metabolic condition, rather it was a neuro immune condition. Is this a link between the two i.e. a primary neuro immune condition with a consequent shift in metabolism (assuming that this paper is proposing --- metabolic shift etc).

Jonathan any thoughts re this paper?

Also where is the primary neuro immune trigger/how do we find this? Do we rely on Mark Davis's approach to finding this (see community symposium YouTube)?

 

[Murph]

I sent a link to the study to Derya Unutmaz on Twitter. (he's one of the three NIH funded researchers.) He replied with the following:

"Yes very interesting study. We are working along similar ideas for human T cells - metabolism is key in reprogramming immune function."