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Continues T cells activation and metabolic changes

Discussion in 'Other Health News and Research' started by Zara, Dec 13, 2017.

  1. Zara

    Zara

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    It is currently known that individual T cells change their metabolism to meet their energy needs after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. To understand the systemic effects, the group looked at T cell activation in mice designed to lack a surface receptor called PD-1, which is necessary for inhibiting the activity of T cells. T cells remain activated in mice without the receptor, similar to those in the immune systems of people with certain types of autoimmune disease. In these mice, they found that amino acids—molecules that are used to build proteins—were depleted in the blood, and that they were increased in the T cells themselves, implicating the T cells in the change.

    The team tracked and imaged amino acids in many organs, and found that the depletion of amino acids from the blood was taking place due to the accumulation of amino acids in activated T cells in the lymph nodes, showing that strong or long lasting immune responses can cause metabolic changes elsewhere in the body.

    The remaining question was whether this depletion of amino acids was actually having any systemic effect. By analyzing the biochemistry of the brain, they found that the systemic decrease in the amino acids tryptophan and tyrosine in blood led to lower amounts available in the brain, limiting production of the neurotransmitters serotonin and dopamine. These neurotransmitters affect emotions, motivation and fear—for example, serotonin is often a target of drugs that combat depression. The researchers found that their depletion in mice without PD-1 resulted in behavioral changes dominated by anxiety and exacerbated fear responses, which could be remedied by providing a diet rich in an essential amino acid.

    This research, which was published in Nature Immunology, required teamwork and collaboration to link diverse fields of biology: immunology, neuroscience and behavior, using cutting edge metabolite measurements and imaging methods. "Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system" says Michio Miyajima, one of the four first co-authors of this study.

    According to Sidonia Fagarasan, the leader of the group, "We were fascinated to see that this happens-as it revealed the power of the immune system to influence many aspects of the body's physiology besides infection and immunity. It will be interesting in the future to investigate whether the trigger of fear and anxiety by T cell activation is merely a side effect of the process, or whether there is an evolutionary benefit of this adaptation. We would also like to further investigate these changes, as the blockade of PD-1 is being investigated as an anti-cancer therapy, and it is important to understand if this could have behavioral changes such as increases in anxiety."

    https://m.medicalxpress.com/news/2017-10-immune-cells-behavioral.html
     
    Ema, pattismith, ukxmrv and 1 other person like this.
  2. Zara

    Zara

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    This article indicates maybe what is going on in me/cfs?
    T cell keep being activated which leads to metabolomic changes elsewhere in the body and effects brain...
    I find it very interesting
     
    pattismith and ljimbo423 like this.
  3. pattismith

    pattismith Senior Member

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    amino acid supplementation seems to help ME, so your question is legitimate, thank you for this article :thumbsup:
     
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  4. ljimbo423

    ljimbo423 Senior Member

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    I think this is the very same thing that is happening in CFS. Immune cell activation is causing mito dysfunction as well as other dysfunctions but I think the mito dysfunction is a big cause of symptoms.

    The depletion of amino acids fits in with Chris Armstrong's metabolomic's study findings. That in CFS our cells use mainly amino's instead of glucose, causing our amino's to be low.

    Jim
     
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  5. Zara

    Zara

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    @Jim: yes I remember I read that somewhere..

    Is this what dr Mark Davis from
    Standford is looking at?

    I have read that he is focussing on T cells.
    Dont know if it is the same theory or thesis he is testing..maybe we have pd - deficiency that allows for continues t cell activation....??

    Here the correct citation of article.
    Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior
    Received:
    23 August 2017
    Accepted:
    03 October 2017
    Published online:
    23 October 2017
     
    ljimbo423 likes this.
  6. ljimbo423

    ljimbo423 Senior Member

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    Mark Davis is looking at elevated levels of CD8+ T cells specifically I think. He is trying to find out what type of antigen (from a pathogen etc.) is causing them to be elevated and any tissue that might be targeted.

    Here is a quote from Mark Davis from the cfs symposium he was part of a few months ago-

    "There's an antigen, almost certainly an antigen triggered event, that is causing them (CD8+ T cells) to divide. There could be multiple antigens but there certainly are some, more than normal."

    I don't know of any research that has found a PD-1 deficiency yet in cfs. I do think that immune system activation in cfs causes anxiety in many that can range from mild to horrific anxiety and panic attacks.

    I have noticed a big decrease in my anxiety in the last several months from treating dysbiosis and leaky gut and big improvements in my overall health as well!:)

    Jim
     
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  7. Zara

    Zara

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    Continue linking PD-1 receptor to me/cfs and ongoing activation of T cells

    PD-1 receptor ( programmed cell death)
    you can find this receptor on b cells, activated t cells, macrophages.
    Function: downregulates activated T cells ( negative regulation of immune response)

    Link with Mark Davis theory or prelimenary findings:
    Relationship pd-1 with cd8+ Tcells:
    Pd-1 inhibits activation expansion and acquisition of cd 8+ Tcells.

    My thoughts:
    Mark Davis exploring continues activation of cd 8+ t cells..maybe cause of continues activation is not caused by viruses but by defect pd-1.

    Wikipedia:
    Overexpression of PD1 on CD8+ T cells is one of the indicators of T-cell exhaustion (eg in chronic infection or cancer).[7][26] ( wikipedia)

    Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4+ and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV viral vector model of chronic infection, Rafi Ahmed’s group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.[23]

    Further thoughts:
    T cells develop and mature in thymus in our early years. Maybe when we get a virus like EBV in our early years something goes wrong with the activation of T cells and cd8+ cells e.g The pd-1 is not working correctly. Years later we get exposed to more virusses and bacteia and other patagons. This leads to the start of the disease , continous activation of T cells and in particular cd8..this leads to metabolomic changes and changes in brain.
     
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  8. Zara

    Zara

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    Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity

    https://www.jci.org/articles/view/92167


    "Oversupply of the glycolytic intermediate pyruvate in mitochondria from CAD macrophages promoted expression of PD-L1 via induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulatory factor 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway".
     

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