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Mitochondrial DNA discovered to be emitted by cells as danger signal

Discussion in 'Other Health News and Research' started by Murph, Jan 29, 2018.

  1. Murph

    Murph :)

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    http://www.pnas.org/content/115/3/E478.long

    Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E478-E487. doi: 10.1073/pnas.1711950115. Epub 2018 Jan 2.
    Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C.
    Ingelsson B1, Söderberg D2, Strid T1, Söderberg A1, Bergh AC1, Loitto V1, Lotfi K2,3, Segelmark M2,4, Spyrou G1, Rosén A5.
    Author information
    Abstract

    Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C.

    The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production.

    In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

    KEYWORDS:
    CpG-C; DAMP; immune DNA sensing; lymphocyte signaling; mitochondrial DNA release

    PMID:
    29295921
    PMCID:
    PMC5776968
    [Available on 2018-07-16]
    DOI:
    10.1073/pnas.1711950115
     
  2. Murph

    Murph :)

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    Okay so the abstract is a bit hard to read. But this has made a splash on twitter with Sten Helmfird saying researchers are looking for me/cfs applications, and Janet Dafoe weighing in to let him know that she has forwarded the paper to her husband.



    I've asked Sten if the molecular weight of mtDNA is hig enough that it could be the mystery large molecule in serum. (my initial reading is yes, mtdna seems fairly large as molecules go, but I will see what he says.)
     
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  3. Learner1

    Learner1 Forum Support Assistant

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    @Murph This seems really interesting. Does anyone have a layperson's description of this? Might it contribute to hypercoagulation? Could it be measured through lab work like fibrinogen, d-dimer, sed rate, etc.?

    Why would this happen? What would be the function of the filament danger signals? Why filaments and not a liquid biochemical?
     
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  4. Jesse2233

    Jesse2233 Senior Member

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    also what's the relationship between extracellular mtDNA, eATP and purinergic signalling?
     
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  5. melihtas

    melihtas Senior Member

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    Can the limited improvement from Rituximab and then relapsing again be explained with this mechanism? Depleted B cells mean less extracellular mtDNA. When B cells come back, symptoms come back too.

    We already know Cyclophosphamide is more effective than RTX because it depletes both B cells and T cells. Even less mtDNA. Now, the question is whether ME patients taking Cyclo also relapse. We'll find out soon when CycloME trial paper is published.
     
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  6. Murph

    Murph :)

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    I am getting impatient for the CycloME paper!! Hopefully soon. Perhaps the peer reviewers have been extra vigilant since the Ritux result became known?
     
  7. Richard7

    Richard7 Senior Member

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    https://liu.se/en/news-item/nytt-varningssystem-upptackt-i-kroppens-immunforsvar
     
  8. junkcrap50

    junkcrap50 Senior Member

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    Unfortunately, this type of molecule seems like it would be quite difficult to filter out or precipitate out of the blood. Anyone have any hypothetical ideas on removing it from serum?

    Interesting that the mtDNA can be dissolved. Wonder how it is dissolved and by what.

    Does anyone know if Interferon Type 1 was high in any of the metabolomic or big data studies on me/cfs?
     
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  9. junkcrap50

    junkcrap50 Senior Member

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    Perhaps someone here might like to summarize some ME/CFS research, highlighting Ron Davis's findings and his Nordic colleagues Fluge and Mella, and include them in an email to Dr. Ingelsson to inform him about ME/CFS and how he should consider applying his research to it.
     
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  10. Lindberg

    Lindberg

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