Mitochondrial DNA discovered to be emitted by cells as danger signal

[Murph]

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

 

[Murph]

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.

https://twitter.com/i/web/status/957706507973550081

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.)

 

[Learner1]

@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?

 

[Jesse2233]

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

 

[melihtas]

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.

 

[Murph]

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.

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

 

[Richard7]

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

Researchers at LiU have discovered a previously unknown warning system that contributes to the body’s immune system. Mitochondria in the white blood cells secrete a web of DNA fibres that raises the alarm. The results have been published in the scientific journal PNAS, and may lead to increased knowledge about autoinflammatory diseases and cancer.

Visualization of extracellular DNA in cell culture medium after treatment of CLL B cells with CpG-C. Photo credit: Reproduced with permission from Proceedings of the National Academy of Sciences USA

White blood cells are major components of the body’s immune defence, and the research group has shown that several types of these cells react against small DNA fragments that are similar to the DNA from bacteria and viruses. The white blood cells spray out a web consisting of mitochondrial DNA (mtDNA) strands. Mitochondria are present in all cells and normally produce the energy needed by the cell, by burning sugar and fat to form water and carbon dioxide.

The web that the mitochondria release sends signals to the surrounding cells that the body is under attack, and cause other white blood cells to release a signal substance known as “interferon type 1”. This substance helps the immune system to combat the infection.

Active process
Previous studies have shown that the level of mtDNA in the blood can be elevated after certain inflammatory diseases and after some surgical traumas.

Björn Ingelsson.
Photo credit: Oskar Lürén/AR2 Reklambyrå“We show that the white blood cells in the immune system can release mtDNA outside the cells in an active process in response to infectious agents such as bacteria and viruses. The discovery raises the possibility of further studies in which we will try to reduce the release of mtDNA, and in this way reduce the inflammation that it causes,” explains Björn Ingelsson, researcher and associate lecturer at the Department of Clinical and Experimental Medicine at Linköping University. He has conducted the research together with Professor Emeritus Anders Rosén and other co-workers.

Quick response
Other types of web formed by white blood cells in the immune system (known as “neutrophils”) have been previously known. These cells release meshes coated with antibacterial proteins. However, the formation of the newly discovered mtDNA webs differs fundamentally from that of the other types of web. The LiU researchers have shown that the mtDNA webs are activated within a couple of minutes, which is faster than the neutrophil-based meshes. The latter also lack the signal function that the mtDNA webs have. Further, the mtDNA webs survive in the blood longer before being dissolved.

But surely this is a positive process in which the immune defence works to remove the intruding bacteria or viruses?

“Well, of course it’s positive that the defence mechanisms are activated. But remember that you can have too much of a good thing. If an unintentional secretion of mtDNA occurs, or if the secreted mtDNA is not removed from the blood, undesired inflammation may occur, and it is this side-effect we want to prevent,” says Björn Ingelsson.

Interpret the warning signals
High levels of interferon type 1, the signal substance activated by the mtDNA webs, occur in several autoimmune diseases and several types of cancer. The researchers believe that it may be possible to quantify the secreted mtDNA molecules and interpret the warning signals, and in this way understand these diseases better.

The research has been financed with support from Linköping Medical Society, Linköping University, Region Östergötland, the Ingrid Asp Foundation and the Swedish Cancer Society.

 

[junkcrap50]

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.)

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?

Further, the mtDNA webs survive in the blood longer before being dissolved.

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

High levels of interferon type 1, the signal substance activated by the mtDNA webs, occur in several autoimmune diseases and several types of cancer. The researchers believe that it may be possible to quantify the secreted mtDNA molecules and interpret the warning signals, and in this way understand these diseases better.

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

 

[junkcrap50]

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.

 

[Lindberg]

http://www.sciencemag.org/news/2018/01/white-blood-cells-launch-dna-webs-warn-invaders