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Circulating Mitochondrial DNA Alerts Immune System to Danger

In response to short DNA fragments, lymphocytes release mitochondrial DNA that helps trigger an immune response.

Mar 1, 2018
Katarina Zimmer

SPIDEY SENSE: Lymphocytes ejected weblike, fluorescing strands of mitochondrial DNA (green) when exposed to certain oligonucleotides. PNAS

EDITOR'S CHOICE IN IMMUNOLOGY

THE PAPER
B. Ingelsson et al., “Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C,” PNAS, 115:E478-87, 2018.

MOLECULAR BATTLEGROUND
Beyond acting as a genetic blueprint, DNA can play a direct role in the immune system. For instance, neutrophils cast webs of DNA and antibacterial proteins into the bloodstream to trap pathogens. When a team of Swedish researchers observed that B lymphocytes also appear to eject DNA, they decided to investigate further.

IMMUNE ARTILLERY
The researchers isolated several types of lymphocytes—B cells, T cells, and natural killer cells—from healthy blood donors and leukemia patients. They exposed them to a variety of triggering molecules, such as ionomycin from Streptomyces conglobatus, together with a fluorescent DNA-binding substance in vitro. Only when exposed to a specific type of oligonucleotide that resembled pathogenic microbial DNA did the cells rapidly eject weblike, fluorescing strands of mitochondrial DNA (mtDNA). The lymphocytes remained intact and healthy.

DANGER SIGNAL
To see whether the lymphocyte mtDNA elicited an immune response, the researchers tested it on another type of white blood cell, peripheral blood mononuclear cells (PBMCs). An immunosorbent assay revealed that mtDNA induced the PBMCs to release interferon type 1, which can trigger an immune response. “It’s like a new warning system,” says Anders Rosén, a cell biologist at Linköping University and senior author of the paper.

UNTANGLING THE WEB
Dana Crawford, an immunologist at Albany Medical College who was not involved in the study, is surprised and puzzled by the finding. “It almost seems to be redundant that these cells are being exposed to a type of DNA, and . . . in response they’re releasing DNA that triggers a response,” he notes. The advantage of having a system set up in this way is yet to be understood.

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