La Jolla Institute scientists get first glimpse of how mysterious particles break off of immune cells
By Madeline McCurry-Schmidt
December 4, 2020 -- LA JOLLA—Researchers
at La Jolla Institute for Immunology (LJI) have found that people with sepsis
have never-before-seen particles in their blood. The scientists are the first
to show that these particles, called elongated neutrophil-derived structures
(ENDS), break off of immune cells and change their shape as they course through
the body.
“We actually found a new particle in the
human body that had never been described before,” explains LJI Instructor Alex
Marki, M.D., who served as first author of the study. “That’s not something
that happens every day.”
The research, published December 4, 2020
in the Journal of Experimental Medicine shows the importance
of understanding how immune cells change over the course of a disease.
“ENDS are not normal—they are not
detectable in healthy people or mice,” says LJI Professor Klaus Ley, M.D., who
served as senior author of the study. “But ENDS are very high in sepsis, and I
would not be surprised if they were high in other inflammatory diseases.”
The beginning of the ENDS
The discovery of ENDS started with an
odd observation.
Marki was studying neutrophils, a kind of
immune cell that moves through the bloodstream and slips into tissues to fight
infections. At the time, he was studying living mice to confirm the presence of
tubes called tethers. These tethers are attached to neutrophils as they roll on
the blood vessel wall.
During these experiments Marki noticed
long, thin objects of neutrophil origin sticking to the vessel wall. Since no
such structure was described in the scientific literature, the team had to come
up with a name for them. The initial lab slang name “sausages” was eventually
replaced by the elongated neutrophil-derived structures or ENDS.
Desperate for learning more about these
new objects, the LJI team developed a series of new techniques to study how
ENDS form and degrade—and to detect them in human and mouse blood plasma.
Thanks to sophisticated imaging
techniques, the LJI team figured out that tethers become ENDS.
As the neutrophils flop and roll along, their tethers get longer and longer.
Eventually the tethers become too thin—just 150 nanometers (around 1/500th the
width of a human hair). Then they break in the middle. Part of the tether stays
with the neutrophil, but the broken fragment flies away in the bloodstream, off
to form an ENDS.
The researchers showed that these ENDS
curl against the vessel wall until they get a rounded shape. It’s likely that
the ENDS stay intact for a while, but not for long. Without any life-sustaining
organelles inside, the ENDS begin to die. In fact, the researchers found that
the ENDS secrete tell-tale signaling molecules that promote inflammation.
Compared with healthy subjects, the
researchers showed that ENDS are around 100-fold more detectable in septic
patients.
What this means for sepsis
Sepsis can occur when the immune system
overreacts to an infection by flooding the body with dangerous chemicals.
Instead of just fighting the infection, these chemicals trigger organ damage as
they course through the bloodstream. The mortality rate for septic “shock” is
30 percent.
“Once you’re in the hospital, sepsis is
the most common cause of death,” Ley says.
Ley and Marki are still not sure why
ENDS form in patients with sepsis. To learn more, Marki hopes to collect more
patient samples to track ENDS formation and frequency over time. “I’d like to
study blood from several time points from each patient—to see the dynamics of
how ENDS change,” he says.
Ley says it is theoretically possible
that ENDS could one day serve as a biomarker for early sepsis detection, but it
is currently impossible to detect them in a clinical setting. “Right now, the
assay is not practical because it takes specialized instrumentation,” says Ley.
Rather than serving as a diagnostic, Ley
thinks studying ENDS could reveal secrets to how the immune system evolved.
He’s curious to learn how the process to form ENDS evolved—and why.
“Neutrophils are very soft cells that
can deform to reach almost any place in the body,” says Ley. “So one hypothesis
I have is that ENDS might be the price you pay for having such a soft cell—that
if you pull too hard, it falls apart.”
This study, titled “Elongated
neutrophil-derived structures are blood-borne microparticles formed by rolling
neutrophils during sepsis,” was supported by The National Institutes of Health
(grants P01 HL078784, P01 HL151433, R01HL145454, S10OD021831), the American
Heart Association (17POST33410940, 18POST34060251, 16POST31160014,
18CDA34110426) and a DFG award (GZ WI 4811/1-1).
Marki is a recipient of the Tullie and
Rickey Families SPARK Award at La Jolla Institute for Immunology.
No comments:
Post a Comment