“We actually found a new particle in the human body that had never been described before,” explained Alex Marki, MD, an instructor at La Jolla Institute for Immunology (LJI). “That’s not something that happens every day.”
Researchers at LJI have found that people with sepsis have never-before-seen particles in their blood. Their study is 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.
Their findings were published in the Journal of Experimental Medicine in a paper titled “Elongated neutrophil-derived structures are blood-borne microparticles formed by rolling neutrophils during sepsis.”
“ENDS are not normal—they are not detectable in healthy people or mice,” said LJI professor Klaus Ley, MD, who led the study. “But ENDS are very high in sepsis, and I would not be surprised if they were high in other inflammatory diseases.”
At the time, Marki was studying neutrophils in living mice to confirm the presence of tubes called tethers, which are attached to neutrophils as they roll on the blood vessel wall. Marki observed long, thin objects of neutrophil origin sticking to the vessel wall. The researchers originally nicknamed the structures “sausages” until they decided on elongated neutrophil-derived structures or ENDS.
The researchers developed a series of new techniques to detect and study ENDS in human and mouse blood plasma. Using imaging techniques, the LJI team found that the tethers become ENDS. As the neutrophils flop and roll along, the tethers grow longer. The tethers become very thin at just 150 nm (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, and becomes an ENDS. In their study, the researchers demonstrate how ENDS curl against the vessel wall until they get a rounded shape. Without any life-sustaining organelles inside, the ENDS begin to die. However, 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. Sepsis is a potentially life-threatening condition caused by the body’s response to an infection. The body normally releases chemicals into the bloodstream to fight infection. Sepsis occurs when the body’s response to these chemicals is out of balance, triggering changes that can damage multiple organ systems.
“Once you’re in the hospital, sepsis is the most common cause of death,” Ley added.
It is still unclear as to why ENDS form in patients with sepsis. The researchers are hoping 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 said.
Ley believes that 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,” said Ley.
The researchers believe further study on ENDS could reveal insights into how the immune system evolved.
“Neutrophils are very soft cells that can deform to reach almost any place in the body,” said 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.”