Red Blood Cells Play Significant Role in Immune System, Bind Cell-Free DNA


Red blood cells function as immune sensors by binding cell-free DNA called nucleic acid, which is present in the body's circulation during sepsis and COVID-19, according to a study published by Science Translational Medicine. The study found that this DNA-binding capability triggers removal of the cells from circulation, driving inflammation and anemia during severe illness, meaning that red blood cells play a larger role in the immune system than previously thought.

“Anemia is common, affecting about a quarter of the world's population. Acute inflammatory anemia is often seen early after an infection such as parasitic infections that cause malaria,” said Nilam Mangalmurti, MD, assistant professor of Medicine at the University of Pennsylvania, in a press release. "For a long time, we haven't known why people—when they are critically ill from sepsis, trauma, COVID-19, a bacterial infection, or parasite infection—develop an acute anemia. These findings explain one of the mechanisms for the development of acute inflammatory anemia for the first time.”

Toll-like receptors (TLRs) are a class of proteins that play a key role in the immune system, activating immune responses, such as cytokine production. According to the study, during sepsis and COVID-19, red blood cells express an increased amount of the TLR protein TLR9 on their surface. When these cells bind too much to inflammation-causing nucleic acid, they lose their normal structure, causing the body to cease recognizing them. Macrophages then remove these blood cells from circulation, causing the immune system to become activated in otherwise unaffected organs, resulting in inflammation, according to the study.

“Right now, when patients in the ICU become anemic, which is almost all of our critically ill patients, the standard is to give them blood transfusions, which has long been known to be accompanied by a host of issues including acute lung injury and increased risk of death,” Mangalmurti said in the release. “Now that we know more about the mechanism of anemia, it allows us to look at new therapies for treating acute inflammatory anemia without transfusions, such as blocking TLR9 on the red blood cells. Targeting this TLR9 may also be a way to dampen some of the innate immune activation without blocking this receptor in immune cells, which are very important for the host when fighting a pathogen or injury.”

According to Mangalmurti, this discovery could have implications for using red blood cells as diagnostic tools. As an example, a physician may be able to take red blood cells from a patient with pneumonia, sequence the nucleic acid that has been soaked up from the infection, and identify the specific kind of pathogen to better determine what kind of antibiotic to prescribe.


Red blood cells play much larger role in immune system through discovery of DNA-binding capability, study finds [news release]. ScienceDaily; October 20, 2021. Accessed October 25, 2021.

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