Penn Medicine Study Finds Red Blood Cells Play Much Larger Role in Immune System Through Discovery of DNA-Binding Capability

PHILADELPHIA—New research has revealed that red blood cells function as critical immune sensors by binding cell-free DNA, called nucleic acid, present in the body’s circulation during sepsis and COVID-19, and that this DNA-binding capability triggers their removal from circulation, driving inflammation and anemia during severe illness and playing a much larger role in the immune system than previously thought. Scientists have long known that red blood cells, which are essential in delivering oxygen throughout the body, also interacted with the immune system, but didn’t know whether they directly altered inflammation, until now. The study, led by researchers at the Perelman School of Medicine at the University of Pennsylvania, was published today in Science Translational Medicine.

“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 senior author Nilam Mangalmurti, MD, an assistant professor of Medicine at Penn. “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 by activating immune responses like cytokine production. This study examined the red blood cells of about 50 sepsis patients and 100 COVID-19 patients and found that, during these illnesses, red blood cells express an increased amount of the specific TLR protein called TLR9 on their surface.

Results showed that when the red blood cells bind too much inflammation-causing nucleic acid, they lose their normal structure, causing the body to not recognize them anymore. This leads immune cells, called macrophages, to ‘eat’ them, taking them out of circulation in the body. When this happens it causes the immune system to become activated in otherwise unaffected organs, creating inflammation. This mechanistic discovery opens the door to research on how to block this specific receptor and create targeted therapies for autoimmune diseases, infectious diseases, and a whole host of inflammatory illnesses associated with acute anemia.

“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. “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.”

Mangalmurti says that this DNA-binding discovery could also have implications for research into using red blood cells in diagnostics. For example, whether a physician could 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.

Mangalmurti and fellow researchers are studying whether this is a valid option in diagnosing infection in critically ill patients and if this DNA-binding mechanism by red blood cells is a universal mechanism of anemia in parasitic infections.

The research was funded by the National Institutes of Health (R01 HL126788, R01 AI 091595, UM1 AI126620) and the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program.

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