CXCL4

A mechanism that led some patients to experience cases of deadly clotting following some types of Covid-19 vaccination has been identified in new research. A mechanism that led some patients to experience cases of deadly clotting following some types of Covid-19 vaccination has been identified in new research. In a paper published in Blood, scientists from the University of Birmingham funded by the National Institute for Health and Care Research and the British Heart Foundation have been able to identify how deadly blood clots, in the disease known as Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT), occur. Previous studies have shown that patients with VITT produce antibodies that stick to a protein called Platelet factor 4 (PF4) to create a large cluster of molecules called an immune complex. Following the development of a complex, platelets and cells of the immune system causing clotting and inflammation are activated, but the precise nature of what PF4 does in this event was unknown. In this latest study, the team used blood taken from healthy donors, as well as serum and plasma from patients with VITT, and have been able to learn for the first time how PF4 was directly involved in the activation of platelets and resulted in thrombotic events. By sticking to a receptor called c-Mpl on the surface of platelets, PF4 triggered the production of the small cells known to cause clotting. Dr Pip Nicolson, Associate Clinical Professor in Cardiovascular Medicine at the University of Birmingham and senior author of the study said: "The major advances seen in vaccine development during the global Covid-19 pandemic were thrown into sharp relief following the tragic, rare cases of vaccine-induced immune thrombosis. While there were alternative vaccines available to continue to provide protection against the coronavirus in some countries around the world, understanding the mechanisms behind these cases is critical to ensuring that the technology for delivering vaccines can be used with confidence in the future." Dr Richard Buka, Research Fellow in the Institute of Cardiovascular Sciences and co-lead author "As well as identifying a new way in which platelets are being activated in a potentially deadly manner in VITT, our research has also been able to find how this mechanism may lead to new drugs to protect against blood clots in VITT and blood clots in general." Variations on a drug used to treat bone marrow cancers could be developed to protect VITT patients from deadly clotting, the research also found. The team used ruxolitinib, a drug used to treat some types of blood cancer, to block the receptor being triggered by PF4 following the vaccine-induced event. Although they note that the current form of the drug is unsuitable for use in VITT patients, the team nevertheless identified that blocking the pathway through ruxolitinib slowed down platelet aggregation and demonstrates a potential future way to protect patients from blood clots. Dr Samantha Montague, Research Fellow in the Institute of Cardiovascular Sciences at the University of Birmingham and co-lead author of the paper said: "It is gratifying that we have been able to identify a new, important biological mechanism through trying to thoroughly understand a new disease. This work helps us to understand more fundamental things about how blood clots form and may also be relevant in other related diseases that are more common. "Our ongoing research funded by the British Heart Foundation is looking at how we can identify patients who may develop VITT, with a view that future vaccine programmes around the world can be delivered while understanding and managing the potential risk for those few at greatest risk."

New findings suggest the old way of thinking around what makes B cells self-react in autoimmune disease might have left out some key details. Scientists have found a new piece in the puzzle that explains why B cells self-react in autoimmune disease—and, with it, a potential new treatment strategy. In an article published Sept. 29 in the Journal of Experimental Medicine, a research team led by scientists from the Yale University School of Medicine and the Hospital for Special Surgery in New York reported that the loss of the receptor TLR9, found in immune cells called B cells, can cause those cells to attack the body’s own tissues. The findings could ultimately inform new treatments for patients with conditions like lupus and scleroderma. “Our data … provide a rationale for the development of novel therapeutic strategies for [scleroderma and lupus] that will aim at correcting impaired TLR9 function in B cells to restore both central and peripheral B cell tolerance and suppress autoimmune manifestations,” the researchers wrote in their paper. Scientists have known for years that self-reactive B cells are one of the culprits behind autoimmune disease. Prior to this study, the prevailing dogma was that the rogue cells weren’t taken out by the body because of abnormalities in a different receptor called a B-cell receptor. Under normal conditions, if a developing B cell in the bone marrow binds to a self-antigen—that is, a protein found on the surface of a body’s own cells—other immune cells will destroy it in a process known as central tolerance. But certain gene mutations or environmental exposures can cause the B-cell receptor to malfunction in a way that it evades destruction. The new findings, however, show that there’s more to the story. Following clues from previous studies that suggested that the TLR9 receptor, found inside B cells, was required for central tolerance, the scientists set out to see how altering it would make a difference in autoimmune disease development. First, they took B cells from patients with scleroderma and lupus and tested their TLR9 responses. They found that, unlike in healthy cells, the TLR9 receptor didn’t respond to stimulation, suggesting it was impaired. The link between that finding and autoimmune disease was validated in mice: Depleting TLR9 led to an increase in self-reactive B cells and antibodies. What might be the source of the dysfunction? One possible answer came from previous studies on a signaling protein called CXCL4 that showed it was elevated in the blood of patients with scleroderma, lupus and other autoimmune diseases that affect the joints, tendons and bones. To see how the protein interacted with the TLR9 receptor, the researchers tried to stimulate the TLR9 receptor in the presence of CXCL4 in human and mouse B cells. Signaling molecules involved in central tolerance were inhibited; upon closer examination, the scientists saw that this stemmed from CXCL4 binding to and preventing the delivery of DNA fragments to TLR9, which otherwise would have upregulated those molecules and induced central tolerance. These results led the scientists to see whether they could replicate the same findings in animals. Mice that were engineered to express excess CXCL4 had lower levels of TLR9 activation, more self-reactive B cells and antibodies, and lower B-cell tolerance, as they expected. The findings add a new dimension to the source of autoimmune disease by showing that a mechanism other than B-cell receptor signaling is responsible for removing self-reactive B cells, study co-lead Eric Meffre, Ph.D., who was at Yale at the time of the study but is now with Stanford, noted in a press release. They also suggest that inhibiting CXCL4 could provide a potential means of therapy, “Correcting defective TLR9 function in B cells from patients with [scleroderma] and perhaps other autoimmune diseases, potentially by neutralizing CXCL4, may represent a novel therapeutic strategy to restore B cell tolerance,” he said in the release.

Researchers have found an injection of a specific blood factor can replicate the benefits of exercise in the brain. They've discovered that platelets secrete a protein, exerkine CXCL4/Platelet factor 4 or PF4, that rejuvenates neurons in aged mice in a similar way to physical exercise. This protein, which is released from platelets after exercise, results in regenerative and cognitive improvements when injected into aged mice. Pre-clinical trials by University of Queensland researchers have found an injection of a specific blood factor can replicate the benefits of exercise in the brain. Dr Odette Leiter and Dr Tara Walker from UQ's Queensland Brain Institute led a team which discovered platelets, the tiny blood cells critical for blood clotting, secrete a protein that rejuvenates neurons in aged mice in a similar way to physical exercise. "We know exercise increases production of new neurons in the hippocampus, the part of the brain important for learning and memory, but the mechanism hasn't been clear," Dr Leiter said. "Our previous research has shown platelets are involved, but this study shows platelets are actually required for this effect in the aged mice." The researchers focused on exerkines, the biological compounds released into the bloodstream during exercise, which are believed to stimulate the exercise-induced response in the brain. "We discovered that the exerkine CXCL4/Platelet factor 4 or PF4, which is released from platelets after exercise, results in regenerative and cognitive improvements when injected into aged mice," Dr Leiter said. Dr Walker said the findings have significant implications for the development of drug interventions. "For a lot of people with health conditions, mobility issues or of advanced age, exercise isn't possible, so pharmacological intervention is an important area of research," she said. "We can now target platelets to promote neurogenesis, enhance cognition and counteract age-related cognitive decline." The researchers said the next step is to test the response in Alzheimer diseased mice, before moving towards human trials. "It's important to note this is not a replacement for exercise," Dr Walker said. "But it could help the very elderly or someone who has had a brain injury or stroke to improve cognition." The study is published in Nature Communications.