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.

衰老，是一个复杂、多阶段、渐进的过程，发生在生命的整个过程。随着年龄的增长，我们都将面临衰老，身体和认知功能都会发生一些变化，这会导致衰老相关疾病发病率的增加，因此，确定延缓并可能逆转与年龄相关的认知能力下降的治疗方法至关重要。2023年8月16日，美国加州大学旧金山分校的研究人员在" Nature "期刊上发表了一篇题为" Platelet factors attenuate inflammation and rescue cognition in ageing "的研究论文。该研究显示，血液中的血小板因子4（PF4），是逆转大脑衰老的关键，血小板因子的注射可以显著减轻老年小鼠的认知功能障碍，还能够降低老年小鼠体内的炎症水平。进一步分析显示，血小板因子通过抑制炎症介质的产生和调节炎症信号通路来发挥作用。早期研究显示，年轻血液（联体共生）、运动和长寿激素klotho都可以让老年个体提高认知能力，然而，尚不清楚这些因素导致的认知增强的分子机制。在该研究中，研究人员分析了幼鼠血浆，通过离心的方法收集幼鼠的血浆组分，分别将收集的血浆、血小板或生理盐水注射给衰老小鼠，以确认是哪种成分给衰老大脑带来有益作用。研究发现，注射年轻血浆或血小板成分可减少老年海马的神经炎症。早期的研究发现，不管是人类还是小鼠，年轻个体血浆中中的PF4都高于老年个体，因此，研究人员进一步分析了PF4。通过对老年小鼠注射PF4或生理盐水发现，与注射生理盐水的小鼠相比，注射PF4的老年小鼠的海马体促炎基因表达降低，小胶质细胞减少，还减少了炎症信号的表达，以及表现出与突触可塑性相关的分子变化。当研究人员敲除PF4基因后发现，小鼠海马体中的小胶质细胞有所增加，表明缺失PF4会加速中年神经炎症的增加。PF4可减轻神经炎症并引发衰老海马体中突触相关的变化此外，研究还发现，PF4注射可以使老化的免疫系统恢复活力，在骨髓细胞群中，PF4治疗恢复了更年轻的基因特征并减少了炎症信号的表达，在淋巴样细胞中，PF4治疗使细胞转向年轻的T细胞基因特征。这表明，PF4可以部分将衰老的外周免疫系统的细胞组成和分子特征恢复到更年轻的状态。最后，认知功能检测发现，PF4可以让老年个体提高认知能力，PF4的丧失会以年龄依赖性方式加速认知功能下降。研究人员表示，对22个月（相当于70多岁的人）的小鼠进行测试发现，PF4可以让认知功能回复至30-40岁时认知水平。同一天，美国加州大学的研究人员在" Nature Aging "期刊上发表了一篇题为" Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice "的研究论文。研究发现，注射klotho改善老年动物的认知能力，与PF4有关。在小鼠中，注射klotho，增加血浆中多种血小板因子的水平，包括 PF4。而抑制血小板活化的药物可以阻止klotho介导的认知增强，这表明klotho发挥的益处与血小板有关。进一步研究发现，在年轻小鼠中，注射PF4增强了突触可塑性和认知能力。在老年小鼠中，PF4减少了认知缺陷，并恢复了衰老引起的海马体中与认知表现相关的特定因素的增加。在缺乏PF4的小鼠中，注射klotho对认知的改善依然存在，表明PF4可以增强klotho的作用，但不是必须的。不仅如此，同一天，澳大利亚昆士兰大学的研究人员在" Nature Communications "期刊上发表了一篇题为" Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice "的研究论文。研究显示，运动可以改善认知功能，运动后血小板将PF4释放至血液中，增加PF4可以以海马神经发生依赖性方式改善与年龄相关的再生和认知障碍。首先，研究人员观察到老年小鼠的海马神经发生较年轻小鼠明显减少。然后，注射了PF4到老年小鼠的大脑中，并发现这种注射可以显著增加海马神经发生。这意味着PF4可以促进新神经元的生成，从而有助于恢复认知功能。此外，研究人员还测试了老年小鼠在认知任务中的表现。发现注射PF4后，老年小鼠在学习和记忆方面的表现明显改善。这表明PF4对于恢复老年小鼠的认知功能起到了积极的作用。综上，三篇独立的研究发现了相同的结论，无论是年轻血液、klotho、亦或是运动，对认知功能带来的益处，都与血小板因子4有关，它可以减轻老年炎症反应并改善认知功能。这三项研究为我们提供了新的视角，认识到血小板因子在老年炎症和认知功能中的重要作用，为老年认知功能障碍的治疗和预防提供新的方向和策略。文章来源“生物谷”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~