Abstract:
Blood vessels are indispensable for host survival and are protected from inappropriate inflammation by immune privilege. This protection is lost in patients with autoimmune vasculitides, a heterogeneous group of diseases causing damage to arteries, arterioles, and capillaries. Vasculitis leads to vascular wall destruction and/or luminal occlusion, resulting in hemorrhage and tissue ischemia. Failure in the quantity and quality of immunosuppressive regulatory T cells (Treg) has been implicated in the breakdown of the vascular immune privilege. Emerging data suggest that Treg deficiencies are disease-specific, affecting distinct pathways in distinct vasculitides. Mechanistic studies have identified faulty CD8+ Tregs in Giant Cell Arteritis (GCA), a vasculitis of the aorta and the large aortic branch vessels. Specifically, aberrant signaling through the NOTCH4 receptor expressed on CD8+ Treg cells leads to rerouting of intracellular vesicle trafficking and failure in the release of immunosuppressive exosomes, ultimately boosting inflammatory attack to medium and large arteries. In Kawasaki\'s disease, a medium vessel vasculitis targeting the coronary arteries, aberrant expression of miR-155 and dysregulated STAT5 signaling have been implicated in undermining CD4+ Treg function. Explorations of mechanisms leading to insufficient immunosuppression and uncontrolled vascular inflammation hold the promise to discover novel therapeutic interventions that could potentially restore the immune privilege of blood vessels and pave the way for urgently needed innovations in vasculitis management.
摘要:
血管对于宿主生存是必不可少的,并且通过免疫特权保护免受不适当的炎症。这种保护在自身免疫性血管炎患者中丧失,一组导致动脉损伤的异质性疾病,小动脉,和毛细血管。血管炎导致血管壁破坏和/或管腔闭塞,导致出血和组织缺血。免疫抑制调节性T细胞(Treg)的数量和质量的失败与血管免疫特权的破坏有关。新数据表明Treg缺乏是疾病特异性的,影响不同的血管炎的不同途径。机制研究已经确定了巨细胞动脉炎(GCA)中的错误CD8Treg,主动脉和大的主动脉分支血管的血管炎。具体来说,通过CD8+Treg细胞上表达的NOTCH4受体的异常信号导致细胞内囊泡运输的重新路由和免疫抑制外泌体释放的失败,最终促进对中大动脉的炎症攻击。在川崎病中,针对冠状动脉的中等血管血管炎,miR-155的异常表达和STAT5信号传导失调与CD4+Treg功能受损有关。探索导致免疫抑制不足和不受控制的血管炎症的机制有望发现新颖的治疗干预措施,这些干预措施可能潜在地恢复血管的免疫特权,并为血管炎管理中迫切需要的创新铺平道路。