Mechanisms of vascular damage in ANCA vasculitis.

IF 7.9 2区 医学 Q1 IMMUNOLOGY Seminars in Immunopathology Pub Date : 2022-05-01 DOI:10.1007/s00281-022-00920-0
David Massicotte-Azarniouch, Carolina A Herrera, J Charles Jennette, Ronald J Falk, Meghan E Free
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引用次数: 8

Abstract

The discovery of anti-neutrophil cytoplasmic antibodies (ANCA) and their antigenic targets, myeloperoxidase (MPO) and proteinase 3 (PR3), has led to further understanding as to the pathophysiologic processes that underlie vascular and tissue damage in ANCA vasculitis. ANCA trigger neutrophil activation leading to vascular damage in ANCA vasculitis. However, decades of study have determined that neutrophil activation alone is not sufficient to cause disease. Inflammatory stimuli are drivers of ANCA autoantigen expression and ANCA production. Certain infections or bacterial peptides may be crucial players in the initial steps of ANCA immunopathogenesis. Genetic and epigenetic alterations of gene encoding for MPO and PR3 provide additional disturbances to the immune homeostasis which provide a substrate for pathogenic ANCA formation from an adaptive immune system predisposed to autoreactivity. Promoted by inflammatory cytokines, ANCA binding leads to neutrophil activation, a process characterized by conformational changes, production and release of cytotoxic substances, and alternative complement pathway activation, thus creating an intense inflammatory milieu. This cascade of events perpetuates a vicious cycle of further inflammatory cell recruitment and activation, culminating in tissue necrosis. Our understanding of the pathogenic process in ANCA vasculitis paves the way for the development of therapies targeting crucial steps in this process. The greater appreciation of the role for complement, monocytes, and the adaptive immune system has already led to novel complement blockers and is poised to lead to further innovations which will allow for tailored antigen- or cell-specific immunotherapy targeting the autoimmune process without exposure to undue risks or toxicities.

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ANCA血管炎血管损伤的机制。
抗中性粒细胞胞浆抗体(ANCA)及其抗原靶点髓过氧化物酶(MPO)和蛋白酶3 (PR3)的发现,使人们对ANCA血管炎中血管和组织损伤的病理生理过程有了进一步的了解。ANCA触发中性粒细胞活化导致ANCA血管炎的血管损伤。然而,几十年的研究已经确定,中性粒细胞激活本身并不足以引起疾病。炎症刺激是ANCA自身抗原表达和ANCA产生的驱动因素。某些感染或细菌肽可能在ANCA免疫发病的初始步骤中起关键作用。MPO和PR3编码基因的遗传和表观遗传改变为免疫稳态提供了额外的干扰,这为适应性免疫系统倾向于自身反应性的致病性ANCA形成提供了底物。在炎症细胞因子的促进下,ANCA结合导致中性粒细胞活化,这一过程以构象改变、细胞毒性物质的产生和释放以及补体途径的激活为特征,从而产生强烈的炎症环境。这一连串的事件延续了一个恶性循环,进一步的炎症细胞募集和激活,最终导致组织坏死。我们对ANCA血管炎致病过程的理解为开发针对这一过程关键步骤的治疗方法铺平了道路。对补体、单核细胞和适应性免疫系统的作用的进一步认识已经导致了新的补体阻滞剂的出现,并有望导致进一步的创新,这将允许针对自身免疫过程的定制抗原或细胞特异性免疫治疗,而不会暴露于过度的风险或毒性。
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来源期刊
Seminars in Immunopathology
Seminars in Immunopathology 医学-病理学
CiteScore
19.80
自引率
2.20%
发文量
69
审稿时长
12 months
期刊介绍: The aim of Seminars in Immunopathology is to bring clinicians and pathologists up-to-date on developments in the field of immunopathology.For this purpose topical issues will be organized usually with the help of a guest editor.Recent developments are summarized in review articles by authors who have personally contributed to the specific topic.
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