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The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

机译:先天免疫对aNCa相关性血管炎发病机制的贡献

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摘要

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a group of vasculitides characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of ANCA in the circulation. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. NETs were first described to be involved in capture and elimination of pathogens but dysregulated production and/or clearance of NETs are thought to contribute to vessel inflammation in AAV; directly by damaging endothelial cells and indirectly by acting as a link between the innate and adaptive immune system through the generation of pathogenic PR3-ANCA and MPO-ANCA that can activate neutrophils. ANCA can, however, be found in all individuals and are therefore suggested to belong to the repertoire of natural antibodies produced by innate-like B cells, implying that not all ANCA are pathogenic.  In paper I, we found neutrophils in patients to be more prone to undergo NETosis/necrosis spontaneously compared with neutrophils in healthy controls (HC), as well as that active patients possessed elevated levels of NETs in the circulation. Our results also suggest that ANCA during remission could contribute to the clearance of NETs as we observed an inverse relation between ANCA and NETs. In paper II, we observed neutrophils in patients to be more easily activated upon ANCA stimulation as they produced more ROS than neutrophils in HC. In paper III, we showed for the first time that cells of adaptive immunity (B and T cells) in addition to cells of innate immunity can release ET-like structures, in this case consisting of mitochondrial (mt) DNA. mtDNA can act as a damage-associated pattern molecule (DAMP) and promote inflammation, and increased levels of mtDNA has been observed in AAV. Our finding broadens our perspective of the possible roles of T and B cells in immunological responses, and should be further investigated in AAV. In paper IV, we observed reduced frequencies of MZ-like B cells, considered to be innate-like B cells that produce natural antibodies, and of the proposed regulatory B (Breg) cell populations CD24highCD27+ and CD25+CD27+ B cells in patients, particularly in those with active disease. We also observed the phenotypes of these different Breg cell populations to be different from the corresponding cells in HC. We hypothesize that the increased activation potential by neutrophils in AAV to produce ROS and undergo NETosis/necrosis contribute to the excessive inflammation as well as an increased antigen load of PR3 and MPO, and that this in combination with dysregulation of innate-like B cells and Breg cells could lead to break of tolerance to these antigens and production of pathogenic autoantibodies. ANCA can in turn activate neutrophils to release NETs, suggesting a vicious circle in disease development.
机译:抗中性粒细胞胞浆抗体(ANCA)相关血管炎(AAV)构成一组脉管炎,其特征是富含中性粒细胞的小血管坏死性炎症和循环中ANCA的存在。血管壁周围垂死的嗜中性粒细胞是AAV的组织学标志。传统上认为这些中性粒细胞会因坏死而死亡,但是最近在血管病变部位可见中性粒细胞胞外陷阱(NETs)。 NETs首先被描述为与病原体的捕获和消除有关,但人们认为NETs的生产和/或清除失调会导致AAV中的血管炎症。直接通过破坏内皮细胞而间接发挥作用,并通过生成可激活嗜中性粒细胞的致病性PR3-ANCA和MPO-ANCA充当先天和适应性免疫系统之间的联系。然而,ANCA可以在所有个体中发现,因此被认为属于先天性B细胞产生的天然抗体库,这意味着并非所有的ANCA都是致病性的。在论文I中,我们发现与健康对照(HC)中的中性粒细胞相比,患者中的中性粒细胞更容易自发发生NETosis /坏死,而且活跃患者的血液中NETs水平升高。我们的结果还表明,缓解期间的ANCA可能有助于NETs的清除,因为我们观察到ANCA与NETs之间存在反比关系。在论文II中,我们观察到患者中的中性粒细胞在ANCA刺激下更容易被激活,因为它们比HC中的中性粒细胞产生更多的ROS。在论文III中,我们首次证明了先天免疫细胞之外的适应性免疫细胞(B细胞和T细胞)可以释放ET样结构,在这种情况下由线粒体(mt)DNA组成。 mtDNA可以充当损伤相关模式分子(DAMP)并促进炎症,并且已在AAV中观察到mtDNA含量增加。我们的发现拓宽了我们对T细胞和B细胞在免疫应答中可能作用的认识,应在AAV中进一步研究。在论文IV中,我们观察到MZ样B细胞(被认为是产生天然抗体的先天样B细胞)以及拟议的调节性B(Breg)细胞群体CD24highCD27 +和CD25 + CD27 + B细胞(尤其是患者)的频率降低在那些患有活动性疾病的人中。我们还观察到这些不同的Breg细胞群体的表型与HC中的相应细胞不同。我们假设中性粒细胞在AAV中产生ROS并发生NETosis /坏死的活化潜能增加,导致过度的炎症以及PR3和MPO的抗原负载增加,并且这与先天性B细胞和Breg细胞可能导致对这些抗原的耐受性破坏和致病性自身抗体的产生。反过来,ANCA可以激活中性粒细胞以释放NETs,这提示疾病发展的恶性循环。

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    Söderberg, Daniel;

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  • 年度 2018
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  • 正文语种 eng
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