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Circulation:动脉粥样硬化和自身免疫疾病之间的联系机制

2012-04-10 Beyond 生物谷

患有自身免疫性疾病的个体也显示出罹患动脉粥样硬化症的倾向,动脉粥样硬化症俗称血管硬化。慕尼黑的临床研究者与维尔茨堡研人员合作发现了一种新机制有助于解释两种疾病之间存在的联系。两种疾病之间的联系在于称为浆细胞样树突状细胞(pDCs)的特定免疫细胞。在自身免疫性疾病中,浆细胞样树突状细胞受到受损坏和死亡细胞释放的DNA刺激,分泌干扰素蛋白以刺激免疫反应。这项新的研究表明特定的DNA-蛋白质复合物刺激浆

患有自身免疫性疾病的个体也显示出罹患动脉粥样硬化症的倾向,动脉粥样硬化症俗称血管硬化。慕尼黑的临床研究者与维尔茨堡研人员合作发现了一种新机制有助于解释两种疾病之间存在的联系。两种疾病之间的联系在于称为浆细胞样树突状细胞(pDCs)的特定免疫细胞。在自身免疫性疾病中,浆细胞样树突状细胞受到受损坏和死亡细胞释放的DNA刺激,分泌干扰素蛋白以刺激免疫反应。这项新的研究表明特定的DNA-蛋白质复合物刺激浆细胞样树突状细胞导致动脉粥样硬化的发生发展。

动脉粥样硬化是西方社会中死亡的主要原因。这种疾病是由于慢性、局部炎症反应引发主动脉壁上的粥样硬化斑块的形成不溶性物质诱发的。通过减少血流量,斑块可引起心脏病发作和中风。一类被称为树突状细胞的免疫细胞在促进这些斑块形成过程中起着至关重要的作用。但到现在为止树突状细胞类型对动脉粥样硬化的潜在意义尚未探索清楚。慕尼黑基督教韦伯教授Yvonne D?ring博士领导的研究小组与维尔茨堡大学、Zernecke博士一起完成的研究揭示了浆细胞样树突状细胞是如何促进动脉粥样硬化发展的,解释了为什么自身免疫性疾病如牛皮癣或系统性红斑狼疮患者有发展成动脉粥样硬化的倾向。

利用实验室小鼠作为实验模型,研究人员表明浆细胞样树突状细胞对血管中主动脉粥样斑块形成早期阶段的作用。浆细胞样树突状细胞的刺激使他们分泌大量的干扰素,这是一种强烈刺激炎症反应的蛋白质。干扰素诱导释放的蛋白质是由专门聚集在炎症部位的免疫细胞释放的,不产生这种蛋白质的小鼠斑块形成也较少。浆细胞样树突状细胞的刺激导致斑块中的巨噬细胞数量增加,巨噬细胞通常消除细胞碎片和脂肪沉积。然而巨噬细胞也可以“放纵”自己,能消化更多的脂肪。当发生这种情况,巨噬细胞就变成了所谓的泡沫细胞,促进动脉粥样硬化而不是抵抗动脉粥样硬化。此外,激活的、成熟的浆细胞样树突状细胞可以启动免疫反应对抗动脉粥样硬化中某些病理分子,从而进一步加剧整个过程。

D?ring说:“自身抗原刺激浆细胞样树突状细胞,促发自身免疫反应导致牛皮癣和系统性红斑狼疮等疾病”。事实上,这是众所周知,干扰素激活浆细胞样树突状细胞的分泌有助于一些自身免疫性疾病的发生。

Weber说:“这项新发现浆细胞样树突状细胞参与动脉粥样硬化的发展,浆细胞样树突状细胞使得这种疾病和自身免疫反应之间建立了直接的联系,研究还揭示了为什么刺激浆细胞样树突状细胞会促进动脉粥样硬化的发展。(生物谷:Bioon)

doi:10.1161/CIRCULATIONAHA.111.046755
PMC:
PMID:

Auto-Antigenic Protein-DNA Complexes Stimulate Plasmacytoid Dendritic Cells to Promote Atherosclerosis

Yvonne Dring1; Helga Manthey2; Maik Drechsler3; Dirk Lievens3; Remco Megens3; Oliver Soehnlein3; Martin Busch2; Marco Manca4; Rory R. Koenen3; Jaroslav Pelisek5; Mat J. Daemen4; et al.

Background—Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid DCs (pDCs) are specialized to produce type-I interferons in response to pathogenic single-stranded nucleic acids but can also sense self-DNA released from dying cells or in neutrophil extracellular traps (NETs) complexed to the antimicrobial peptide Cramp/LL37 in autoimmune disease. However, the exact role of pDCs in atherosclerosis remains elusive.

Methods and Results—Here we demonstrate that pDCs can be detected in murine and human atherosclerotic lesions. Exposure to oxLDL enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. pDCs can be stimulated to produce IFN-α by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of NETs in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient (Apoe-/-) mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-dsDNA antibody titers. Moreover, the specific activation of pDCs and IFN-α treatment promoted plaque growth, associated with enhanced anti-ds-DNA antibody titers. Accordingly, anti-dsDNA-antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis.

Conclusions—Self-DNA, e.g. released from dying cells or in NETs, and an increased expression of the antimicrobial peptide Cramp/LL37 in atherosclerotic lesions may thus stimulate a pDC-driven pathway of autoimmune activation and the generation of anti-ds-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets.

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