Oxidation-specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis.
Oxidation-specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis.
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DOI：
10.1016/j.coph.2013.02.005
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发表时间：
2013-04
影响因子：
4
通讯作者：
Tsimikas, Sotirios
中科院分区：
文献类型：
--
作者：
Leibundgut, Gregor;Witztum, Joseph L.;Tsimikas, Sotirios
氧化特异表位(OSE)存在于氧化低密度脂蛋白(OxLDL)、细胞凋亡、细胞碎片和血管壁上修饰的蛋白质上，在高胆固醇血症时积聚，并产生强大的促炎和疾病特异性抗原。它们代表了一类重要的“危险相关分子模式”(DAMP)，针对它们的是一种协调一致的先天免疫反应。OSE被天然的“模式识别受体”识别，如树突状细胞和单核/巨噬细胞上的清道夫受体，以及天然蛋白，如IgM天然抗体和可溶性蛋白，如C-反应蛋白和补体因子H。这些天然免疫反应提供了抵御动脉粥样硬化特异性抑制的第一道防线，并参与了由T和B-2细胞提供的适应性免疫反应，从而提供了更特异和明确的反应。这种免疫反应通常是为了清除外来病原体，如微生物病原体上发现的病原体，但当持续或不适应时，会导致宿主损害。在这种背景下，动脉粥样硬化可以被认为是一种全身性慢性炎症性疾病，由OSE类型的阻滞剂积聚而起，由先天免疫系统和适应性免疫系统的不良适应反应持续存在。对这一范例的理解导致了定义心血管风险的新方法，并提出了新的治疗模式。因此，OSE已成为诊断和治疗药物的潜在靶点。人类和小鼠的OSE靶向抗体已经被开发出来，现在被用作人类研究的生物标记物，并被实验用于富氧化斑块的非侵入性分子成像和免疫治疗的翻译应用。
Oxidation-specific epitopes (OSE), present on oxidized LDL (OxLDL), apoptotic cells, cell debris and modified proteins in the vessel wall, accumulate in response to hypercholesterolemia, and generate potent pro-inflammatory, disease-specific antigens. They represent an important class of ‘danger associated molecular patterns’ (DAMPs), against which a concerted innate immune response is directed. OSE are recognized by innate ‘pattern recognition receptors’, such as scavenger receptors present on dendritic cells and monocyte/macrophages, as well as by innate proteins, such as IgM natural antibodies and soluble proteins, such as C-reactive protein and complement factor H. These innate immune responses provide a first line of defense against atherosclerosis-specific DAMPs, and engage adaptive immune responses, provided by T and B-2 cells, which provide a more specific and definitive response. Such immune responses are ordinarily directed to remove foreign pathogens, such as those found on microbial pathogens, but when persistent or maladaptive, lead to host damage. In this context, atherosclerosis can be considered as a systemic chronic inflammatory disease initiated by the accumulation of OSE type DAMPs and perpetuated by maladaptive response of the innate and adaptive immune system. Understanding this paradigm leads to new approaches to defining cardiovascular risk and suggests new modes of therapy. Therefore, OSE have become potential targets of diagnostic and therapeutic agents. Human and murine OSE-targeting antibodies have been developed and are now being used as biomarkers in human studies and experimentally in translational applications of non-invasive molecular imaging of oxidation-rich plaques and immunotherapeutics.
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