Identification of a Lipid Peroxidation Product as the Source of Oxidation-specific Epitopes Recognized by Anti-DNA Autoantibodies
Identification of a Lipid Peroxidation Product as the Source of Oxidation-specific Epitopes Recognized by Anti-DNA Autoantibodies
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DOI：
10.1074/jbc.m110.165175
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发表时间：
2010-10-29
影响因子：
4.8
通讯作者：
Uchida, Koji
中科院分区：
文献类型：
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作者：
Otaki, Natsuki;Chikazawa, Miho;Uchida, Koji
组织和组织组分中的脂质过氧化是一种降解过程，这是主要涉及膜多不饱和脂肪酸的自由基反应的产生和传播的结果，并且与许多疾病的发病机制有关，包括系统性红斑狼疮（SLE）。我们已经发现，牛血清白蛋白与过氧化多不饱和脂肪酸孵育显着交叉反应的血清从MRL-lpr小鼠，SLE的代表性小鼠模型。为了鉴定负责产生SLE血清识别的自身抗原表位的活性物质，我们对13-氢过氧-9Z，11 E-十八碳二烯酸的主要来源进行了活性指导分离，并鉴定了4-氧代-2-壬烯醛（ONE），一种源自ω 6多不饱和脂肪酸过氧化的高反应性醛，作为自身抗原表位的来源。当在来自MRL-lpr小鼠和对照MRL-MpJ小鼠的血清中测量针对ONE修饰蛋白的抗体滴度的年龄依赖性变化时，所有MRL-lpr小鼠都产生了抗ONE滴度，其与抗DNA滴度相当。引人注目的是，从SLE小鼠产生的抗DNA单克隆抗体的子集显示出对DNA的识别特异性，与ONE特异性表位交叉反应。此外，这些双特异性抗体迅速结合并内化到活细胞中。这些发现提出了一种可能性，即增强的脂质过氧化作用，随后产生的ONE可能参与了自身免疫性疾病的发病机制。
Lipid peroxidation in tissue and in tissue fractions represents a degradative process, which is the consequence of the production and the propagation of free radical reactions primarily involving membrane polyunsaturated fatty acids, and has been implicated in the pathogenesis of numerous diseases, including systemic lupus erythematosus (SLE). We have found that bovine serum albumin incubated with peroxidized polyunsaturated fatty acids significantly cross-reacted with the sera from MRL-lpr mice, a representative murine model of SLE. To identify the active substances responsible for the generation of autoantigenic epitopes recognized by the SLE sera, we performed the activity-guiding separation of a principal source from 13-hydroperoxy-9Z, 11E-octadecadienoic acid and identified 4-oxo-2-nonenal ( ONE), a highly reactive aldehyde originating from the peroxidation of omega 6 polyunsaturated fatty acids, as the source of the autoantigenic epitopes. When the age-dependent change in the antibody titer against the ONE-modified protein was measured in the sera from MRL-lpr mice and control MRL-MpJ mice, all of the MRL-lpr mice developed an anti-ONE titer, which was comparable with the anti-DNA titer. Strikingly, a subset of the anti-DNA monoclonal antibodies generated from the SLE mice showing recognition specificity toward DNA cross-reacted with the ONE-specific epitopes. Furthermore, these dual-specific antibodies rapidly bound and internalized into living cells. These findings raised the possibility that the enhanced lipid peroxidation followed by the generation of ONE may be involved in the pathogenesis of autoimmune disorders.