The Endoplasmic Reticulum Stress-Inducible Protein, Herp, Is a Potential Triggering Antigen for Anti-DNA Response
The Endoplasmic Reticulum Stress-Inducible Protein, Herp, Is a Potential Triggering Antigen for Anti-DNA Response
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DOI：
10.4049/jimmunol.0900670
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发表时间：
2010-03-15
影响因子：
4.4
通讯作者：
Harigae, Hideo
中科院分区：
文献类型：
--
作者：
Hirabayashi, Yasuhiko;Oka, Yumiko;Harigae, Hideo
抗dsDNA抗体是系统性红斑狼疮（SLE）高度特异性的指标，在狼疮性肾炎中起致病作用。人抗dsDNA抗体很可能是由Ag驱动机制产生的。然而，负责触发抗dsDNA抗体产生的Ag尚未确定。为了寻找与抗dsDNA抗体交叉反应的蛋白质，我们用O-81人源抗ss/dsDNA单克隆抗体的单链抗体，通过双杂交系统从SLE患者的cDNA文库中筛选。同型半胱氨酸诱导的内质网蛋白（Herp），内质网（ER）应激诱导的ER膜蛋白，被鉴定和显示结合原始O-81抗体和人狼疮抗dsDNA抗体。通过Herp固定化亲和层析从活动性SLE患者中纯化的一些IgG与dsDNA结合。Herp免疫BALB/c小鼠后，出现IgG抗dsDNA抗体、IgG抗核小体抗体和肾小球IgG沉积。活动性SLE患者的部分PBL中Herp反应性强阳性，但在健康对照组中检测不到。此外，在Herp阳性细胞中观察到半胱天冬酶的激活，这意味着ER应激诱导的细胞凋亡可能发生在活动性SLE患者中。Herp暴露于ER应激诱导的凋亡细胞的大泡上，表明Herp可以被免疫细胞识别。这些结果表明Herp在免疫学上模拟DNA的结构决定簇，并且可以在体内具有免疫原性。因此，Herp代表抗DNA Ab的候选自身抗原。本研究可能有助于解释常见环境因素如何诱导抗DNA抗体的产生，并有助于SLE的发展。免疫学杂志，2010，184：3276-3283。
Anti-dsDNA Abs are highly specific indicators of systemic lupus erythematosus (SLE) and play a pathogenic role in lupus nephritis. Human anti-dsDNA Abs are most likely generated by an Ag-driven mechanism. However, the Ag responsible for triggering anti-dsDNA Ab production has not been identified. To search for proteins that are cross-reactive with anti-dsDNA Abs, we screened a cDNA library from a patient with SLE with single-chain Fv of O-81 human anti-ss/dsDNA mAb by using a two-hybrid system. Homocysteine-induced ER protein (Herp), an endoplasmic reticulum (ER) stress-inducible ER membrane protein, was identified and shown to bind to original O-81 Ab and human lupus anti-dsDNA Abs. Some IgG purified from patients with active SLE by Herp-immobilized affinity chromatography bound to dsDNA. BALB/c mice immunized with Herp showed IgG anti-dsDNA Abs, IgG anti-nucleosome Abs, and glomerular IgG deposition. Herp, reactivity was strongly positive in a proportion of PBLs from patients with active SLE, but undetectable in those from healthy controls. Moreover, activation of caspases was observed in the Herp-positive cells, implying that ER stress-induced apoptosis likely occurs in patients with active SLE. Herp is exposed on blebs of ER stress-induced apoptotic cells, suggesting that Herp can be recognized by immune cells. These results indicate that Herp mimics structural determinants of DNA immunologically and can be immunogenic in vivo. Thus, Herp represents a candidate autoantigen for anti-DNA Abs. This study may help explain how common environmental factors induce the production of anti-DNA Abs and contribute the development of SLE. The Journal of Immunology, 2010, 184: 3276-3283.