Modification of lupus-associated 60-kDa Ro protein with the lipid oxidation product 4-hydroxy-2-nonenal increases antigenicity and facilitates epitope spreading
Modification of lupus-associated 60-kDa Ro protein with the lipid oxidation product 4-hydroxy-2-nonenal increases antigenicity and facilitates epitope spreading
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DOI：
10.1016/j.freeradbiomed.2004.11.001
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发表时间：
2005-03-15
影响因子：
7.4
通讯作者：
Hensley, K
中科院分区：
文献类型：
--
作者：
Scofield, RH;Kurien, BT;Hensley, K
系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，其自身抗体几乎是该疾病的普遍特征。Ro核糖核蛋白颗粒由与人细胞质RNA非共价结合的60-kDa蛋白组成，是25-40%狼疮患者中抗体的靶点。发现纯化的人60-kDa Ro被氧化修饰。我们实验室的早期研究显示SLE患者的氧化损伤增加。因此，我们假设氧化副产物，如4-羟基-2-壬烯醛（HNE），可能导致新抗原，如HNE修饰的60-kDa RO，这反过来可能引发自身免疫或驱动表位扩散。为了验证这一假设，我们用HNE修饰的60-kDa Ro或未修饰的Ro免疫家兔。Ro分子内的分子内表位扩散和分子间表位扩散到La，双链DNA，nRNP和Sin优先发生在HNE-Ro免疫动物中。通过用HNE-钥孔血蓝蛋白缀合物免疫产生的非特异性抗FINE抗体不显著结合这些自身抗原。这些数据可能提示了一种迄今未被认识到的机制，即氧化应激促进SLE中表位的扩散。(C)2004年爱思唯尔公司All rights reserved.
Systemic lupus erythematosus (SLE) is a Chronic autoimmune disease with autoantibodies as a near Universal feature of the disease. The Ro ribonucleoprotein particle, composed of a 60-kDa protein noncovatently associated with human cytoplasmic RNA, is the target of antibodies in 25-40% of lupus patients. Purified human 60-kDa Ro was found to be oxidatively modified. Earlier investigations from our laboratory revealed increased oxidative damage in SLE patients. Therefore we hypothesized that oxidation by-products, Such as 4-hydroxy-2-nonenal (HNE), Could lead to neoantigens like HNE-modified 60-kDa RO, Which Could in turn initiate autoimmunity or drive epitope spreading. To test this hypothesis we immunized rabbits with either HNE-modified 60-kDa Ro Or the unmodified Ro. Intramolecular epitope spreading within the Ro molecule and intermolecular epitope spreading to La, double-stranded DNA, nRNP, and Sin occurred preferentially in HNE-Ro-imminized animals. Nonspecific anti-FINE antibody, generated by immunization with HNE-keyhole limpet hemocyanin conjugate, did not significantly bind to these autoantigens. These data May suggest a hitherto unappreciated mechanism by which oxidative stress facilitates epitope spreading in SLE. (C) 2004 Elsevier Inc. All rights reserved.