Novel Autoantigens Associated with Lupus Nephritis.
Novel Autoantigens Associated with Lupus Nephritis.
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DOI：
10.1371/journal.pone.0126564
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hasegawa H
中科院分区：
文献类型：
--
作者：
Onishi S;Adnan E;Ishizaki J;Miyazaki T;Tanaka Y;Matsumoto T;Suemori K;Shudou M;Okura T;Takeda H;Sawasaki T;Yasukawa M;Hasegawa H
系统性红斑狼疮(SLE)的特点是产生多种自身抗体。虽然抗双链DNA抗体在狼疮性肾炎(LN)的发病机制中起作用，但它们不足以诊断和评估疾病的活动性。为了获得与LN相关的其他自身抗体，我们使用从小麦无细胞蛋白生产系统创建的N-末端生物素化蛋白文库来筛选与LN患者血清反应的自身抗原。筛选出活动期SLE患者血清中阳性信号高于静止期、SLE肾炎患者血清中阳性信号高于非肾炎患者血清中阳性信号的蛋白质共17个。其中，核糖体RNA处理蛋白8(RRP8)和精子细胞核转移蛋白1(TNP1)是LN相关自身抗原。循环中的抗RRP8和抗TNP1自身抗体被识别并沉积在肾小球中作为免疫复合体(IC)。在注射RRP8或TNP1的C57BL/6小鼠中，IC优先沉积在肾小球而不是其他器官。各种风湿病患者血清中RRP8和TNP1的反应率分别为20%和14.7%，而其他风湿病患者RRP8和TNP1的反应率很低或为零。在SLE患者中，LN患者抗RRP8和抗TNP1抗体阳性率分别为63.6%和45.5%，而非肾炎组分别为12.5%和9.4%。这两种蛋白质都是阳离子的，它们各自的抗体都不与dsDNA发生交叉反应。这些从凋亡细胞中释放的蛋白质与每个自身抗体形成ICs，其ICs可能被困在肾小球基底膜的阴离子位置，导致肾小球沉积。这些自身抗体可能有助于预测抗dsDNA抗体阴性的SLE患者亚群的LN。
Systemic lupus erythematosus (SLE) is characterized by production of a variety of autoantibodies. Although anti-double-stranded DNA (anti-dsDNA) antibodies contribute to the pathogenesis of lupus nephritis (LN), they are not sufficient for diagnosis and evaluation of disease activity. To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system. We screened 17 proteins that showed higher positive signals in the active phase than in the inactive phase of SLE, and higher positive signals in the serum of SLE patient with nephritis than in that of patient without nephritis. Of these, two LN-associated autoantigens, ribosomal RNA-processing protein 8 (RRP8) and spermatid nuclear transition protein 1 (TNP1) were identified by immunoprecipitation and immunofluorescence of renal tissues. Circulating anti-RRP8 and anti-TNP1 autoantibodies were recognized and deposited as an immune complex (IC) in glomeruli. IC was deposited preferentially in glomeruli rather than in other organs in C57BL/6 mice injected with RRP8 or TNP1. ELISA analysis of sera from patients with various rheumatic diseases demonstrated reactivity for RRP8 and TNP1 in 20% and 14.7% of SLE patients, respectively, whereas there was little or no reactivity in patients with other rheumatic diseases. Among SLE patients, 63.6% and 45.5% of those with LN were positive for anti-RRP8 and anti-TNP1 antibodies, compared with 12.5% and 9.4% of SLE patients without nephritis, respectively. Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA. These proteins released from apoptotic cells form ICs with each autoantibody, and their ICs may become trapped at anionic sites in the glomerular basement membrane, leading to deposition in glomeruli. These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.
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