Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis.
Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis.
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DOI：
10.1002/art.23596
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发表时间：
2008-07
影响因子：
--
通讯作者：
Rosen, Antony
中科院分区：
文献类型：
--
作者：
Harris, Michelle L.;Darrah, Erika;Lam, Gordon K.;Bartlett, Susan J.;Giles, Jon T.;Grant, Audrey V.;Gao, Peisong;Scott, William W., Jr.;El-Gabalawy, Hani;Casciola-Rosen, Livia;Barnes, Kathleen C.;Bathon, Joan M.;Rosen, Antony
蛋白质瓜氨酸化是类风湿性关节炎（RA）特异性自身抗体识别的一种重要翻译后修饰。瓜氨酸化酶之一，肽基精氨酸脱亚胺酶4型（PAD-4），在某些人群中与RA的发生有遗传相关性，尽管介导这种效应的机制尚不清楚。在不同的风湿性疾病中已经描述了抗PAD-4自身抗体。本研究旨在研究抗PAD-4抗体是否对RA具有特异性，是否与疾病表型或严重程度相关，以及PAD-4多态性是否影响抗PAD-4自身抗体应答。通过体外翻译的PAD-4的免疫沉淀法，测定来自已确诊RA患者、患有其他风湿性疾病的患者和健康成人的血清中的抗PAD-4自身抗体。使用各种PAD-4截短对PAD-4自身抗体识别的表位进行作图。用TaqMan法对RA患者进行PAD-4基因分型。使用Sharp/货车der Heijde方法对手部和足部X线片的关节侵蚀进行评分。PAD-4自身抗体在36-42%的RA患者中发现，在对照组中非常罕见。通过抗PAD-4自身抗体的识别需要119个N-末端氨基酸，其包括与疾病易感性相关的3个非同义多态性。引人注目的是，抗PAD-4免疫应答与PADI 4的RA易感性单倍型相关。抗PAD-4抗体与RA中更严重的关节破坏相关。我们的研究结果表明，抗PAD-4抗体是RA的特异性标志物，与更严重的疾病独立相关，这表明抗PAD-4免疫反应可能参与这种疾病的关节损伤途径。PADI 4基因的多态性影响对PAD-4蛋白的免疫应答，可能导致疾病传播。
Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)–specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti–PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti–PAD-4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD-4 polymorphisms influence the anti–PAD-4 autoantibody response. Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti–PAD-4 autoantibodies by immunoprecipitation of in vitro–translated PAD-4. The epitope(s) recognized by PAD-4 autoantibodies were mapped using various PAD-4 truncations. PAD-4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method. PAD-4 autoantibodies were found in 36–42% of RA patients, and were very infrequent in controls. Recognition by anti–PAD-4 autoantibodies required the 119 N-terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti–PAD-4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti–PAD-4 antibodies were associated with more severe joint destruction in RA. Our findings indicate that anti–PAD-4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti–PAD-4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation.
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影响因子：
4.9
作者：
Hoppe B;Häupl T;Gruber R;Kiesewetter H;Burmester GR;Salama A;Dörner T
通讯作者：
Dörner T
影响因子：
158.5
作者：
Edwards, JCW;Szczepanski, L;Shaw, T
通讯作者：
Shaw, T
影响因子：
--
作者：
Barton, A;Bowes, J;Worthington, J
通讯作者：
Worthington, J
影响因子：
5.5
作者：
Harney, SMJ;Meisel, C;Brown, MA
通讯作者：
Brown, MA
影响因子：
158.5
作者：
Genovese, MC;Becker, J;Dougados, M
通讯作者：
Dougados, M