Cantaert T, Coucke P, De Rycke L, Veys E M, De Keyser F, Baeten D
Department of Rheumatology, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium.
Ann Rheum Dis. 2005 Sep;64(9):1316-20. doi: 10.1136/ard.2004.033548. Epub 2005 Mar 10.
Haplotypes of PADI4, encoding for a citrullinating enzyme, were associated with rheumatoid arthritis in a Japanese population. It was suggested they were related to the presence of anticitrullinated protein antibodies (ACPA).
To explore the relation between PADI4 haplotypes, the presence of rheumatoid arthritis specific intracellular citrullinated proteins in synovial membrane, and serum ACPA titres.
Synovial biopsies and peripheral blood samples were obtained in 59 patients with rheumatoid arthritis. Synovial intracellular citrullinated proteins were detected by immunohistochemistry. Serum ACPA titres were measured by anti-CCP2 ELISA. PADI4 haplotypes were determined by direct sequencing of the four exonic PADI4 single nucleotide polymorphisms.
PADI4 haplotype frequencies and the presence of synovial intracellular citrullinated proteins and ACPA were comparable with previous studies. There was no significant association between PADI4 haplotype 1 or 2 and the presence of synovial intracellular citrullinated proteins, although these proteins were associated with higher serum ACPA. There was no correlation between PADI4 haplotypes and serum ACPA, either by continuous analysis using the titres or by dichotomous analysis using the diagnostic cut off. Further analyses in homozygotes for haplotype 1 or 2 or in heterozygotes (1/2) also failed to show an association between PADI4 polymorphisms and ACPA. This contrasted with the clear association between ACPA levels and HLA-DR shared epitope.
The link between synovial intracellular citrullinated proteins and ACPA emphasises the role of deimination of synovial proteins in rheumatoid arthritis, but the biological relevance of the PADI4 haplotypes for this autoimmune process is questionable, at least in a European population.
编码瓜氨酸化酶的肽基脯氨酰异构酶4（PADI4）单倍型与日本人群的类风湿关节炎相关。有研究提示它们与抗瓜氨酸化蛋白抗体（ACPA）的存在有关。
探讨PADI4单倍型、滑膜中类风湿关节炎特异性细胞内瓜氨酸化蛋白的存在与血清ACPA滴度之间的关系。
收集59例类风湿关节炎患者的滑膜活检组织和外周血样本。通过免疫组织化学检测滑膜细胞内瓜氨酸化蛋白。采用抗环瓜氨酸肽2（anti-CCP2）酶联免疫吸附测定（ELISA）法检测血清ACPA滴度。通过对PADI4四个外显子单核苷酸多态性进行直接测序来确定PADI4单倍型。
PADI4单倍型频率以及滑膜细胞内瓜氨酸化蛋白和ACPA的存在情况与先前研究相当。PADI4单倍型1或2与滑膜细胞内瓜氨酸化蛋白的存在之间无显著关联，尽管这些蛋白与较高的血清ACPA水平相关。无论是使用滴度进行连续分析还是使用诊断临界值进行二分法分析，PADI4单倍型与血清ACPA之间均无相关性。对单倍型1或2的纯合子或杂合子（1/2）进行的进一步分析也未能显示PADI4多态性与ACPA之间存在关联。这与ACPA水平和人类白细胞抗原-DR（HLA-DR）共享表位之间的明确关联形成对比。
滑膜细胞内瓜氨酸化蛋白与ACPA之间的联系强调了滑膜蛋白瓜氨酸化在类风湿关节炎中的作用，但PADI4单倍型在这一自身免疫过程中的生物学相关性值得怀疑，至少在欧洲人群中是这样。
