Brink Mikael, Hansson Monika, Mathsson Linda, Jakobsson Per-Johan, Holmdahl Rikard, Hallmans Göran, Stenlund Hans, Rönnelid Johan, Klareskog Lars, Rantapää-Dahlqvist Solbritt
Umeå University, Umeå, Sweden.
Arthritis Rheum. 2013 Apr;65(4):899-910. doi: 10.1002/art.37835.
The presence of antibodies against cyclic citrullinated peptides has been demonstrated to precede the onset of symptoms of rheumatoid arthritis (RA) by several years. The aim of this study was to analyze antibodies against 10 citrullinated autoantigen-derived peptides for reactivity before the onset of RA symptoms.
A case-control study was conducted within the Medical Biobank of Northern Sweden. The study was performed in 409 individuals, 386 of whom donated 717 blood samples before the onset of symptoms of RA (pre-patients). The median period of time predating the onset of RA was 7.4 years. A total of 1,305 population-based control subjects were also studied. Antibodies to 10 citrullinated peptides, fibrinogen α573 (Fibα573), Fibα591, Fibβ36-52, Fibβ72, Fibβ74, α-enolase (citrullinated α-enolase peptide 1 [CEP-1]), triple-helical type II collagen peptide C1 (citC1III), filaggrin, vimentin 2-17 (Vim2-17), and Vim60-75, were analyzed using a microarray system.
The fluorescence intensity of antibodies against Fibβ36-52, Fibβ74, CEP-1, citC1III, and filaggrin was significantly increased in pre-patients compared with controls (P<0.001). The levels of the earliest-detectable antibodies (Fibα591 and Vim60-75) fluctuated over time, with only a slight increase after the onset of disease. The frequency of antibodies against Fibβ36-52, CEP-1, and filaggrin increased gradually, reaching the highest levels before symptom onset. The frequency of a cluster of antibodies, citC1III, Fibα573, and Fibβ74, increased only slightly before the onset of symptoms but increased prominently after disease onset. The odds ratio for the development of RA in individuals expressing both CEP-1 and Fibβ36-52 antibodies (using data from samples obtained <3.35 years predating symptom onset) was 40.4 (95% confidence interval 19.8-82.3) compared with having either antibody alone.
Development of an immune response toward citrullinated peptides is initially restricted but expands with time to induce a more specific response, with levels, particularly those of antibodies against CEP-1, Fibβ36-52, and filaggrin, increasing during the predating time period closer to the onset of symptoms.
抗环瓜氨酸肽抗体的存在已被证明比类风湿关节炎（RA）症状出现早数年。本研究的目的是分析针对10种瓜氨酸化自身抗原衍生肽的抗体在RA症状出现前的反应性。
在瑞典北部医学生物库内进行了一项病例对照研究。该研究纳入409名个体，其中386名在RA症状出现前（患者前期）捐献了717份血样。RA症状出现前的中位时间为7.4年。还研究了总共1305名基于人群的对照受试者。使用微阵列系统分析针对10种瓜氨酸化肽的抗体，即纤维蛋白原α573（Fibα573）、Fibα591、Fibβ36 - 52、Fibβ72、Fibβ74、α -烯醇化酶（瓜氨酸化α -烯醇化酶肽1 [CEP - 1]）、三螺旋II型胶原蛋白肽C1（citC1III）、丝聚蛋白、波形蛋白2 - 17（Vim2 - 17）和Vim60 - 75。
与对照组相比，患者前期针对Fibβ36 - 52、Fibβ74、CEP - 1、citC1III和丝聚蛋白的抗体荧光强度显著增加（P<0.001）。最早可检测到的抗体（Fibα591和Vim60 - 75）水平随时间波动，疾病发作后仅略有增加。针对Fibβ36 - 52、CEP - 1和丝聚蛋白的抗体频率逐渐增加，在症状出现前达到最高水平。一组抗体citC1III、Fibα573和Fibβ74的频率在症状出现前仅略有增加，但在疾病发作后显著增加。与单独拥有任何一种抗体相比，同时表达CEP - 1和Fibβ36 - 52抗体的个体（使用症状出现前<3.35年获得的样本数据）发生RA的比值比为40.4（95%置信区间19.8 - 82.3）。
对瓜氨酸化肽的免疫反应最初受到限制，但随时间扩展以诱导更特异性的反应，其水平，特别是针对CEP - 1、Fibβ36 - 52和丝聚蛋白的抗体水平，在接近症状出现的前期时间段内增加。
