Antibodies to Several Citrullinated Antigens Are Enriched in the Joints of Rheumatoid Arthritis Patients
Antibodies to Several Citrullinated Antigens Are Enriched in the Joints of Rheumatoid Arthritis Patients
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DOI：
10.1002/art.25036
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发表时间：
2010-01-01
影响因子：
--
通讯作者：
Malmstrom, Vivianne
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文献类型：
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作者：
Snir, Omri;Widhe, Mona;Malmstrom, Vivianne
Objective.高滴度的特异性抗瓜氨酸化蛋白抗体（ACPA）经常存在于类风湿性关节炎（RA）患者的血清中，但其在滑液中的存在特征不太清楚。本研究的目的是比较血清和滑液中4种明确的瓜氨酸化候选RA自身抗原的抗体水平，并确定一种瓜氨酸化抗原的抗体是否优于另一种瓜氨酸化抗原。此外，我们研究了它们与突变的瓜氨酸波形蛋白（MCV）的关系，一种新发现的RA特异性血清测定，以及定义明确的HLA-DR组滑液中的经典环瓜氨酸肽（CCP）。分析了290名RA患者的配对血清和滑液样本以及100名年龄和性别匹配的健康对照的血清样本中是否存在抗MCV和抗CCP抗体，以及对瓜氨酸纤维蛋白原、α-烯醇化酶、II型胶原蛋白的反应性。和波形蛋白。共对290例患者中的219例进行了HLA-DR共有表位等位基因的基因分型。与血清相比，在滑液中发现了针对所有RA相关瓜氨酸化抗原的抗体比例显著更高。MCV和CCP反应也是如此，但非RA相关的抗破伤风类毒素抗体不是如此。正如预期的那样，我们发现瓜氨酸化波形蛋白和MCV反应之间存在高度相关性。所有滑液ACPA主要与HLA-DRB 1 *04等位基因相关，且仅限于CCP+/MCV+患者亚群。MCV和CCP阳性代表RA患者的相似子集，而具有不同精细特异性的ACPA属于抗CCP +/抗MCV+患者亚组。所有特定ACPA的水平在滑液中升高，表明在RA易感基因控制的炎症部位存在局部抗体产生和/或ACPA保留。
Objective. High titers of specific anti-citrullinated protein antibodies (ACPAs) are frequently present in the serum of rheumatoid arthritis (RA) patients, but their presence in synovial fluid is less well characterized. The purpose of this study was to compare the levels of antibody to 4 well-defined citrullinated candidate RA autoantigens in serum and synovial fluid and to determine whether antibodies to one citrullinated antigen are dominant over another. Furthermore, we studied their relationships with mutated citrullinated vimentin (MCV), a newly identified RA-specific serum assay, and the classic cyclic citrullinated peptide (CCP) in the synovial fluid of well-defined HLA-DR groups.Methods. Paired serum and synovial fluid samples from 290 RA patients and serum samples from 100 age-and sex-matched healthy controls were analyzed for the presence of anti-MCV and anti-CCP antibodies and for reactivity to citrullinated fibrinogen, alpha-enolase, type II collagen, and vimentin. A total of 219 of the 290 patients were genotyped for the HLA-DR shared epitope alleles.Results. Significantly higher proportions of antibodies against all RA-associated citrullinated antigens were found in synovial fluid as compared with serum. This was also true for the MCV and CCP responses but not for non-RA-associated anti-tetanus toxoid antibodies. As expected, we found a high correlation between citrullinated vimentin and MCV responses. All synovial fluid ACPAs were predominantly associated with HLA-DRB1*04 alleles and were confined to the CCP+/MCV+ subset of patients.Conclusion. MCV and CCP positivity represent a similar subset of RA patients, whereas ACPAs with different fine specificities fall into subgroups of anti-CCP+/anti-MCV+ patients. The levels of all specific ACPAs were elevated in synovial fluid, suggesting that there is local antibody production and/or retention of ACPAs at the site of inflammation governed by RA-predisposing genes.