纤维蛋白衍生的瓜氨酸化肽β60-74Cit₆₀,₇₂,₇₄ 携带类风湿关节炎特异性抗瓜氨酸化纤维蛋白原自身抗体和抗-CCP2 抗体识别的主要 ACPA 表位。
The fibrin-derived citrullinated peptide β60-74Cit₆₀,₇₂,₇₄ bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies.
机构信息
, Epidermis Differentiation and Rheumatoid Autoimmunity' Laboratory, UMR CNRS 5165, INSERM U 1056, Toulouse III University, , Toulouse, France.
出版信息
Ann Rheum Dis. 2014 Jun;73(6):1246-52. doi: 10.1136/annrheumdis-2012-202868. Epub 2013 May 1.
OBJECTIVES
To evaluate the proportions of rheumatoid arthritis (RA) sera containing anticitrullinated proteins autoantibodies (ACPA) reactive to α36-50Cit₃₈,₄₂ and/or β60-74Cit₆₀,₇₂,₇₄, two peptides identified as bearing the immunodominant epitopes of their major target, citrullinated fibrin. To analyse the relationships of anti-α36-50Cit₃₈,₄₂ and anti-β60-74Cit₆₀,₇₂,₇₄ autoantibodies with autoantibodies reactive to the complete citrullinated human fibrinogen molecule (AhFibA) and with anti-CCP2 antibodies.
METHODS
617 sera from 181 patients with established RA and 436 with non-RA rheumatic diseases were tested by ELISA for AhFibA, anti-CCP2, anti-α36-50Cit₃₈,₄₂, anti-β60-74Cit₆₀,₇₂,₇₄ autoantibodies, and by nephelometry for rheumatoid factor (RF). Diagnostic indexes, correlations and concordances between tests were analysed. Crossreactivity of anti-α36-50Cit₃₈,₄₂ and anti-β60-74Cit₆₀,₇₂,₇₄ autoantibodies was assessed in competition experiments.
RESULTS
At a diagnostic specificity of 95%, the diagnostic sensitivity of AhFibA (83%) was significantly higher than that of all other tests. The diagnostic sensitivity of anti-β60-74Cit₆₀,₇₂,₇₄ (71%) was significantly higher than that of anti-α36-50Cit₃₈,₄₂ autoantibodies (51%) but similar to that of anti-CCP2 (74%). Titres of RF, anti-α36-50Cit₃₈,₄₂ and anti-β60-74Cit₆₀,₇₂,₇₄ autoantibodies were weakly correlated with each other, whereas titres of anti-β60-74Cit₆₀,₇₂,₇₄ were strongly correlated with those of AhFibA (r=0.633) and anti-CCP2 (r=0.634). Anti-α36-50Cit₃₈,₄₂ and anti-β60-74Cit₆₀,₇₂,₇₄ mainly corresponded to two non-crossreactive subfamilies of ACPA. More than 90% of AhFibA-positive or anti-CCP2-positive sera recognised the α36-50Cit₃₈,₄₂ and/or the β60-74Cit₆₀,₇₂,₇₄ peptide.
CONCLUSIONS
Autoantibodies reactive to α36-50Cit₃₈,₄₂ and β60-74Cit₆₀,₇₂,₇₄ form two distinct, non-overlapping subfamilies of ACPA that, together, cover practically all the ACPA reactivity to citrullinated fibrinogen and to CCP2 antigens. In established RA, anti-β60-74Cit₆₀,₇₂,₇₄ autoantibodies show diagnostic indexes similar to those of anti-CCP2.
目的
评估类风湿关节炎（RA）血清中含有抗瓜氨酸化蛋白自身抗体（ACPA）的比例，这些抗体可与两种肽段反应，即α36-50Cit₃₈，₄₂和β60-74Cit₆₀，₇₂，₇₄，这两种肽段被鉴定为其主要靶标瓜氨酸化纤维蛋白的免疫显性表位。分析抗α36-50Cit₃₈，₄₂和抗β60-74Cit₆₀，₇₂，₇₄自身抗体与针对完整瓜氨酸化人纤维蛋白原分子（AhFibA）的自身抗体以及抗 CCP2 抗体的关系。
方法
使用 ELISA 法检测 181 例确诊 RA 患者和 436 例非 RA 风湿性疾病患者血清中的 AhFibA、抗 CCP2、抗α36-50Cit₃₈，₄₂、抗β60-74Cit₆₀，₇₂，₇₄自身抗体，用散射比浊法检测类风湿因子（RF）。分析检测指标的诊断指数、相关性和一致性。在竞争实验中评估抗α36-50Cit₃₈，₄₂和抗β60-74Cit₆₀，₇₂，₇₄自身抗体的交叉反应性。
结果
在特异性为 95%的情况下，AhFibA（83%）的诊断敏感性显著高于其他所有检测。抗β60-74Cit₆₀，₇₂，₇₄（71%）的诊断敏感性显著高于抗α36-50Cit₃₈，₄₂自身抗体（51%），但与抗 CCP2（74%）相似。RF、抗α36-50Cit₃₈，₄₂和抗β60-74Cit₆₀，₇₂，₇₄自身抗体的滴度相互弱相关，而抗β60-74Cit₆₀，₇₂，₇₄的滴度与 AhFibA（r=0.633）和抗 CCP2（r=0.634）的滴度强相关。抗α36-50Cit₃₈，₄₂和抗β60-74Cit₆₀，₇₂，₇₄主要对应于 ACPA 的两个非交叉反应亚家族。超过 90%的 AhFibA 阳性或抗 CCP2 阳性血清识别 α36-50Cit₃₈，₄₂和/或 β60-74Cit₆₀，₇₂，₇₄肽。
结论
与α36-50Cit₃₈，₄₂和β60-74Cit₆₀，₇₂，₇₄反应的自身抗体形成了两个独特的、不重叠的 ACPA 亚家族，它们共同涵盖了针对瓜氨酸化纤维蛋白原和 CCP2 抗原的几乎所有 ACPA 反应性。在确诊的 RA 中，抗β60-74Cit₆₀，₇₂，₇₄自身抗体的诊断指数与抗 CCP2 相似。
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