The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the α- and β-chains of fibrin
The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the α- and β-chains of fibrin
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DOI：
10.4049/jimmunol.166.6.4177
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发表时间：
2001-03-15
影响因子：
4.4
通讯作者：
Serre, G
中科院分区：
文献类型：
--
作者：
Masson-Bessière, C;Sebbag, M;Serre, G
IgG 抗聚丝蛋白自身抗体 (AFA) 是类风湿关节炎最特异的血清学标志物。在上皮组织中，它们识别存在于各种分子形式的（原）聚丝蛋白上的带有瓜氨酸的表位。用瓜氨酸抗体对类风湿滑膜进行组织学分析，显示间质无定形沉积物和各种类型的单核细胞的标记。对相同组织的详尽连续提取物进行的免疫化学分析表明，它们含有几种脱亚胺化（含瓜氨酸）蛋白质。其中，存在于尿素 DTT 和胍提取物中的两种蛋白质 p64-78 和 p55-61 通过免疫印迹显示是 AFA 特异性靶向的。通过氨基末端测序，这些蛋白质分别被鉴定为纤维蛋白 α 链和 β 链的脱亚胺化形式。使用几种针对 A α 和/或 此外，AFA 阳性类风湿性关节炎 (RA) 血清和纯化的 AFA 仅在通过肽基精氨酸脱亚氨酶对分子进行脱亚胺后才与人纤维蛋白原的 A α 和 B β 链高度反应，从 RA 血清池中亲和纯化到脱亚胺纤维蛋白原上的自身抗体是 对 AFA 的所有上皮和滑膜靶点均有反应，这证实了纤维蛋白原脱亚氨基 A α 和 B β 链的自身抗体、滑膜蛋白 p64-78 和 p55-61 的自身抗体以及最后的 AFA 构成了很大程度上重叠的自身抗体群体。这些结果表明，沉积在类风湿滑膜中的脱亚胺形式的纤维蛋白是 AFA 的主要靶标，这表明针对脱亚胺纤维蛋白的自身免疫是 RA 发病机制中的关键步骤。
IgG antifilaggrin autoantibodies (AFA) are the most specific serological markers of rheumatoid arthritis. In epithelial tissues, they recognize citrulline-bearing epitopes present on various molecular forms of (pro)filaggrin. Histological analysis of rheumatoid synovial membranes with an Ab to citrulline showed labeling of interstitial amorphous deposits and mononuclear cells of various types. Immunochemical analysis of exhaustive sequential extracts of the same tissues showed that they contain several deiminated (citrulline containing) proteins. Among them, two proteins, p64-78 and p55-61, present in urea-DTT and guanidine extracts, were shown by immunoblotting to be specifically targeted by AFA, By amino-terminal sequencing the proteins were identified as deiminated forms of the alpha- and beta -chains of fibrin, respectively, Their identity was confirmed using several Abs specific for the A alpha -and/or to the B beta -chain of fibrin(ogen), Moreover, AFA-positive rheumatoid arthritis (RA) sera and purified AFA were highly reactive to the A alpha- and B beta -chains of human fibrinogen only after deimination of the molecules by a peptidylarginine deiminase, Autoantibodies affinity purified from a pool of RA sera onto deiminated fibrinogen were reactive toward all of the epithelial and synovial targets of AFA, This confirmed that the autoantibodies to the deiminated A alpha -and B beta -chains of fibrinogen, the autoantibodies to the synovial proteins p64-78 and p55-61, and, lastly, AFA, constitute largely overlapping autoantibody populations. These results show that deiminated forms of fibrin deposited in the rheumatoid synovial membranes are the major target of AFA, They suggest that autoimmunization against deiminated fibrin is a critical step in RA pathogenesis.