The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues.
The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues.
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DOI：
10.4049/jimmunol.162.1.585
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发表时间：
1999-01
影响因子：
4.4
通讯作者：
E. Girbal-Neuhauser;Jean‐Jacques Durieux;M. Arnaud;P. Dalbon;M. Sebbag;C. Vincent;M. Simon;T. Senshu;C. Masson-Bessière;C. Jolivet‐Reynaud;M. Jolivet;G. Serre
中科院分区：
文献类型：
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作者：
E. Girbal-Neuhauser;Jean‐Jacques Durieux;M. Arnaud;P. Dalbon;M. Sebbag;C. Vincent;M. Simon;T. Senshu;C. Masson-Bessière;C. Jolivet‐Reynaud;M. Jolivet;G. Serre
抗微丝蛋白自身抗体(AFA)是一组与类风湿关节炎(RA)相关的免疫球蛋白自身抗体，包括所谓的抗角蛋白抗体和抗核周围因子。AFA是RA最特异的血清学标志物。我们以前发现它们识别人类表皮微丝蛋白和其他各种上皮组织的Profilaggrin相关蛋白。在这里，我们报告了AFA靶向的蛋白AGS和表位的进一步表征。所有表现出大量中性/酸性等电变异体的AGS都被免疫化学证明是去亚胺蛋白。在体外，用肽基精氨酸脱亚胺酶对重组人微丝蛋白进行脱亚胺，在蛋白质上产生AFA表位。此外，从一系列RA血清中提纯的三个丝状蛋白衍生的合成肽中，有两个被AFA亲和识别并广泛识别。这些结果表明，瓜氨酸残基是AFA表位的组成部分，但仅在微丝蛋白的特定氨基酸序列的背景下。在竞争实验中，这两个肽取消了RA血清的AFA反应性，表明它们呈现主要的AFA表位。这些数据将有助于确定一种假定的去亚胺的AFA诱导或交叉反应的关节自身抗原，并为RA的发病机制提供新的见解。它们还可以为RA的特异性免疫抑制和/或预防性治疗开辟道路。
Antifilaggrin autoantibodies (AFA) are a population of IgG autoantibodies associated to rheumatoid arthritis (RA), which includes the so-called "antikeratin" Abs and antiperinuclear factor. AFA are the most specific serological markers of RA. We previously showed that they recognize human epidermal filaggrin and other profilaggrin-related proteins of various epithelial tissues. Here, we report further characterization of the protein Ags and epitopes targeted by AFA. All the Ags that exhibit numerous neutral/ acidic isoelectric variants were immunochemically demonstrated to be deiminated proteins. In vitro deimination of a recombinant human filaggrin by a peptidylarginine deiminase generated AFA epitopes on the protein. Moreover, two of three filaggrin-derived synthetic peptides with a citrulline in the central position were specifically and widely recognized by AFA affinity-purified from a series of RA sera. These results indicate that citrulline residues are constitutive of the AFA epitopes, but only in the context of specific amino acid sequences of filaggrin. In competition experiments, the two peptides abolished the AFA reactivity of RA sera, showing that they present major AFA epitopes. These data should help in the identification of a putative deiminated AFA-inducing or cross-reactive articular autoantigen and provide new insights into the pathogenesis of RA. They could also open the way toward specific immunosuppressive and/or preventive therapy of RA.