Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins
Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins
复制标题
DOI：
10.1002/eji.200535790
复制
发表时间：
2006-08-01
影响因子：
5.4
通讯作者：
Serre, Guy
中科院分区：
文献类型：
--
作者：
Sebbag, Mireille;Moinard, Nathalie;Serre, Guy
类风湿性关节炎(RA)特异性抗瓜氨酸蛋白(ACPA)自身抗体识别的表位的形成需要将其精氨酸残基转化为瓜氨酸残基，但也受其氨基酰环境的影响。通过与五个含主要ACPA表位的瓜氨酸微丝蛋白衍生多肽的竞争，我们证实了微丝蛋白和瓜氨酸纤维蛋白之间存在密切的交叉反应。为了确定ACPA识别的纤维蛋白上的序列表位，用对5种微丝蛋白具有不同反应性的ACPA阳性RA血清，用ELISA法检测了71个含有精氨酸残基的纤维蛋白α链和β链上所有位置的瓜氨酸化15聚体多肽。我们鉴定了18个含有ACPA表位的纤维蛋白衍生肽。关于纤维蛋白原精氨酸残基在体外被瓜氨酸化的能力，其中11个多肽可能对应于体内的靶向表位。其中两个带有主要表位，位于蛋白质的中心球状结构域。在滑膜组织中，纤维蛋白瓜氨酸化和ACPA结合可抑制纤溶酶对纤维蛋白的降解。因此，ACPA和纤维蛋白之间的免疫冲突不仅可以通过促炎效应机制维持滑膜炎症，还可以通过损害纤溶作用来维持滑膜炎症。
Formation of the epitopes recognized by the rheumatoid arthritis (RA)-specific autoantibodies to citrullinated proteins (ACPA) on filaggrin and on the alpha- and beta-chains of fibrin, their synovial target, requires conversion of their arginyl residues into citrullyl residues, but is also affected by their amino-acyl environment. Using competition with five citrullinated filaggrin-derived peptides bearing major ACPA epitopes, we confirmed the close cross-reactivity between filaggrin and citrullinated fibrin. To identify the sequential epitopes recognized on fibrin by ACPA, 71 citrullinated 15-mer peptides derived from all the sites of the alpha- and beta-chains of fibrin harboring arginyl residues were tested by ELISA using ACPA-positive RA sera exhibiting different reactivity profiles to the five filaggrin peptides. We identified 18 fibrin-derived peptides bearing ACPA epitopes. Regarding the ability of fibrinogen arginyl residues to be citrullinated in vitro, 11 of the peptides likely correspond to in vivo targeted epitopes. Two out of them bear major epitopes and are located in the central globular domain of the protein. In the synovial tissue, fibrin citrullination and ACPA binding could impair fibrin degradation by plasmin. The immunological conflict between ACPA and fibrin could therefore sustain synovial inflammation not only via pro-inflammatory effector mechanisms but also via impairment of fibrinolysis.