In the rat, citrullinated autologous fibrinogen is immunogenic but the induced autoimmune response is not arthritogenic
In the rat, citrullinated autologous fibrinogen is immunogenic but the induced autoimmune response is not arthritogenic
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DOI：
10.1111/j.1365-2249.2006.03168.x
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发表时间：
2006-09-01
影响因子：
4.6
通讯作者：
Sebbag, M.
中科院分区：
文献类型：
--
作者：
Duplan, V.;Foulquier, C.;Sebbag, M.
精氨酸基到瓜氨酸基的转化(瓜氨酸化)对于类风湿性关节炎(RA)相关的瓜氨酸蛋白(ACPA)自身抗体识别的表位的形成至关重要。ACPA是由类风湿滑膜组织的浆细胞分泌的，在那里它们的主要靶标瓜氨酸纤维蛋白含量很高。尽管众多的论据表明ACPA在RA中起着重要作用，但它们的病理相关性仍有待确定。在本研究中，我们评估了完全弗氏佐剂乳化的自体瓜氨酸纤维蛋白原(C-rFBG)和非瓜氨酸纤维蛋白原(NC-rFBG)对Lewis(LEW)和Brown-挪威大鼠的免疫原性和关节炎原性，这两种大鼠对诱导性自身免疫性疾病的易感性存在显著差异。NC-rFBG不能诱导抗体反应。相比之下，单次注射C-rFBG可诱导主要针对rFBG的瓜氨酸决定簇的免疫球蛋白反应。然而，直到接种C-rFBG后3个月，所有品系的大鼠都没有关节炎的临床和组织学迹象。接下来，在卢大鼠身上，我们测试了对C-rFBG的自身免疫是否会加重关节内注射不完全弗氏佐剂(IFA)引发的急性脚踝关节炎。然而，在存在或不存在抗C-rFBG自身抗体的情况下，这种关节炎的演变是相同的。然而，注射IFA的关节没有瓜氨酸纤维蛋白沉积。因此，瓜氨酸可以破坏免疫耐受性，但产生的自身免疫反应不是自发的关节炎。它是否可以通过瓜氨酸纤维蛋白沉积来加重关节炎还有待评估。
Conversion of arginyl to citrullyl residues (citrullination) is essential for the formation of the epitopes recognized by rheumatoid arthritis (RA)-associated autoantibodies to citrullinated proteins (ACPA). ACPA are secreted by plasma cells of the rheumatoid synovial tissue where their major target, citrullinated fibrin, is abundant. Although numerous arguments suggest that ACPA play an important role in RA, their pathological relevance remains to be established. In the present study, we assessed the immunogenicity and arthritogenicity of complete Freund's adjuvant-emulsified autologous citrullinated (C-rFBG) or non-citrullinated (NC-rFBG) fibrinogen in Lewis (LEW) and Brown-Norway rats, which exhibit drastic differences in their susceptibility to induced autoimmune diseases. NC-rFBG induced no antibody response. In contrast, a single injection of C-rFBG induced an IgG response directed mainly to citrullinated determinants of rFBG. However, all rat strains remained devoid of clinical and histological signs of arthritis up to 3 months after C-rFBG inoculation. Next, in LEW rats, we tested whether autoimmunity to C-rFBG could aggravate acute ankle arthritis triggered by intra-articular injection of incomplete Freund's adjuvant (IFA). However, such arthritis evolved identically in the presence or absence of anti-C-rFBG autoantibodies. However, IFA-injected joints were devoid of citrullinated fibrin deposits. Therefore, citrullination allows breakdown of immunological tolerance but the autoimmune response developed is not spontaneously arthritogenic. Whether or not it can aggravate arthritis with citrullinated fibrin deposits remains to be evaluated.