Presence and Role of AntiCitrullinated Protein Antibodies in Experimental Arthritis Models
Presence and Role of AntiCitrullinated Protein Antibodies in Experimental Arthritis Models
复制标题
DOI：
10.1002/art.37839
复制
发表时间：
2013-04-01
影响因子：
--
通讯作者：
Baeten, Dominique
中科院分区：
文献类型：
--
作者：
Cantaert, Tineke;Teitsma, Christine;Baeten, Dominique
目的抗瓜氨酸蛋白抗体（ACPAs）是类风湿关节炎的血清学标志。关于ACPAs在实验性关节炎中作用的功能研究产生了相互矛盾的结果，因此，本研究旨在系统地评估瓜氨酸化蛋白是否真的能诱导ACPAs并调节小鼠关节炎。方法用天然或瓜氨酸化纤维蛋白原、髓鞘碱性蛋白（MBP）和II型胶原（CII）免疫Balb/c、SJL和DBA/1小鼠。ACPAs检测与肽为基础的酶联免疫吸附试验（ELISA）和蛋白质印迹法使用纤维蛋白原作为底物。通过用弗氏完全佐剂中的CII免疫或通过注射抗胶原抗体在小鼠中诱导关节炎。结果瓜氨酸肽ELISA法检测瓜氨酸蛋白免疫小鼠血清呈假阳性。相比之下，使用瓜氨酸化或天然纤维蛋白原作为底物的蛋白质印迹分析可靠地检测瓜氨酸化纤维蛋白原、MBP和CII免疫的Balb/c小鼠中的ACPA。然而，这些ACPA在抗胶原抗体诱导的关节炎模型中不能诱导或加重Balb/c小鼠的疾病。瓜氨酸纤维蛋白原免疫诱导ACPA，但不会导致SJL和DBA/1小鼠关节炎的发生。相比之下，瓜氨酸化CII的免疫接种未能诱导ACPA或在胶原诱导的关节炎模型中增强这些菌株的疾病。结论小鼠可以产生真正的ACPAs，但ACPAs的检测高度依赖于菌株、免疫原、免疫方案和检测方法。鼠ACPA不是明显的致病性，因为既不存在ACPA也不使用瓜氨酸化胶原作为免疫原调节关节炎的临床过程。
Objective Anticitrullinated protein antibodies (ACPAs) are the serologic hallmark of rheumatoid arthritis. Functional studies on the role of ACPAs in experimental arthritis have yielded conflicting results, and therefore the present study was undertaken to assess systematically whether citrullinated proteins can really induce ACPAs and modulate arthritis in mice. Methods Balb/c, SJL, and DBA/1 mice were immunized with either native or citrullinated fibrinogen, myelin basic protein (MBP), and type II collagen (CII). ACPAs were detected with a peptide-based enzyme-linked immunosorbent assay (ELISA) and with Western blotting using fibrinogen as substrate. Arthritis was induced in mice by immunization with CII in Freund's complete adjuvant or by injection of anticollagen antibodies. Results Analysis of the sera of mice immunized with citrullinated proteins revealed false-positive results with the citrulline peptidebased ELISA. In contrast, Western blot analysis using either citrullinated or native fibrinogen as substrate reliably detected ACPAs in Balb/c mice immunized with citrullinated fibrinogen, MBP, and CII. However, these ACPAs failed to induce or aggravate disease in Balb/c mice in the anticollagen antibodyinduced arthritis model. Immunization with citrullinated fibrinogen induced ACPAs but did not lead to arthritis development in SJL and DBA/1 mice. In contrast, immunization with citrullinated CII failed to induce ACPAs or enhance disease in these strains in the collagen-induced arthritis model. Conclusion Mice can develop genuine ACPAs, but detection of ACPAs is highly dependent on strain, immunogen, immunization protocol, and detection assay. Murine ACPAs are not overtly pathogenic, since neither preexisting ACPAs nor the use of citrullinated collagen as immunogen modulates the clinical course of arthritis.