Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease
Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease
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DOI：
10.1038/90696
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发表时间：
2001-08-01
影响因子：
30.5
通讯作者：
Ditzel, HJ
中科院分区：
文献类型：
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作者：
Schaller, M;Burton, DR;Ditzel, HJ
在K/BxN T细胞受体转基因小鼠中，自发性炎性关节炎表现出许多人类类风湿关节炎(RA)的特征，由T细胞启动，但几乎完全由自身抗原葡萄糖-6-磷酸异构酶(GPI)抗体维持。这些观察结果与人类疾病的相关性受到了质疑。在这里，我们发现%的RA患者，而不是对照组，血清和滑液中抗GPI免疫球蛋白G(Ig G)浓度升高。此外，RA患者血清和滑液中的可溶性GPI浓度也升高，从而导致免疫复合体的形成。利用噬菌体展示技术，从一例类风湿关节炎患者体内克隆了一组高亲和力的人源性抗GPI抗体。这些抗体是高度体细胞突变的，这表明是由抗原驱动的亲和力成熟的反应。RA滑膜免疫组织化学显示滑膜衬里表面和小动脉内皮细胞表面均有较高浓度的GPI表达，提示抗GPI抗体可诱发关节病变。结果表明，在K/BxN小鼠模型中导致自身免疫性疾病发生的免疫事件也可能发生在人类RA中。这些数据可能被用来开发新的治疗干预策略。
In K/BxN T cell receptor-transgenic mice, spontaneous inflammatory arthritis exhibiting many of the features of human rheumatoid arthritis (RA) is initiated by T cells, but is almost entirely sustained by antibodies to the self-antigen glucose-6-phosphate isomerase (GPI). The relevance of these observations to human disease has been questioned. Here we show that 64% of humans with RA, but not controls, had increased concentrations of anti-GPI immunoglobulin G (IgG) in serum and synovial fluid. In addition, the concentrations of soluble GPI in the sera and synovial fluids of RA patients were also elevated, which led to immune complex formation. Using phage-display methods, we cloned a panel of specific high-affinity human monoclonal anti-GPI IgGs from a patient with RA. These antibodies were highly somatically mutated, which was indicative of an affinity-matured response that was antigen driven. Immunohistochemistry of RA synovium showed high concentrations of GPI on the surface of the synovial lining and on the endothelial cell surface of arterioles; this indicated a mechanism by which antibodies to GPI may precipitate joint disease. The results indicate that the immunological events that lead to the development of autoimmune disease in the K/BxN mouse model may also occur in human RA. This data may be used to develop new strategies for therapeutic intervention.