Functional effects of antibodies to collagen on cartilage synthesis and degradation

已有研究表明，在早期类风湿关节炎患者中，约70%的患者软骨中存在抗II型胶原抗体，提示软骨胶原自身免疫可能在这一破坏性关节炎的发生发展中起一定作用。一种被广泛用作人类类风湿关节炎模型的动物模型是胶原性关节炎(CIA)。它是通过用II型胶原免疫小鼠而诱导的；II型胶原抗体对CIA的发展至关重要。然而，并不是所有这些抗体都与疾病相关。在胶原蛋白分子上可能有特定的区域，在那里抗体结合会导致损伤。该项目基于一种假设，即可转移小鼠关节炎的II型胶原抗体是那些与胶原纤维区域发生特异性反应的抗体，这些区域对软骨的稳定性和功能至关重要。我们计划使用培养的软骨在体外系统中验证这一假设。根据我们的初步数据，我们预测，来自CIA小鼠的II型胶原抗体将干扰软骨的正常组装和结构。我们将通过在精确定义的条件下向培养的软骨添加抗体，并分析合成的基质来测试这一点。然后，这项研究将扩展到类风湿关节炎，比较II型胶原与鼠源性和人源性抗体反应的区域。显示II型胶原抗体具有直接破坏性，从而了解其作用部位和作用方式，将极大地促进我们对类风湿关节炎病因的理解，并将导致更有效的治疗形式。

It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early rheumatoid arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of this destructive arthritis. An animal model widely used as a model of human RA is the disease collagen induced arthritis (CIA). It is induced by immunisation of mice with collagen II; antibodies to collagen II are critical for the development of CIA. However not all such antibodies are disease-associated. There may be particular regions on the collagen molecule where antibody-binding causes damage. This project is based on the hypothesis that antibodies to collagen type II, which transfer arthritis in mice, are those that react specifically with regions of the collagen fibrils that are crucial for cartilage stability and function. We plan to test this hypothesis in an in vitro system using cultured cartilage. We predict, based on our preliminary data, that antibodies to collagen II from mice with CIA will interfere with the normal assembly and structure of cartilage. We will test this by adding antibodies under precisely defined conditions to cultured cartilage, and analysing the matrix that is synthesised. The study would then be extended to RA with a comparison of the regions of collagen II that react with antibodies of mouse and human origin. Showing that antibodies to collagen II are directly destructive, allowing for an understanding of their site and mode of action, would greatly advance our understanding of the cause of RA and would lead to more effective forms of treatment.