Arthritogenic Igs

描述（由申请人提供）：类风湿性关节炎（RA）是一种针对滑膜关节的慢性进行性自身免疫性疾病。其病因和发病机制仍有争议。K/BxN小鼠提供了一种表现良好的RA模型，它自发地发展出一种与人类疾病惊人相似的疾病（尽管也有一些差异）。该模型中的疾病发展取决于T和B细胞对糖酵解酶葡萄糖-6-磷酸异构酶或GPI的反应性。来自关节炎K/BxN小鼠的血清或抗GPI抗体（Abs）可以快速、稳健和重复地将关节炎转移到健康受体中。该系统已经允许在剖析最终导致K/BxN关节炎的终末期效应器机制方面取得重大进展-涉及炎性细胞因子、有限的一组细胞类型、Fc受体和补体网络以及含GPI的免疫复合物。在这些研究结果的基础上，已经构建了一个能够解释该模型的联合特异性的发病机制。 在此竞争性续期申请中，将实现三个特定目标： 1.未探索或未充分探索的补体网络元件在K/BxN血清转移性关节炎中的作用评估 2.抗GPI诱导的关节炎的关键分子和细胞要求的整合，重点是中性粒细胞功能。 3.探索K/BxN疾病机制与人类RA的相关性。 这些实验的结果应该从两个方面证明是重要的：首先，它们将提供对K/BxN关节炎期间发挥作用的终末期效应机制的更深入理解。其次，它们将允许对K/BxN和人类关节炎之间的关系进行更明智的评估。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease directed at the synovial joints. Its etiology and pathogenesis remain controversial. A performant model of RA is provided by the K/BxN mouse, which spontaneously develops a disorder with striking similarities to the human one (though with some differences as well). Disease development in this model depends on combined T and B cell reactivity to the glycolytic enzyme glucose-6-phosphate isomerase, or GPI. Sera or anti-GPI antibodies (Abs) from arthritic K/BxN mice can rapidly, robustly and repeatedly transfer arthritis into healthy recipients. This system has permitted significant progress in dissecting the end-stage effector mechanisms that culminate in K/BxN arthritis - implicating inflammatory cytokines, a limited set of cell types, both Fc receptors and the complement network, and GPI-containing immune complexes. On the basis of these findings, a pathogenetic scenario capable of accounting for the joint specificity of this model has been constructed. In this competing renewal application, three Specific Aims will be undertaken: 1. An assessment of the roles of un- or under-explored elements of the complement network in K/BxN serum-transferred arthritis. 2. An integration of the key molecular and cellular requirements for anti-GPI-induced arthritis, with a focus on neutrophil functions. 3. An exploration of the relevance of K/BxN disease mechanisms to human RA. Results from these experiments should prove important from two perspectives: First, they will provide a deeper understanding of the end-stage effector mechanisms that come into play during K/BxN arthritis. Second, they will allow a more informed assessment of the relationship between K/BxN and human arthritis.