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RA的高性能模型，该模型自发地发展出一种与人类惊人相似的疾病（尽管也有一些差异）。该模型中的疾病发展取决于T细胞和B细胞对糖酵解酶葡萄糖-6-磷酸异构酶（GPI）的联合反应性。来自关节炎K/BxN小鼠的血清或抗gpi抗体（Abs）可以快速、稳健和反复地将关节炎转移到健康受体。该系统在分析最终导致K/BxN关节炎的终末期效应机制方面取得了重大进展-涉及炎症细胞因子，一组有限的细胞类型，Fc受体和补体网络，以及含有gpi的免疫复合物。在这些发现的基础上，已经构建了一个能够解释该模型的联合特异性的发病情景。

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.