Arthritogenic Igs

描述(申请人提供)：类风湿性关节炎(RA)是一种慢性进行性自身免疫性疾病，主要累及滑膜关节。其病因和发病机制仍存在争议。K/BxN小鼠提供了一种RA的行为模型，它自发地发展出一种与人类疾病有惊人相似之处的疾病(尽管也有一些不同)。在这个模型中，疾病的发展依赖于T和B细胞对糖酵解酶葡萄糖-6-磷酸异构酶或GPI的联合反应。来自关节炎K/BxN小鼠的血清或抗GPI抗体(Abs)可以快速、有力和反复地将关节炎转移到健康的受者身上。该系统在解剖最终导致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有GPI的免疫复合体。在这些发现的基础上，构建了能够解释该模型的关节特异性的致病情景。 在这项相互竞争的续期申请中，将实现三个具体目标： 1.对K/BxN血清转移性关节炎中补体网络中未被开发或未被开发的元件的作用进行评估。 2.整合了抗GPI诱导的关节炎的关键分子和细胞需求，重点放在中性粒细胞功能上。 3.探讨K/BxN病与人类类风湿关节炎的相关性。 这些实验的结果应该从两个角度被证明是重要的：首先，它们将提供对K/BxN关节炎过程中发挥作用的终末效应机制的更深层次的理解。其次，它们将允许对K/BxN和人类关节炎之间的关系进行更有见地的评估。

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.