SHPS-1 As a Regulator of Innate Immunity in Arthritis

描述(由申请人提供)： 这项R21申请是为了回应一项研究建议的请求，这些研究将发展出一项“了解先天免疫在自身免疫性风湿性疾病的病因中的作用”的研究，特别是与了解“疾病病因的早期事件”有关的研究。为此，我们联合了两种新的方法。我们研究的分子焦点是SHPS-1，这是一种主要在巨噬细胞系细胞上表达的调节性受体。SHPS-1调节天然免疫的激活和随之而来的获得性免疫的激活，以及白细胞的迁移和巨噬细胞形成破骨细胞。因此，SHPS-1在自身免疫发展的许多阶段都有可能调节天然免疫系统(巨噬细胞)和获得性免疫(淋巴细胞)之间的相互作用，但其在自身免疫中的作用尚未被研究过。我们建议通过研究一种新的类风湿性关节炎小鼠模型SKG小鼠来做到这一点，在这种模型中，关节炎的发展严重依赖于天然免疫系统的激活。我们的目标是建立和鉴定SHPS-1在SKG小鼠类风湿关节炎中的作用的3个模型。它们是： 1.用SHPS-1封闭型单抗体内治疗SKG小鼠。 2.SHPS-1胞浆结构域缺失的SKG小鼠。 3.不表达SHPS-1的SKG小鼠。 如果这些模型支持SHPS-1在调节关节炎中的作用，它们将提供极好的模型来剖析导致SKG小鼠类RA疾病的细胞相互作用。由于SHPS-1在人类中具有密切的同源性(Sirpal)，因此该结果可能直接应用于RA患者。

DESCRIPTION (provided by applicant): This R21 application is in response to a Request for Proposals for studies that will develop an "understanding of the role of innate immunity in the etiopathogenesis of autoimmune rheumatic diseases," with particular relevance to an understanding of "the earlier events of the etiopathogenesis of disease." To this end, we have united two new approaches. The molecular focus of our studies is SHPS-1, a regulatory receptor that is expressed primarily on cells of macrophage lineage. SHPS-1 regulates the activation of innate immunity and the consequent activation of adaptive immunity, as well as leukocyte migration and the formation of osteoclasts from macrophages. Thus, SHPS-1 has the potential to regulate the interactions between the innate immune system (macrophages) and adaptive immunity (lymphocytes) at many points in the development of autoimmunity, but its role in autoimmunity has not previously been studied. We propose to do so through the study of a new mouse model for rheumatoid arthritis, SKG mice, in which the development of arthritis is heavily dependent on activation of the innate immune system. Our goal is to develop and characterize 3 models in which the role of SHPS-1 in the RA-like disease of SKG mice can be studied. These are: 1. SKG mice treated in vivo with a blocking monoclonal antibody to SHPS-1. 2. SKG mice in which SHPS-1 lacks the cytoplasmic domain. 3. SKG mice in which SHPS-1 is not expressed at all. If these models support a role of SHPS-1 in the regulation of arthritis, they will provide excellent models to dissect the cellular interactions that elicit the RA-like disease in SKG mice. Because SHPS-1 has a close homologue in humans (SIRPal), the results may have direct application to patients with RA.