Genetic analysis of murine spondyloarthropathy

描述（由申请人提供）：慢性脊柱炎症是强直性脊柱炎（AS）的主要异常，仅在美国就有70多万人患有这种疾病。虽然AS的病因是知之甚少，环境和遗传成分是关键的危险因素，在这种情况下。迄今为止，已知最强的遗传风险因素是主要组织相容性复合体（MHC），而对非MHC基因的了解要少得多，尽管已知有十几个染色体区域与AS有关。为了研究该疾病的遗传学和病理生理学，我们开发了一种小鼠模型，其中脊柱炎是通过用蛋白聚糖全身免疫诱导的（蛋白聚糖诱导的脊柱炎，PGIS）。该模型是独特的，值得研究，因为自身免疫性脊柱炎是在强大的非MHC基因的遗传控制。在初步工作中，我们已经发现，在允许的MHC背景下，只有位于染色体18（Pgis 1）和2（Pgis 2）上的两个主要基因座共同控制疾病易感性。重要的是，Pgis 2主要控制脊柱炎症和炎性细胞浸润的初始阶段，Pgis 1主要负责椎间盘吸收和关节强直。这两个基因座之间的相互作用是该疾病的基本特征，因为Pgis 2是Pgis 1基因座的完全缺失所必需的。这两个基因座同源的染色体片段连接到人类AS和牵连在一些人类自身免疫性疾病的小鼠模型。本申请将研究其中Pgis 1和Pgis 2易感基因座已从DBA/2抗性品系转移到BALB/c遗传背景的同类小鼠。将确定脊柱炎的发展和免疫学位点特异性亚表型。我们将通过连续两阶段选择性表型分析方法缩小基因座的大小。确定主要的遗传因素和发现的机制，启动和发展的脊椎炎，将提供重要的见解，自身免疫性疾病的发病机制。

DESCRIPTION (provided by applicant): Chronic spine inflammation is the major abnormality in ankylosing spondylitis (AS), the disease that affects more than 700,000 people only in USA. Although the AS etiology is poorly understood, environmental and genetic components are critical risk factors in this scenario. To date, the strongest known genetic risk factor is the major histocompatibility complex (MHC) and much less is known about non-MHC genes, despite a dozen chromosome regions known to be linked to AS. To study the genetics and pathophysiology of the disease, we have developed a murine model, where the spondylitis is induced by systemic immunization with proteoglycan (proteoglycan-induced spondylitis, PGIS). The model is unique and worthy of study because autoimmune spondylitis is under strong genetic control of non-MHC genes. In preliminary work we have found that on a permissive MHC background only two major loci located on chromosomes 18 (Pgisl) and 2 (Pgis2) jointly control disease susceptibility. Importantly, Pgis2 mainly controls the initial phase of spine inflammation and inflammatory cells infiltration, and Pgisl is primarily responsible for disks resorption and ankylosis. Interaction between these two loci is an essential feature of the disease, since Pgis2 is required for the full penetrance of the Pgisl locus. Both loci were homologous to chromosome segments linked to human AS and were implicated in a number of murine models for human autoimmune diseases. The application will study congenic mice in which Pgisl and Pgis2 susceptibility loci have been transferred from the DBA/2 resistant strain to BALB/c genetic background. Development of spondylitis and immunological loci-specific subphenotypes will be established. We will narrow the size of loci by a sequential two-stage selective phenotyping approach. Identification of the primary genetic factors and discovery of the mechanism for initiation and progression of spondylitis should provide significant insights into the pathogenesis of autoimmune diseases.