Genetic analysis of murine spondyloarthropathy

描述(申请人提供)：慢性脊柱炎是强直性脊柱炎(AS)的主要异常，该疾病仅在美国就影响了70多万人。尽管对AS的病因知之甚少，但在这种情况下，环境和遗传因素是关键的风险因素。到目前为止，已知的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12个染色体区域与AS有关。为了研究这种疾病的遗传学和病理生理学，我们建立了一种小鼠模型，其中脊柱炎是通过蛋白多糖(蛋白多糖诱导的脊柱炎，PGIs)系统免疫诱导的。该模型是独一无二的，值得研究，因为自身免疫性脊柱炎受到非MHC基因的强烈遗传控制。在前期工作中，我们发现在允许的MHC背景下，只有位于18号染色体(Pgis1)和2号染色体(Pgis2)上的两个主要基因座共同控制疾病的易感性。重要的是，Pgis2主要控制脊柱炎症和炎性细胞浸润的初始阶段，而Pgis1主要负责椎间盘的吸收和强直。这两个基因座之间的相互作用是该病的一个基本特征，因为Pgis2是Pgis1基因完全外显所必需的。这两个基因座都与人类AS相关的染色体片段同源，并与许多人类自身免疫性疾病的小鼠模型有关。该应用将研究Pgis1和Pgis2易感基因已从DBA/2耐药株转移到BALB/c遗传背景的同源小鼠。将建立脊柱炎的发生和免疫位点特异性亚型。我们将通过连续的两阶段选择性表型方法来缩小基因座的大小。主要遗传因素的识别和脊柱炎发生和发展机制的发现将为自身免疫性疾病的发病机制提供重要的见解。

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.