HLA-B27 and Experimental Spondyloarthropathy

描述（由申请人提供）：IMHC类等位基因HLA-B27在强直性脊柱炎及相关疾病（脊柱炎，SpA）患者中具有很高的患病率。已知B27，通常是一种正常的免疫成分，它本身参与SpA，但它是如何参与的尚不清楚。SpA还与炎症性肠病（IBD）和细胞内细菌感染有关。我们的目标是确定B27是如何引起SpA和慢性炎症的。在这个项目中，这个目标将在动物模型中实现。具有高转基因拷贝数和表达的B27转基因大鼠会自发地患上一种类似于人类SpA的疾病（大鼠SpA），患有关节炎和结肠炎，而具有低B27基因或具有高另一等位基因HLA-B7转基因含量的基因相同的大鼠则保持健康。无菌B27大鼠保持健康。与人类SpA一样，rSpA对抗tnf治疗有反应。已知在人类细胞系和B27大鼠中，B27重链在白细胞内质网内发生错误折叠，触发未折叠蛋白反应（UPR）并产生B27重链低聚物。在Specific Aim I中，我们将验证B27的这种错误折叠和/或UPR过程参与rSpA发病机制的假设。几个可能的机制，这将通过各种生物化学和遗传方法进行研究。将测试B27本身或随后的UPR:[1]是否会改变toll样受体或ibd相关Nod2蛋白的细菌感知；[2]触发一种或多种导致树突状细胞功能障碍的通路；[3]改变细胞内细菌入侵激活的途径；[4]引起关键细胞不适当凋亡；[5]引起p2微球蛋白沉积，随后引起关节炎。所有这些发现都将与各种转基因系的临床结果相关联。在Specific Aim II中，经典假设将被检验疾病是由B27的肽呈递引起的。最近产生的CDS零突变体的大鼠将与B27大鼠杂交，以评估干扰MHC i类T细胞识别对rSpA的影响。在两个特定目的的发现之后，将通过实验产生更多相关的转基因和敲除大鼠。总的来说，该项目将对解决HLA-B27和先天免疫在慢性炎症疾病中的作用的几个重要问题作出重大贡献。

DESCRIPTION (provided by applicant): The class IMHC allele HLA-B27 is found with high prevalence in patients with ankylosing spondylitis and related diseases (spondyloarthritis, SpA). It is known that B27, ordinarily a normal immune component, itself participates in SpA, but how it does so is unknown. SpA is also associated with inflammatory bowel disease (IBD), and with intracellular bacterial infection. Our goal is to identify how B27 causes SpA and chronic inflammation. In this project this goal will be pursued in an animal model. B27 transgenic rats with a high transgene copy number and expression spontaneously develop a disease (rat SpA) that resembles human SpA, with arthritis and colitis, whereas genetically identical rats with low B27, or with high transgene content of another allele, HLA-B7, remain healthy. Germfree B27 rats remain healthy. Like human SpA, rSpA responds to anti-TNF therapy. It is known that in human cell lines and in the B27 rats that B27 heavy chain undergoes misfolding within the endoplasmic reticulum of leukocytes, triggering the unfolded protein response (UPR) and creating B27 heavy chain oligomers. In Specific Aim I, the hypothesis will be tested that this misfolding and/or UPR process of B27 participates in the pathogenesis of rSpA. Several possible mechanisms for this will be investigated through a variety of biochemical and genetic approaches. It will be tested whether B27 itself, or the subsequent UPR: [1] alters bacterial sensing by Toll-like receptors or the IBD-associated Nod2 protein; [2] triggers one or more pathways that cause dysfunction of dendritic cells; [3] alters the pathways activated by intracellular bacterial invasion; [4] cause inappropriate apoptosis of critical cells; [5] causes deposition of p2-microglobuin and subsequent arthritis. All of these findings will be correlated with the clinical outcome in the various transgenic lines. In Specific Aim II, the classical hypothesis will be tested that disease results from peptide presentation by B27. Rats with a recently produced CDS null mutant will be crossed with B27 rats to assess the effect on rSpA of interfering with T cell recognition of MHC class I. Findings in both specific aims will be followed up by experiments to produce additional relevant transgenic and knockout rats. Overall, the project should contribute substantially to resolving several important issues about the role of HLA-B27 and innate immunity in chronic inflammatory disease.