ROLE OF HLA-B27 IN EXPERIMENTAL SPONDYLOARTHROPATHY

HLA-B27是人类I类MHC等位基因，其在被称为脊柱关节病（SpA）的风湿性疾病患者中的患病率显著增加。 有令人信服的证据表明，B27分子，通常是免疫系统的正常组成部分，本身参与SPA的发病机制。 明确B27在SpA发病机制中的分子作用将是理解慢性特发性炎症性疾病发病机制的重要进展。 本申请描述了一个项目，其中B27在SpA中的作用将在动物模型，即HLA-B27转基因大鼠中进行研究。 这些大鼠自发地发展出一种在许多基本方面类似于人类SpA的疾病（rSpA）。 重点将放在B27转基因大鼠品系之间的比较，开发rSpA和其他品系的相同的近交系，不。 这两种类型的品系之间的唯一遗传差异是B27转基因的拷贝数和B27的表达水平。 关于B27在SpA中的作用的一个有吸引力的假设是，它以启动或放大致病性免疫应答的方式向CD 8 T细胞呈递一种或多种肽，这一作用与B27的生理功能有关。 然而，最近的研究表明，与其他HLA I类分子相比，B27在人类中有时可能在其生物合成中表现出不寻常的行为。据推测，这种不寻常的行为可能是SpA发病机制的一个关键特征。 在本项目中，这些假设将在B27转基因大鼠品系中进行检验。 在具体目标I中，将详细比较易患病品系和抗病品系中B27合成和降解的生物化学。 在特异性目标II中，将使用一种敏感的方法结合溶细胞T细胞，HPLC和质谱法来寻找由B27特异性地在疾病易感系中呈递的肽。 在Specific Aim III中，将应用一种基于MHC和肽特异性识别和纯化CD 8 T细胞的新方法，使用Specific Aim II的肽信息，以识别疾病易感系中的潜在致病性T细胞。 这些研究的结果应该提供大量的新信息B27在疾病发病机制中的作用。 如果该机制涉及疾病相关肽，这些研究可能会识别它们。 如果没有，这些研究应该有助于确立这一事实，并确定B27生物学的各个方面，这些方面是其致病作用的基础。

HLA-B27 is a human class I MHC allele that is found with strikingly increased prevalence in patients with the rheumatic diseases termed spondyloarthropathies (SpA). There is persuasive evidence that the B27 molecule, ordinarily a normal component of the immune system, itself participates in the pathogenesis of SPA. It would represent a significant advance in the understanding of the pathogenesis of chronic idiopathic inflammatory diseases to identify the molecular role of B27 in the pathogenesis of SpA. This application describes a project in which the role of B27 in SpA will be studied in an animal model, namely, rats transgenic for HLA-B27. These rats spontaneously develop a disease (rSpA) that in many essential ways resembles human SpA. The focus will be on comparisons between lines of B27 transgenic rats that develop rSpA and other lines of the same inbred strains that do not. The only genetic difference between these two types of lines is the number of copies of the B27 transgene and the level of expression of B27. One attractive hypothesis for the role of B27 in SpA is that it presents one or more peptides to CD8 T cells in a manner that initiates or amplifies a pathogenic immune response, a role that is related to the physiologic function of B27. However, it has recently been shown that B27 in humans may sometimes exhibit unusual behavior in its biosynthesis, compared with other HLA class I molecules. It has been hypothesized that this unusual behavior may be a key feature to SpA pathogenesis. In this project, these hypotheses will be tested in the lines of rats transgenic for B27. In Specific Aim I, the biochemistry of B27 synthesis and degradation in the disease-prone and disease-resistant lines will be compared in detail. In Specific Aim II, a sensitive approach combining cytolytic T cells, HPLC, and mass spectrometry will be used to look for peptides presented by B27 specifically in the disease-prone lines. In Specific Aim III, a new methodology for identifying and purifying CD8 T cells on the basis of MHC and peptide specificity will be applied, using the peptide information of Specific Aim II, to identify potentially pathogenic T cells in disease-prone lines. The results of these studies should provide substantial new information regarding the role of B27 in disease pathogenesis. If the mechanism involves disease-associated peptides, these studies are likely to identify them. If not, these studies should help establish this fact and identify the aspects of B27 biology that underlie its pathogenic role.