Role of T Cells in Experimental Spondyloarthropathy

HLA-B27是一种人类I类MHC等位基因，在被称为脊椎关节病（SpA）的风湿病患者中发现的患病率显著增加。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，本身参与了SpA的发病机制。确定B27在SpA发病机制中的分子作用，将是对慢性特发性炎症性疾病发病机制认识的重大进展。我们已经为这种疾病开发了一种动物模型，即HLA-B27转基因大鼠。这些大鼠会自发患上一种疾病（rSpA），在许多基本方面与人类的SpA相似。我们之前已经证明这些大鼠的疾病依赖于T淋巴细胞。这项建议的重点是获得这些细胞在疾病过程中的作用的更清晰的图像。在Specific Aim I中，我们将尝试确定在B27转基因大鼠（rSpA）炎症性疾病的早期病变中是否存在T细胞受体（TCR）的低克隆性。需要验证的具体假设是，在rSpA大鼠中可以发现致病性抗原特异性T细胞的克隆扩增。在Specific Aim II中，我们将研究CD8 T细胞的消耗对HLA-B27转基因大鼠炎症性疾病的影响。在Specific Aim III中，我们将确定肽转运蛋白Tap2基因多态性是否会影响肽与HLA-B27和rSpA的结合。这些实验将直接检验Tap2a对B27肽库和疾病表现的影响。

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. We have developed an animal model for this disease, namely, rats transgenic for HLA-B27. These rats spontaneously develop a disease (rSpA) that in many essential ways resembles human SpA. We have previously shown that the disease in these rats is dependent upon T lymphocytes. The focus of this proposal is to gain a clearer picture of the role of these cells the disease process. In Specific Aim I, we will attempt to determine whether T cell receptor (TCR) oligoclonality is present in early lesions of the inflammatory disease in B27 transgenic rats (rSpA). The specific hypothesis to be tested is that clonal expansions of pathogenic antigen-specific T cells can be found in rats with rSpA. In Specific Aim II, we will investigate the effect of depletion of CD8 T cells on the inflammatory disease of HLA-B27 transgenic rats. In Specific Aim III, we will determine if there is an effect of a polymorphism in the gene for the peptide transporter Tap2 on peptide binding to HLA-B27 and on rSpA. These experiments will examine directly the effect of Tap2a on the B27 peptide repertoire and on disease manifestations.