Role of T Cells in Experimental Spondyloarthropathy

HLA-B27是一种人类I类MHC等位基因，在被称为脊柱关节病(SpA)的风湿性疾病患者中发现患病率显著增加。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。明确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。我们已经建立了一种针对这种疾病的动物模型，即人类白细胞抗原B27转基因大鼠。这些大鼠自发地患上一种疾病(RSPA)，这种疾病在许多基本方面与人类水疗相似。我们之前已经证明，这些大鼠的疾病依赖于T淋巴细胞。这项提议的重点是更清楚地了解这些细胞在疾病过程中的作用。在特定目的I中，我们将尝试确定T细胞受体(TCR)寡克隆是否存在于B27转基因大鼠(RSPA)炎症性疾病的早期病变中。需要检验的特定假设是，在患有RSPA的大鼠中，可以发现致病抗原特异性T细胞的克隆性扩张。在特定的目的II，我们将研究CD8T细胞耗尽在人类白细胞抗原B27转基因大鼠炎症疾病中的作用。在特定的目标III中，我们将确定多肽转运蛋白Tap2基因的多态性是否影响多肽与人类白细胞抗原B27和RSPA的结合。这些实验将直接检验Tap2a对B27多肽谱系和疾病表现的影响。

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.