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.
| Tran, Tri Minh; Satumtira, Nimman; Dorris, Martha L et al. (2004) HLA-B27 in transgenic rats forms disulfide-linked heavy chain oligomers and multimers that bind to the chaperone BiP. J Immunol 172:5110-9 |
| May, Ekkehard; Dorris, Martha L; Satumtira, Nimman et al. (2003) CD8 alpha beta T cells are not essential to the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats. J Immunol 170:1099-105 |
