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.
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