The expression patterns of non-classical and classical forms of HLA-B27 in spondyloarthritis

The strong association of the human leukocyte antigen HLA-B27 (B27), with spondyloarthropathies (SpA), was discovered more than four decades ago, yet the role B27 plays in disease pathogenesis remains unclear. It has been demonstrated that HLA-B27 can form non-classical FHC forms, including B27 FHC homodimers (B272) and misfolded FHCs. Two leading theories of SpA pathogenesis proposed that both cell surface NC-B27 (the B27 homodimer theory) and intracellular (the B27 misfolding and UPR theory) can drive immune responses in SpA. Several studies demonstrated that cell surface NC-B27 binds to immune receptors and suggested that these interactions can activate Th17 immunity. My DPhil project focuses on the investigation of the cell surface expression of NC-B27 molecules in cells and tissues obtained from AS patients and B27 TG2 rats. I used both existing reagents and a novel HD6 antibody, generated against B272, to examine the expression of HLA-B27 by flow cytometry, confocal microscopy and immunoprecipitation. This thesis provides evidence that the expression of HD6- and HC10-reactive molecules in AS patients is rather restricted to specific cell types (e.g. osteoclasts) and possibly particular environmental factors and tissue types (e.g. synovial fluid and joint tissue). My data using B27 TG2 rats demonstrated that resident joint cells express HD6- and HC10-reactive molecules before the onset of clinical manifestations. Furthermore, I showed increased expression of NC-B27 on antigen presenting cells (APCs), and CD161+ and CD8+ cell populations in blood and secondary lymphoid organs. Based on these findings I hypothesized that cell surface expression of NC-B27 may not only be crucial for activation of Th17-driven immune responses, but may also shift the balance between immune tolerance and activation. Importantly, the expression of potentially pathogenic HD6-reactive molecules is restricted to specific cell and tissue types hence HD6 antibody may be a potential future therapeutic agent in SpA