The role of HLA-B27 homodimers in disease pathogenesis
We are currently investigating possible mechanisms by which HLA-B27 homodimers could be directly involved in disease pathogenesis.
We have observed that HLA-B27 heavy chains can form stable homodimers lacking ß2m, both in vitro and in vivo. These homodimers are expressed at the cell surface.
Tetrameric complexes of HLA-B27 homodimers bind to Natural Killer and related immunoreceptors on populations of lymphocytes, monocytes and natural killer cells from patients with spondyloarthritis. Patients with AS express increased numbers of one of these receptors (KIR3DL2) on their blood and joint Natural Killer cells and CD4 T lymphocytes. Much of this work is carried out in close collaboration with Dr Simon Kollnberger within NDORMS.
We are currently determining the specificity of a panel of B27 dimer-specitfic monoclonal antibodies (mAbs) generated from a phage display library in collaboration with Professor Christoph Renner in Zurich. The antibodies will enable us to monitor for the presence of homodimers on different cell types in patients and through blocking studies will lead to better functional characterization of the interaction between B27 homodimer and KIR3DL2. Such reagents might ultimately be suitable for clinical therapeutic trial.
Funded by Arthritis Research UK.