The 2000 Michael Mason prize essay - HLA B27 in health and disease: a double-edged sword?

The strong association of the HLA class 1 allele HLA B27 with ankylosing spondylitis (AS) has been recognized for over 25 yr, however the pathogenic mechanism linking HLA B27 with AS and other spondyloarthropathies remains a mystery. We now know that the principal natural function of HLA B27 is an immunologic one, namely to bind antigenic peptides and then present them to T lymphocytes. I have shown that HLA B27 functions as an excellent antigen molecule in both spondyloarthropathy patients and healthy individuals. A working molecular model of how T cells recognize HLA B27 has been generated and tested. Evidence that T cells have a role in spondyloarthritis has also been found. First, expanded populations of T lymphocytes were found in both the blood and synovial fluid of patients with reactive arthritis (ReA). Secondly, a strong cytotoxic T-cell response to an HLA B27-restricted peptide epitope from Chlamydia trachomatis was found in a patient with ReA. This peptide, derived from a bacterium known to trigger ReA, is thus a candidate 'arthritogenic' peptide. We have also found evidence that HLA B27 has an unusual cell biology compared with other HLA molecules. HLA B27 demonstrates an unusual ability to form heavy chain homodimers in vitro. Dimerization is dependent upon disulphide bonding through an unpaired cysteine at position 67. Remarkably these dimers lack beta2 microglobulin, previously thought to be an essential component of all mature MHC class 1 molecules. HLA B27 homodimer formation has also been demonstrated in certain cell lines in vivo, and preliminary data suggest that significant numbers of T cells from patients with spondyloarthropathy express a ligand for HLA 27 homodimers. These findings have extended our understanding of the beneficial immunologic function of HLA B27, and have also led us to propose the testable new hypothesis that HLA B27 heavy chain dimerization may be involved in the pathogenesis of spondyloarthritis.