Selected publications

• Wright C, Edelmann M, diGleria K, Kollnberger S, Kramer H, McGowan S, McHugh K, Taylor S, Kessler B, and Bowness P (2009) Ankylosing spondylitis monocytes show upregulation of proteins involved in inflammation and the ubiquitin proteasome pathway. Ann Rheum Dis, 68(10):1626-32.

• Chan Antoni, Filer Andrew, Parsonage Greg, Kollnberger Simon, Gundle Roger, Buckley Christopher D, and Bowness Paul (2008) Mediation of the proinflammatory cytokine response in rheumatoid arthritis and spondylarthritis by interactions between fibroblast-like synoviocytes and natural killer cells. Arthritis Rheum, 58(3):707-17.

• Chan Antoni, Hong Deng-Li, Atzberger Ann, Kollnberger Simon, Filer Andrew D, Buckley Christopher D, McMichael Andrew, Enver Tariq, and Bowness Paul (2007) CD56bright human NK cells differentiate into CD56dim cells: role of contact with peripheral fibroblasts. J Immunol, 179(1):89-94.

• Kollnberger Simon, Chan Antoni, Sun Mei-Yi, Chen Li Y, Wright Cynthia, di Gleria Kati, McMichael Andrew, and Bowness Paul (2007) Interaction of HLA-B27 homodimers with KIR3DL1 and KIR3DL2, unlike HLA-B27 heterotrimers, is independent of the sequence of bound peptide. Eur J Immunol, 37(5):1313-22.

• Kasprowicz V, Isa A, Jeffery K, Broliden K, Tolfvenstam T, Klenerman P, and Bowness P (2006) A highly restricted T-cell receptor dominates the CD8+ T-cell response to parvovirus B19 infection in HLA-A*2402-positive individuals. J Virol, 80(13):6697-701.

Paul Bowness

Introduction -  What is the role of HLA-B27 in the pathogenesis of spondyloarthritis?

Development of a number of common forms of inflammatory arthritis (the spondyloarthritides), which include Ankylosing Spondylitis is strongly associated with possession of the Human Leukocyte Antigen (HLA) class I allele HLA-B27.  We have previously studied the natural function of HLA-B27 at the molecular level, for example solving the crystal structures of HLA-B27 bound to short antigenic peptides derived for example from HIV, EBV and Influenza viruses. Despite extensive studies, the pathogenic role of HLA-B27 in the spondyloarthritides remains unknown. We hypothesize that the role of HLA-B27 in spondyloarthropathy stems from its function in antigen presentation, either in peptide selection and binding or in other aspects of its cell biology.  We first described the ability of HLA-B27 to form homodimers and have shown that these homodimers are present on the surface of spondyloarthritis patients’ cells as well as in B27 transgenic models of disease. We have defined a number of cellular receptors for B27 homodimers including KIR3DL2. Notably greatly increased numbers of T and NK cells from patients with spondyloarthritides express KIR3DL2.

Current work

1) The natural role of HLA-B27 in the immune system

We have refolded synthetic HLA-B27 complexes with beta 2 microglobulin and peptides in vitro and studied their structure in collaboration with Prof Yvonne Jones at WTCHG.  We have also established a collaboration with Dr Simon Powis in St Andrews to study trafficking of HLA-B27, and to determine what controls HLA-B27’s ability to present an Influenza peptide to HLA-B27-restricted Flu NP383-391-specifc T cells.

2) The role of HLA-B27 homodimers 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.  Mutagenesis has shown that disulphide bonding through the unpaired cysteine at position 67 is critical for cell surface homodimer formation.  We are currently investigating possible mechanisms by which HLA-B27 homodimers could be directly involved in disease pathogenesis.  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.  We are currently determining the molecular basis for this, in collaboration with Prof. Christoph Renner in Zurich and Dr Katsumi Maenaki in Fukuoka, Japan.  Lastly in collaboration with Dr Benedikt Kessler at CCMP, Oxford, Cynthia Wright is determining differences in the monocyte proteome in patients with AS compared to RA and healthy controls

3) Immune responses to parvovirus and their role in inflammatory arthritis

We have defined for the first time both CD8 and CD4 epitopes to human parvovirus and are studying the fine specificity of these.  We are looking for evidence of cross-reactivity and autoimmunity in adults with acute arthropathy following parvovirus infection, in collaboration with Prof. Paul Klenerman (Nuffield dept of Medicine).

Molecular model of HLA-B27 homodimer