Role of Non-Conventional HLA-B27 in the Pathogenesis of Spondyloarthritis

The strong association between human leukocyte antigen-B27 (HLA-B27) and increased risk for ankylosing spondylitis (AS) and other related spondyloarthritis (SpA) diseases has been known for several decades. However, the role of HLA-B27 in AS pathogenesis and disease progression has yet to be fully elucidated.  

Non-conventional HLA-B27 free heavy chains (NC-B27) have been described to bind innate immune receptors. NC-B27 is expressed prior to the onset of arthritis in transgenic animal models of arthritis. It is also known that non-conventional HLA class I molecules are expressed in joint and gut tissues from patients with SpA. These observations led researchers to suspect that NC-B27 may play a role in the pathogenesis of HLA-B27 in AS.

Oliqia Rysnik, MD, from the University of Oxford in Oxford, UK, and colleagues examined potentially pathogenic NC-B27 expression in synovial and intestinal samples taken from SpA patients. NC-B27 expression was measured with 2 monoclonal antibodies, HC10 and HD6, both of which have overlapping specificities. HC10 antibodies bind to free heavy chain forms of HLA-B and HLA-C alleles, while HD6 displays greater specificity for B2 homodimers.

Using immunohistochemistry, flow cytometry, and confocal microscopy techniques, researchers showed that NC-B27 is expressed in the synovium and small intestine of HLA-B27+ patients diagnosed with SpA. They also found high levels of NC-B27 expressed in inflamed joint tissue isolated from HLA-B27 transgenic rats. Furthermore, NC-B27 expression on splenic and lymph node CD11b/c⁺, CD8α⁺ cells increased with arthritic disease progression.

Samples from both human subjects with SpA and B27 transgenic rats also demonstrated positive HC10 staining of the intimal layers of synovial tissue and of the inflammatory cell infiltrates/lymphoid follicles. 

“Whilst HC10 staining was also observed in synovial tissue from [rheumatoid arthritis] patients, staining of synovial intimal and sublining layers was specific to B27+ SpA patients… [suggesting] that resident or infiltrating cells in the intimal and sublining layers of the synovium could play a role in the arthritis of SpA patients,” the authors stated.

Summary and Clinical Applicability

NC-B27 molecules were expressed in cells derived from the joints and gastrointestinal tract of humans with SpA, as well as in joints from a rat model of SpA.

“Based upon our findings we propose a model in which cell surface expression of NC-B27 is a key factor in initiating or more likely exacerbating joint and gut inflammation in SpA,” the authors concluded.

Limitations and Disclosures

The data did not differentiate between NC-B27 expression in resident cells as opposed to infiltrating cells.

No authors disclosed potential conflicts of interest. The study was supported by grants from the Oxford National Institute of Health Research Biomedical Research Center and the Oxford NIHR Biomedical Research Unit.

Reference

Rysnik O, Mchugh K, Van duivenvoorde L, et al. Non-conventional forms of HLA-B27 are expressed in spondyloarthritis joints and gut tissue. J Autoimmun. 2016;  [Epub ahead of print] March 29, 2016. doi: 10.1016/j.jaut.2016.03.009.