The enigmatic role of HLA-B*27 in spondyloarthritis pathogenesis.

Abstract

Establishing a clear role for HLA-B*27 in the pathogenesis of spondyloarthritis continues to be challenging. Aberrant properties of the heavy chain as well as a potential role presenting arthritogenic peptides continue to be pursued as plausible mechanisms. Recent studies implicate HLA-B*27 in aberrant bone formation. An unanticipated cell surface interaction between HLA-B*27 and the bone morphogenetic protein pathway receptor subunit ALK2 may augment TGFβ superfamily signaling pathways, increasing responsiveness to Activin A and TGFβ. This has the potential to increase bone formation as well as Th17 T cell development, presenting an attractive model to explain several aspects of axial and peripheral spondyloarthritis. In a separate study, intracellular effects of misfolded HLA-B*27 implicate this mechanism in increased osteoblast mineralization and bone formation. HLA-B*27 expression in early osteoblasts activates unfolded protein response-mediated X-box binding protein-1 mRNA splicing and induction of the retinoic acid receptor-β gene, with downstream increases in expression of tissue non-specific alkaline phosphatase. Increased TNAP expression in osteoblasts was linked to increased mineralization in vitro and bone formation in vivo. In the ongoing search for evidence of arthritogenic peptides, high-throughput TCR (T cell receptor) sequencing has provided evidence for reduced clonal expansion and increased TCR diversity in ankylosing spondylitis. In addition to two common CD8+ TCR sequences identified in one study, similar CD8 and CD4 TCR motifs were found in another study. Further work will be needed to shed light on the nature of the peptide-HLA class I complex recognized by these T cells and its role in disease.