Spondyloarthritis and the Human Leukocyte Antigen (HLA)-B*27 Connection

Abstract

Heritability of Spondyloarthritis (SpA) is highlighted by several familial studies and a high association with the presence of human leukocyte antigen (HLA)-B^*27. Though it has been over four decades since the association of HLA-B^*27 with SpA was first determined, the pathophysiological roles played by specific HLA-B^*27 allotypes are not fully understood. Popular hypotheses include the presentation of arthritogenic peptides, triggering of endoplasmic reticulum (ER) stress by misfolded HLA-B^*27, and the interaction between free heavy chains or heavy chain homodimers of HLA-B^*27 and immune receptors to drive IL-17 responses. Several non-HLA susceptibility loci have also been identified for SpA, including endoplasmic reticulum aminopeptidases (ERAP) and those related to the IL-23/IL-17 axes. In this review, we summarize clinical aspects of SpA including known characteristics of gut inflammation, enthesitis and new bone formation and the existing models for understanding the association of HLA-B^*27 with disease pathogenesis. We also examine newer insights into the biology of HLA class I (HLA-I) proteins and their implications for expanding our understanding of HLA-B^*27 contributions to SpA pathogenesis.

Keywords: ER stress; ERAP1; HLA-B*27; IL-23/IL-17 axis; free heavy chain; spondyloarthritis.

Figure 1

Clinical manifestations of Spondyloarthritis. (A) Resolving recurrent acute anterior uveitis of right eye in a case of ankylosing spondylitis. Solid arrow: mild circum-corneal congestion. Arrowhead: posterior synechiae. (B) Dactylitis of third toe of the right foot in a case of Psoriatic arthritis. (C) Enthesitis involving the Achilles tendon in a case of ankylosing spondylitis. Solid arrow: retrocalcaneal bursitis, which co-occurs with Achilles enthesitis. Arrowhead: site of plantar fasciitis. (D) Keratoderma blennorrhagica involving the sole of a patient with Reactive arthritis. (E) Psoriasis (arrowhead) with deforming peripheral arthritis of hand joints. Solid arrow: arthritis and deformity of distal interphalangeal joint.

Figure 2

Possible roles of HLA-B*27 in the pathogenesis of AS. After transport into the ER by the transporter associated with antigen processing (TAP), peptides are assembled onto nascent MHC class I molecules by the peptide loading complex (PLC), comprising TAP, tapasin (Tpn) calreticulin (CRT) and ERp57, and further trimmed by ERAP. The presence of certain ERAP haplotypes results in a significantly decreased number of peptides optimal for HLA-B*27, leading to accumulation of misfolded proteins in the ER or expression of sub-optimally or neoantigen-loaded HLA-B*27 on the cell surface. Neoantigen loaded HLA-B*27 on the cell surface could induce activation of CD8⁺ T cells. Protein misfolding in the ER can cause ER stress and activation of the unfolded protein response (UPR) to induce IL-23 secretion. IL-23 further activates the IL-23/IL-17 axis. On the other hand, free heavy chains or disulfide bond-linked homodimers of HLA-B*27 can be formed and expressed on the cell surface during HLA-B*27 recycling via the endocytic pathway. Engagement of these aberrant species by KIR3DL2 on the surface of Th17 cells is known to enhance their survival, proliferation, and IL-17 expression. IL-17 can promote the release of proinflammatory cytokines to establish inflammation.