Spondyloarthritides are a relatively common group of immune-mediated inflammatory diseases occurring in an estimated 0.5 to 1% of the population (1
). The prototypic form of disease, ankylosing spondylitis, represents approximately one third to one half of cases and exhibits a phenotype that can include axial and peripheral arthritis, gastrointestinal inflammation, inflammation where tendons and joint capsules insert on bone (enthesitis), and abnormal bone formation in the sacroiliac joints and ascending along the spine leading to ankylosis (2
). In 1973, two groups working independently reported a striking association between what we now know as human leukocyte antigen-B27 (HLA-B27) and ankylosing spondylitis. In a four-paragraph letter to Nature
, Caffrey and James (3
) wrote, ‘A study of human lymphocyte phenotypes in unrelated Caucasian individuals with ankylosing spondylitis has revealed a striking similarity in their antigenic pattern. The lymphocytes of fifty such patients, when tested against a panel of twenty-six different specific typing sera, using a two stage lymphocytotoxicity micro-method, were shown to have in common either the antigen HL-A27 (96%) or the antigen W5 (4%). This remarkably high frequency of the antigen HL-A27 compares with the incidence of 5–6% of this antigen in random Caucasian populations’. This report and two additional reports appearing a month later in The Lancet
) and The New England Journal of Medicine
) marked the beginning of an odyssey that has lasted for over three and a half decades as investigators have sought to explain how HLA-B27 contributes to disease. Peaks, valleys, and occasional detours have marked this journey, and it is not yet clear when it will end. Paralleling discoveries of the heterogeneity of HLA class I molecules and their function displaying peptides, it was first proposed that HLA-B27 was the target of autoreactive antibodies and then autoreactive T cells. More recently, considerable attention has been directed toward unusual features of this allele, including a tendency of the HLA-B27 heavy chain to misfold in the ER prior to assembly into complexes with peptide and β2
) and to form disulfide-linked homodimers after reaching the cell surface (8
). There is evidence that abnormal forms of HLA-B27 may be recognized by major histocompatibility complex (MHC) class I receptors on various leukocyte populations, which could play a role in disease (10
). Thus, these features evoke very different ideas about underlying pathogenic mechanisms, including the heretical concept that immunological recognition of HLA-B27 might not be necessary to cause disease if intracellular effects are paramount.
While HLA-B27 constitutes a large proportion of genetic susceptibility to ankylosing spondylitis (20–40%), it is now well recognized that this is a complex genetic disease, and HLA-B27 is only one of several genes determining predisposition and phenotype (12
). Technological advances that enable high throughput genotyping of single nucleotide polymorphisms (SNPs) have revolutionized the field of complex genetics and led to the identification of multiple risk alleles in diseases such as rheumatoid arthritis, lupus, and now ankylosing spondylitis (12
). These genome-wide association studies not only provide a more complete picture of genetic susceptibility to ankylosing spondylitis but should also begin to inform hypotheses about pathogenesis including where HLA-B27 fits in the puzzle. Despite this optimism, experience tells us that understanding the steps in the journey from genotype to phenotype will continue to be a major challenge in this and other complex genetic diseases.
The purpose of this review is to discuss unusual properties of HLA-B27 documented in the last decade, why they occur, and how they may be relevant to its role in disease in light of results from animal models as well as humans. Our focus will be on the concept of HLA-B27 misfolding and its consequences, including new data from transgenic rats suggesting how it may be linked to activation of the interleukin-23 (IL-23)/IL-17 axis and T-helper 17 (Th17) cells. We also identify, from our viewpoint, some of the key questions that need to be addressed.