Predisposing factors in the Spondyloarthropathies: New insights into the role of HLA-B27

Abstract

Spondyloarthropathies represent complex genetic diseases whose development is influenced by environmental factors. Estimates suggest that three to nine loci may be responsible for the majority of the genetic susceptibility to ankylosing spondylitis. The only susceptibility locus identified to date in multiple populations is HLA-B, where several HLA-B27 alleles (subtypes) are strongly associated with disease. Recent evidence implicates cytochrome P450 2D6 as a second locus, although its influence on overall risk appears small. Despite considerable efforts to define how HLA-B27 contributes to disease, its role remains enigmatic. Increasing evidence suggests it has effects that are unrelated to its physiologic function. The basis for this is unknown but may be a consequence of the unusual tendency of this allele to misfold.

HLA-B27-Associated Reactive Arthritis: Pathogenetic and Clinical Considerations

“…Colbert et al showed that in ReA during the antigen processing and assembly pathway in the endoplasmic reticulum, HLA-B27 has a tendency to misfold even without any ␤ 2 -microglobulin or peptide deficiency. This misfolding implicates the B pocket of the molecule and can lead to a stress response, which could increase the production of proinflammatory cytokines by activation of the NF-B (35,36) Additional mechanisms have been proposed to explain the role of HLA-B27. In some genetically predisposed subjects, HLA-B27 appears to lack the ability to eliminate infected macrophages normally (92,111), improving the intracellular survival of pathogens (183).…”