Fifty years after the discovery of the association of HLA B27 with ankylosing spondylitis

Abstract

The human lymphocyte antigen B27 (HLA B27) is a member of the HLA class I family of genes in the major histocompatibility complex whose name goes back to its discovery in studies of transplanted tissue compatibility. Its prevalence in the mid-European population is about 8%. The association of HLA B27 alleles with ankylosing spondylitis (AS), a highly heritable disease, which is part of the spectrum of axial spondyloarthritis (axSpA), was discovered 50 years ago. HLA B27 explains less than 30% of the total genetic load. About 60%-90% of axSpA patients worldwide carry HLA B27. The prevalence of the disease is linked to the frequency of HLA B27 in the population which implies that there are relevant differences. Among the roughly 200 subtypes known there are two which are not disease associated. The function of HLA class I molecules is to present peptides to the immune system to defend the organism against microbes targeted by CD8+T cells. This is much supported by the role of the endoplasmic reticulum aminopeptidase 1 (ERAP 1) in AS, an enzyme that is responsible for the intracellular trimming of peptides, since polymorphisms of this gene are only associated with HLA-B27+ disease. The arthritogenic peptide hypothesis trying to explain the pathogenesis of AS is based on that very immune function assuming that also self peptides can be presented. HLA-B27 also plays an important role in classification, diagnosis and severitiy of axSpA.

Keywords: Arthritis; Inflammation; Spondylitis, Ankylosing.

Figure 1

(A, B): Confirmation of HLA B27. (A) Confirmation of HLA B27 showing 3 alpha chains, ß2 microglobulin and the peptide binding cleft. Sehnal et al. (B) Confirmation of HLA-B*2705 with the alpha chains shown in green and ß2 microglobulin in yellow, complexed to a fragment of the influenza nucleoprotein NP383-391 (red).

Figure 2

Peptide presented in HLA B27. The figure shows a peptide antigen in blue, usually 8–10 amino acids long, present in the pocket of HLA-B27 molecule for presentation to CD8+cytotoxic T cells specific for that peptide antigen. The letter N denotes the amino terminus (end point) and C stands for the carboxy terminus of the bound peptide. The numbers indicate the locations of important amino acids of HLA-B27 molecules. (From: Khan 2005).

Figure 3

Peptide binding sites of HLA B27 subtypes. *Mapping the polymorphic and conserved residues of the HLA-B27 subtypes in terms of the specificity pockets described in the X-ray crystallographic structure of HLA-A*0201. (A) Specificity pockets A-F of HLA- A*0201^#. (B) HLA-B27 subtype polymorphisms (solid areas) and B pocket conserved residues (shaded areas) mapped onto the ribbon structure of HLA-A*0201^##. *Buxton et al. ^#As described by Saper et al. (Copyright permission of Academic Press). ^##As described by Bjorkman et al.

Figure 4

Disease associations at genome-wide significance were observed for 25 loci, including the MHC. Manhattan plots in the European Cohort Analysis Association peaks are colour coded in red if previously identified, orange if novel and in green if identified as suggestive association. MHC, major histocompatibility complex. The strongest association found was, expectedly, for HLA B27 but ERAP 1 and the IL-23 receptor were also clearly associated. The significance of other weaker associations has in most cases remained unclear.