Functional Interaction of the Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 Polymorphism and HLA-B27 in Vivo

Abstract

The association of ERAP1 with ankylosing spondylitis (AS)1 among HLA-B27-positive individuals suggests that ERAP1 polymorphism may affect pathogenesis by altering peptide-dependent features of the HLA-B27 molecule. Comparisons of HLA-B*27:04-bound peptidomes from cells expressing different natural variants of ERAP1 revealed significant differences in the size, length, and amount of many ligands, as well as in HLA-B27 stability. Peptide analyses suggested that the mechanism of ERAP1/HLA-B27 interaction is a variant-dependent alteration in the balance between epitope generation and destruction determined by the susceptibility of N-terminal flanking and P1 residues to trimming. ERAP1 polymorphism associated with AS susceptibility ensured efficient peptide trimming and high HLA-B27 stability. Protective polymorphism resulted in diminished ERAP1 activity, less efficient trimming, suboptimal HLA-B27 peptidomes, and decreased molecular stability. This study demonstrates that natural ERAP1 polymorphism affects HLA-B27 antigen presentation and stability in vivo and proposes a mechanism for the interaction between these molecules in AS.

Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis

“…This allotype was only present in AS cases, albeit at a low frequency (Tables 1 and 2). Despite the association of single SNPs with AS, the demonstration that ERAP1 SNPs assemble into allotypes and that SNPs affect ERAP1 function in cis (15)(16)(17), in the context of these allotypes, shows the limited expediency of simple SNP analysis as a disease marker. Even allotype analysis was of limited value, with the highest precision being achieved only when both allotypes present in a single individual's genome were identified unambiguously.…”

“…Differences in trimming properties may predispose an individual to the formation of ER B27 2 and UPR. In addition, the generation of suboptimal HLA-B27 ligands created by aberrant ERAP1 activity that bind with sufficient affinity to pass intracellular quality control (16,29) may dissociate rapidly at the cell surface, leading to increased aberrant forms of B27. These mechanisms are not necessarily mutually exclusive, nor do they preclude other possible mechanisms such as the ability of different ERAP1 variants to generate specific arthritogenic peptides.…”

“…These types of analyses, however, do not allow for the effects of SNPs that occur in combinations/haplotypes to be determined and are of particular importance because, in a recent study, we showed that naturally occurring ERAP1 molecules are polymorphic, existing as haplotypes, hereafter referred to as allotypes, which consist of multiple combinations of AS-associated SNPs, and that they have functional differences with different amino acid specificities (15). In addition, natural polymorphic ERAP1 molecules have been shown to alter the repertoire of peptides presented by HLA-B27 (16). Indeed, the combined effects of two AS-associated SNPs, K528R and D575N, reveals a hierarchy of activity; K528/N575 have the greatest and R528/D575 the lowest with the relative activity of K528 and R528 dependent on residue 575 (17).…”

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…However, such study suffered from low statistical power due to the small cohorts analysed. Seminal work from Lopez de Castro's group has outlined how the B27 peptidome is influenced by ERAP allotypes [89,90]. The effect impacts mainly the P1 residue and, to a lesser extent, the remaining peptide sequence, the peptide length, the amount of specific ligands and the B27 affinity and thermostability of the overall peptide/B27 complexes.…”

Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis

“…8 Polymorphisms in ERAP1 influence the quality and quantity of major histocompatibility complex class I complexes assembled and presented on the cell surface. 9,10 Considering the imputed and genotyped data across ERAP1, association with AS is most strongly localised to a block of single nucleotide polymorphisms (SNPs) lying in a 4.6 kb region between rs27529 (in exon 9) and rs469758 (in intron 12). 2,11 In this region, the only common (minor allele frequency 41%) coding polymorphisms are rs30187 (Arg528Lys) and rs10050860 (Asp575Asn), 12 and fine-mapping and haplotype evolutionary studies suggest that rs30187 is directly disease associated, and that a second haplotype, tagged by rs10050860, is also AS associated.…”