Ankylosing Spondylitis: A Trade Off of HLA-B27, ERAP, and Pathogen Interconnections? Focus on Sardinia.

Fabiana Paladini,Alberto Cauli,Alessandro Mathieu,Valentina Tedeschi,Rosa Sorrentino,Maria Teresa Fiorillo

doi:10.3389/fimmu.2019.00035

Fabiana Paladini, Alberto Cauli + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2019.00035

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Abstract

The frequency of HLA-B27 in patients with Ankylosing Spondylitis (AS) is over 85%. There are more than 170 recognized HLA-B27 alleles but the majority of them is not sufficiently represented for genetic association studies. So far only two alleles, the HLA-B*2706 in Asia and the HLA-B*2709 in Sardinia, have not been found to be associated with AS. The highly homogenous genetic structure of the Sardinian population has favored the search of relevant variants for disease-association studies. Moreover, malaria, once endemic in the island, has been shown to have contributed to shape the native population genome affecting the relative allele frequency of relevant genes. In Sardinia, the prevalence of HLA-B*2709, which differs from the strongly AS-associated B*2705 prototype for one amino acid (His/Asp116) in the F pocket of the peptide binding groove, is around 20% of all HLA-B27 alleles. We have previously hypothesized that malaria could have contributed to the establishment of this allele in Sardinia. Based on our recent findings, in this perspective article we speculate that the Endoplasmic Reticulum Amino Peptidases, ERAP1 and 2, associated with AS and involved in antigen presentation, underwent co-selection by malaria. These genes, besides shaping the immunopeptidome of HLA-class I molecules, have other biological functions that could also be involved in the immunosurveillance against malaria.

Highlights

HLA-B27 and Ankylosing Spondylitis (AS) is a paradigmatic example of association between the HLA and an immuno-mediated disease [1, 2]
There is a genetic overlap between the two diseases, HLA-B27 remains a hallmark of AS and its role, still undisclosed, appears to be prevalent and specific [8, 9]
Functional variants of the three aminopeptidases ERAP1, ERAP2, and LNPEP show a worldwide distribution compatible with a selective pressure by malaria. Some of these variants co-occur with HLA-B27 subtypes

Summary

INTRODUCTION

HLA-B27 and Ankylosing Spondylitis (AS) is a paradigmatic example of association between the HLA and an immuno-mediated disease [1, 2]. The tale of the HLA-B∗2709 has its origin from studies aimed to characterize, at subtyping level, the HLA-B27-restriction of autoreactive, cytotoxic γδ T cells [15] These cells killed B-LCLs from HLA-B27 positive members of the proband family but not unrelated HLA-B∗2705 positive B-LCLs. cDNA sequencing disclosed a single amino acid variance in the binding groove of the HLA-B27 molecules (Asp/His 116) that made highly specific this recognition. The observation that another allele, the B∗2706, more frequent in Asia and differing from the common B∗2704 for two amino acids Asp/His 114 and Tyr/Asp 116 [11], both located in the peptide binding groove, gave strength to the hypothesis of the “arthritogenic” peptide/s [19] This predicts the existence of a specific HLA-B27-restricted “self immunopeptidome” triggering autoreactive CTLs primarily elicited by cross-reactive microbial peptides. This suggests a role for ERAP2 by mechanisms which go beyond the peptidome shaping

HLA REGION UNDERGOES POSITIVE SELECTION

Findings

CONCLUSIONS