Molecular and pathogenic effects of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in MHC-I-associated inflammatory disorders: Towards a unifying view

Castro, José A. Łópez de; Alvarez-Navarro, Carlos; Brito, Ariadna; Guasp, Pablo; Martín-Esteban, Adrián; Sanz-Bravo, Alejandro

doi:10.1016/j.molimm.2016.08.005

Cited by 90 publications

(104 citation statements)

References 149 publications

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“…In particular, two of these SNPs, rs30187 (Arg528Lys) and rs27044 (Glu730Gln), reached high statistical significance for AS, as the minor alleles were robustly more frequent in AS patients than controls. Afterwards, several studies replicated these genetic associations, imputed ERAP1 haplotypes and found further associations with other SNPs mapping in the coding, UTR or intronic regions [2,78,87]. In 2011, it was proved that the association of ERAP1 with AS occurred exclusively in HLA-B27-positive patients, pointing at a gene-gene epistatic interaction [5].…”

Section: Hla-b27 and Erap1/2 As Players In Ankylosing Spondylitismentioning

confidence: 94%

“…Several studies agree to indicate the high trimming Met349/Lys528/Asp575/Arg725/Gln730 haplotype as being associated most strongly with AS risk, while the low trimming Val349/Arg528/Asn575/Gln725/Glu730 haplotype as the most protective [2,78,88]. In contrast, a report has suggested that rare hyperactive or hypoactive allotype pair combinations found in AS patients could explain the involvement of ERAP1 in the disease [79].…”

Section: Hla-b27 and Erap1/2 As Players In Ankylosing Spondylitismentioning

confidence: 98%

“…Apart from a few exceptions, a higher enzymatic activity marks individual ERAP1 polymorphisms or the entire haplotypes associated with increased risk of AS (Table 1) [2,5,[78][79][80]. Several studies agree to indicate the high trimming Met349/Lys528/Asp575/Arg725/Gln730 haplotype as being associated most strongly with AS risk, while the low trimming Val349/Arg528/Asn575/Gln725/Glu730 haplotype as the most protective [2,78,88].…”

Section: Hla-b27 and Erap1/2 As Players In Ankylosing Spondylitismentioning

confidence: 99%

“…In addition, a prominent role has been attributed to Endoplasmic Reticulum Aminopeptidase (ERAP)1 and, in some cases, ERAP2 genes. We are referring to immunological disorders such as Behc¸et's disease (BD), psoriasis (Ps), birdshot chorioretinopathy (BSCR) and ankylosing spondylitis (AS), each associated by a variable relative risk (odds ratio) with the HLA-B51, HLA-C*0602, HLA-A29 or HLA-B27 genes, respectively [1,2]. Besides peculiar clinical hallmarks due to distinct polygenic backgrounds, such diseases usually affect body sites that undergo physical stress and are located at either external barriers (oral mucosa, skin, gut, eye) or at interior sites (joints, enthesis, cardiac valves, blood vessel walls) [1].…”

Section: Introductionmentioning

confidence: 99%

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

Vitulano

Tedeschi

Paladini

et al. 2017

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryThe human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

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Section: Hla-b27 and Erap1/2 As Players In Ankylosing Spondylitismentioning

confidence: 94%

Section: Hla-b27 and Erap1/2 As Players In Ankylosing Spondylitismentioning

confidence: 98%

Section: Hla-b27 and Erap1/2 As Players In Ankylosing Spondylitismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Vitulano

Tedeschi

Paladini

et al. 2017

Clinical and Experimental Immunology

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“…Naturally occurring ERAP1 protein haplotypes have been previously linked to MHC-I-opathies [8]. Considering 10 amino acid variants in ERAP1 together [21], we identified 8 common (frequency >1%) haplotypes ( Table 1).…”

Section: Erap1 Hap10 Is Associated With Birdshotmentioning

confidence: 99%

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Kuiper

Setten

Devall

et al. 2018

Preprint

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Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed "MHC-I-opathy" family. Genetic studies have pinpointed the ERAP1 and ERAP2 genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression.We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC- 6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2,103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either SNP alone (meta-analysis: p=3.9 × 10(-9)). Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n=3,353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

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Immunogenetics of Cancer

Díaz‐Peña

Mondelo‐Macía

Castro‐Santos

2023

Handbook of Cancer and Immunology

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Molecular and pathogenic effects of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in MHC-I-associated inflammatory disorders: Towards a unifying view

Cited by 90 publications

References 149 publications

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

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

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Immunogenetics of Cancer

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