ERAP2is associated with ankylosing spondylitis inHLA-B27-positive andHLA-B27-negative patients

Robinson, Philip C; Costello, Mary Ellen; Leo, Paul; Bradbury, L.; Hollis, Kelly; Cortés, Adrián; Lee, Seunghun; Joo, Kyung Bin; Shim, Seung Cheol; Weisman, Michael H.; Ward, Michael M.; Zhou, Xiaodong; Garchon, Henri Jean; Chiocchia, Gilles; Nossent, Jiri; Lie, Benedicte A.; Førre, Ø.; Tuomilehto, Jaakko; Laiho, Kari; Jiang, Lei; Liu, Yu; Wu, Xinyu; Elewaut, Dirk; Burgos‐Vargas, Rubén; Gensler, Lianne S.; Stebbings, Simon; Haroon, Nigil; Mulero, Juan; Fernández-Sueiro, José Luís; González-Gay, Miguel Á.; López‐Larrea, Carlos; Bowness, Paul; Gafney, Karl; Gaston, J. S. H.; Gladman, Dafna D.; Rahman, Proton; Maksymowych, Walter P.; Xu, Huji; Horst-Bruinsma, Irene E van der; Chou, Chung Tei; Valle-Oñate, Raphael; Romero-Sánchez, María Consuelo; Hansen, Inger Myrnes; Pimentel-Santos, Fernando; Inman, Robert D.; Martín, Javier; Bréban, Maxime; Evans, David M.; Reveille, John D.; Kim, So Yeon; Wordsworth, B P; Brown, Matthew A.

doi:10.1136/annrheumdis-2015-207416

Cited by 83 publications

(70 citation statements)

References 10 publications

(19 reference statements)

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“…Unlike ERAP1, the association of ERAP2 with AS is independent from HLA-B27, occurring in both B27-positive and -negative carriers [98,99]. This finding allows speculation of a role for the two aminopeptidases not necessarily converging on the same mechanism.…”

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

confidence: 78%

“…This finding allows speculation of a role for the two aminopeptidases not necessarily converging on the same mechanism. Notably, the ERAP2 null-variant rs2248374 is strongly protective for AS (Table 1) [99]. Hence, ERAP2 could be involved in the AS acting at two levels; that is, coupled or uncoupled with ERAP1.…”

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

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: 78%

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

confidence: 99%

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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“…The identification of ERAP-2 as a risk factor for AS (20,21) highlights the importance of determining the role of this enzyme in shaping the B*27:05 peptidome.…”

Section: Discussionmentioning

confidence: 99%

“…Our results suggest some possible mechanisms by which ERAP2 increases AS risk in HLA-B*27-positive individuals (21). Peptide presentation by HLA-B*27 may be altered in various ways.…”

Section: Arthritis and Rheumatologymentioning

confidence: 97%

Functional Interaction of the Ankylosing Spondylitis–Associated Endoplasmic Reticulum Aminopeptidase 2 With the HLA–B*27 Peptidome in Human Cells

Martín-Esteban

Guasp

Barnea

et al. 2016

Arthritis & Rheumatology

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ERAP-2 significantly influences the B*27:05-bound peptidome by destroying some ligands and decreasing the abundance of many more ligands with N-terminal basic residues, while increasing the abundance of nonamers. The former effects are best explained by direct ERAP-2 trimming. The effects on peptide length might be attributed to ERAP-2-induced activation of ERAP-1 trimming. These data support the notion of a peptide-mediated mechanism as the basis for the association of ERAP-2 with ankylosing spondylitis. Analogous effects on other major histocompatibility complex class I peptidomes might explain the involvement of ERAP-2 in HLA-B27-negative spondyloarthritis.

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“…Unlike ERAP1 , ERAP2 plays a role in both HLA-B27 positive and negative AS. 70 Though further studies are needed to understand precise mechanism of how ERAP1 and ERAP2 affect AS status, this finding together with the protective effects of rs30187 implies that inhibiting these proteins may be potential treatment for AS.…”

Section: Aminopeptidase In Asmentioning

confidence: 99%

Progress of genome‐wide association studies of ankylosing spondylitis

Brown

2017

Clin & Trans Imm

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Ankylosing spondylitis (AS) is an immune-mediated arthritis which primarily affects the spine and sacroiliac joints. Significant progress has been made in discovery of genetic associations with AS by genome-wide association studies (GWAS) over past decade. These findings have uncovered novel pathways involved pathogenesis of the disease and have led to introduction of novel therapeutic treatments for AS. In this Review, we discuss the genetic variations associated with AS identified by GWAS, the major pathways revealed by these AS-associated variations and critical cell types involved in AS development.

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ERAP2is associated with ankylosing spondylitis inHLA-B27-positive andHLA-B27-negative patients

Cited by 83 publications

References 10 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

Functional Interaction of the Ankylosing Spondylitis–Associated Endoplasmic Reticulum Aminopeptidase 2 With the HLA–B*27 Peptidome in Human Cells

Progress of genome‐wide association studies of ankylosing spondylitis

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