ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers

Gelfman, Sahar; Monnet, Dominique; Ligocki, Ann J.; Tabary, Thierry; Moscati, Arden; Bai, Xiaodong; Freudenberg, Jan; Cooper, Blerta; Kosmicki, Jack A.; Wolf, Sarah; Ferreira, Manuel A. R.; Overton, John D.; Weyne, Jonathan; Stahl, Eli A.; Baras, Aris; Romano, Carmelo; Cohen, J; Coppola, Giovanni; Brézin, Antoine P.

doi:10.1167/iovs.62.14.3

Cited by 18 publications

(16 citation statements)

References 47 publications

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“…Genome-wide genetic studies identified HLA-A29, ERAP1 , and ERAP2 genes as risk genes for BCR 7,9 . This substantiates peptide processing by ERAP1 and ERAP2 in the endoplasmic reticulum and subsequent peptide presentation by HLA-A29 at the cell surface as a key disease mechanism for BU.…”

Section: Discussionmentioning

confidence: 99%

Retina-arrestin is not a CD8+ T-cell autoantigen in HLA-A29-positive birdshot chorioretinitis

Venema

Hiddingh

Janssen

et al. 2022

Preprint

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BackgroundHLA-A29-positivebirdshot chorioretinitis(BCR) is an inflammatory eye disorder that is generally assumed to be caused by an autoimmune response to HLA-A29-presented peptides from retinal arrestin (SAG), yet the epitopes recognized by CD8+ T cells from patients remain to be identified.ObjectivesThe identification of natural ligands of SAG presented by HLA-A29. To quantify CD8+ T cells reactive to antigenic SAG peptides presented by HLA-A29 in patients and controls.MethodsWe performed mass-spectrometry based immunopeptidomics of HLA-A29 of antigen-presenting cell lines from patients engineered to express SAG. MHC-I Dextramer technology was utilised to identify antigen-specific CD8+ T cells reactive to SAG peptides in complex with HLA-A29 in a cohort of BCR patients, HLA-A29-positive controls, and HLA-A29-negative controls.ResultsWe report on the naturally presented antigenic SAG peptides identified by sequencing the HLA-A29 immunopeptidome of antigen-presenting cells of patients. We show that the N-terminally extended SAG peptide precursors can be trimmedin vitroby the antigen-processing aminopeptidases ERAP1 and ERAP2. Unexpectedly, no antigen engagement by CD8+ T cells upon stimulation with SAG peptides was observed in patients or HLA-A29-positive controls. Multiplexed HLA-A29-peptide dextramer profiling of a case-control cohort revealed that CD8+ T cells specific for these SAG peptides were neither detectable in peripheral blood nor in eye biopsies of patients.ConclusionsCollectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG.

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Section: Discussionmentioning

confidence: 99%

Retina-arrestin is not a CD8+ T-cell autoantigen in HLA-A29-positive birdshot chorioretinitis

Venema

Hiddingh

Janssen

et al. 2022

Preprint

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“…ERAP2 has also been implicated in different HLA-class I-associated diseases such as AS and BSCR. In both cases, the absence of the full length ERAP2 is protective ( 18 , 19 ). Since BSCR patients are virtually 100% HLA-A*29 positive, an epistatic mechanism could not be evaluated ( 20 ).…”

Section: Erap1 Erap2 and Irap In Multifactorial Diseases: Genetic Ass...mentioning

confidence: 99%

The emerging multifunctional roles of ERAP1, ERAP2 and IRAP between antigen processing and renin-angiotensin system modulation

et al. 2022

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The Endoplasmic Reticulum Aminopeptidase 1 and 2 (ERAP1 and ERAP2) and Insulin Regulated Aminopeptidase (IRAP) are three M1 zinc metalloproteases whose role in antigen processing is the refining of peptidome either in the Endoplasmic reticulum (ERAP1 and ERAP2), or in the endosomes (IRAP). However, other novel and distinct functions are emerging. Here, we focus specifically on ERAP2. This gene has a peculiar evolutionary history, being absent in rodents and undergoing in humans to a balanced selection of two haplotypes, one of which not expressing the full length ERAP2. These observations suggest that its role in antigen presentation is not essential. An additional, less investigated role is in the regulation of the Renin Angiotensin System (RAS). ERAP1 and ERAP2 cleave Angiotensin II (Ang II) into Ang III and IV, which counteract the action of Ang II whereas IRAP is itself the receptor for Ang IV. We have recently reported that macrophages, independently from the haplotype, express and release a N-terminus ERAP2 “short” form which directly binds IRAP and the two molecules are co-expressed in the endosomes and on the cell membrane. This new evidence suggests that the maintenance of the ERAP2 gene in humans could be due to its activity in the regulation of the RAS system, possibly as an Ang IV agonist. Its role in the immune-mediated diseases as well as in disorders more specifically related to an imbalance of the RAS system, including hypertension, pre-eclampsia but also viral infections such as COVID-19, is discussed here.

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“…Overall, the exact contribution of HLA-A29 to the pathophysiology of BSCR remains unclear. Indeed, HLA-A29 is relatively common in the European population (7–9%), and very few HLA-A29-positive individuals develop BSCR, suggesting that HLA-A29 is necessary but not sufficient to explain the pathophysiology of the disease, and other factors could be contributing to the development of BSCR [ 18 ].…”

Section: Pathophysiologymentioning

confidence: 99%

“…Expression of ERAP1 and ERAP2 is coordinated, when ERAP1 expression decreases, ERAP2 expression increases [ 21 ]. Gelfman et al suggested that increased ERAP2 along with decreased ERAP1 expression in BSCR cases would lead to higher availability of ERAP2-processed peptides for presentation onto HLA class I proteins [ 18 ]. Exceeding a peptide presentation threshold could activate the immune response in choroids of HLA-A29 carriers.…”

Section: Pathophysiologymentioning

confidence: 99%

Birdshot Chorioretinopathy: A Review

Bousquet

Duraffour

Debillon

et al. 2022

JCM

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Birdshot chorioretinopathy (BSCR) is a bilateral chronic inflammation of the eye with no extraocular manifestations. BSCR affects middle-aged individuals from European descent and is strongly associated with the human leucocyte antigen (HLA)-A29 allele. The immune mechanisms involved are not fully understood, but recent advances have shown the role of Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) in disease pathogenesis. Multimodal imaging, including fluorescein angiography, indocyanine angiography, fundus autofluorescence, and optical coherence tomography, are useful in confirming the diagnosis and monitoring disease activity. Visual field testing is also important to assess the disease progression. To date, there is no consensus for optimal treatment regimen and duration. Local and systemic corticosteroids can be used for short periods, but immunosuppressive or biological therapies are usually needed for the long-term management of the disease. Here, we will review publications focused on birdshot chorioretinopathy to give an update on the pathophysiology, the multimodal imaging, and the treatment of the disease.

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ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers

Cited by 18 publications

References 47 publications

Retina-arrestin is not a CD8+ T-cell autoantigen in HLA-A29-positive birdshot chorioretinitis

Retina-arrestin is not a CD8+ T-cell autoantigen in HLA-A29-positive birdshot chorioretinitis

The emerging multifunctional roles of ERAP1, ERAP2 and IRAP between antigen processing and renin-angiotensin system modulation

Birdshot Chorioretinopathy: A Review

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