Vogt-Koyanagi-Harada Disease and Birdshot Retinochoroidopathy, Similarities and Differences: A Glimpse into the Clinicopathology of Stromal Choroiditis, a Perspective and a Review

Elahi, Sina; Herbort, Carl P.

doi:10.1055/a-0829-6763

Cited by 21 publications

(24 citation statements)

References 92 publications

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“…The motif of cluster 2 peptides is present in the amino acid sequences of proteins encoded by ~300 genes highly expressed in the retina ( Table S7 ), of which putative HLA-A29-restricted peptides (MSi>0.9 for HLA-A29 and MSi<0.6 for 94 other alleles) were found in key factors in melanocyte biology (ARMC9, OCA2, SLC45A2, PLXNC1)( Table S8 ). This is of significance, because progressive loss of ocular melanocytes is a hallmark feature of BU 2,5,8,50,51 . We conclude that these data support that ERAP2 may apply selective pressure on the repertoire of HLA-A29.…”

Section: Resultsmentioning

confidence: 99%

“…It is, however, of interest that among the predicted epitopes we found peptides derived from key factors in melanocyte biology. A hallmark feature of BU is the progressive loss of stromal melanocytes in the choroid corresponding to the characteristic cream-colored birdshot fundus lesions 2,8,50,51 , and BU has been associated with melanoma 5,6,52 .…”

Section: Discussionmentioning

confidence: 99%

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ERAP2 increases the abundance of a peptide submotif highly selective for the Birdshot Uveitis-associated HLA-A29

Venema

Hiddingh

Boer

et al. 2020

Preprint

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Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labelled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ERAP2 increases the abundance of a peptide submotif highly selective for the Birdshot Uveitis-associated HLA-A29

Venema

Hiddingh

Boer

et al. 2020

Preprint

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“…ICGA signs are present before the appearance of characteristic BRC fundus lesions and ICGA is therefore essential for early diagnosis [ 103 ]. In case of early diagnosis thanks to ICGA and early treatment, the rice-shaped birdshot lesions will never develop [ 109 ].…”

Section: Icga-derived Classification and Clinicopathological Mechanisms In Non-infectious Choroiditis And Specific Entitiesmentioning

confidence: 99%

Classification of Non-Infectious and/or Immune Mediated Choroiditis: A Brief Overview of the Essentials

Herbort¹,

Mantovani

Tuğal-Tutkun

et al. 2021

Diagnostics

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The choroid was poorly accessible to imaging investigation until the last decade of the last century. With the availability of more precise imaging methods such as indocyanine green angiography (ICGA) and, later, optical coherence tomography (OCT), enhanced depth OCT (EDI-OCT), and OCT angiography (OCTA), appraisal of choroidal inflammation has substantially gained in accuracy. This allowed to precisely determine which structures were touched in the different non-infectious choroiditis entities and made it possible to classify this group of diseases, ICGA signs, mainly hypofluorescent lesions, were identified and described. Previous publications have divided angiographic findings into two main sets of signs: (1) irregular “geographic” hypofluorescent areas corresponding to choriocapillaris non-perfusion and (2) round more regular, hypofluorescent dark dots more evenly distributed in the fundus corresponding to more deep choroidal stromal foci. These distinct findings allowed to subdivide and classify choroiditis into choriocapillaritis and stromal choroiditis. Additional signs were identified from EDI-OCT and OCTA examination supporting the classification of choroiditis into choriocapillaritis and stromal choroiditis. Results: Diseases involving principally the choriocapillaris included Multiple Evanescent White Dot Syndrome (MEWDS), Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE), Idiopathic Multifocal Choroiditis (MFC), and Serpiginous Choroiditis (SC) as well as mixed forms. Diseases primarily involving the choroidal stroma included HLA-A29 Birdshot Retinochoroiditis (BRC), Vogt-Koyanagi-Harada disease (VKH), Sympathetic Ophthalmia (SO), and Sarcoidosis chorioretinitis (SARC). Thanks to new imaging investigations of the choroid, it is now possible to classify and understand the diverse clinicopathological mechanisms in the group of non-infectious choroiditis entities.

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“…Histopathology studies of eye tissues and modern imaging technologies show that early lesions are located deep inside the vascular layer of the eye (the "choroid") between the retina and the white outer layer of the eyeball (sclera). In the choroid, the large-vessel layer (choroidal stroma)-densely populated with pigmented "melanocyte" cells-shows abnormalities before the characteristic fundus lesions are visible (10,11). Because BU shows early inflammation of the choroidal stroma (12), Herbort and associates proposed to classify BU as a primary stromal choroiditis, together with Vogt-Koyanagi-Harada (VKH) disease.…”

Section: Introduction Into Birdshot Uveitismentioning

confidence: 99%

“…Because BU shows early inflammation of the choroidal stroma (12), Herbort and associates proposed to classify BU as a primary stromal choroiditis, together with Vogt-Koyanagi-Harada (VKH) disease. VKH is a condition characterized by chronic inflammation toward melanocytes that affect multiple parts of the body, including the choroidal stroma and the larger choroidal vessels (11,13). In VKH no retinal involvement at early stages of disease are noticeable.…”

Section: Introduction Into Birdshot Uveitismentioning

confidence: 99%

HLA-A29 and Birdshot Uveitis: Further Down the Rabbit Hole

Kuiper

Venema

2020

Front. Immunol.

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HLA class I alleles constitute established risk factors for non-infectious uveitis and preemptive genotyping of HLA class I alleles is standard practice in the diagnostic work-up. The HLA-A29 serotype is indispensable to Birdshot Uveitis (BU) and renders this enigmatic eye condition a unique model to better understand how the antigen processing and presentation machinery contributes to non-infectious uveitis or chronic inflammatory conditions in general. This review will discuss salient points regarding the protein structure of HLA-A29 and how key amino acid positions impact the peptide binding preference and interaction with T cells. We discuss to what extent the risk genes ERAP1 and ERAP2 uniquely affect HLA-A29 and how the discovery of a HLA-A29-specific submotif may impact autoantigen discovery. We further provide a compelling argument to solve the long-standing question why BU only affects HLA-A29-positive individuals from Western-European ancestry by exploiting data from the 1000 Genomes Project. We combine novel insights from structural and immunopeptidomic studies and discuss the functional implications of genetic associations across the HLA class I antigen presentation pathway to refine the etiological basis of Birdshot Uveitis.

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Vogt-Koyanagi-Harada Disease and Birdshot Retinochoroidopathy, Similarities and Differences: A Glimpse into the Clinicopathology of Stromal Choroiditis, a Perspective and a Review

Cited by 21 publications

References 92 publications

ERAP2 increases the abundance of a peptide submotif highly selective for the Birdshot Uveitis-associated HLA-A29

ERAP2 increases the abundance of a peptide submotif highly selective for the Birdshot Uveitis-associated HLA-A29

Classification of Non-Infectious and/or Immune Mediated Choroiditis: A Brief Overview of the Essentials

HLA-A29 and Birdshot Uveitis: Further Down the Rabbit Hole

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