Abstract
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.
Highlights
INTO BIRDSHOT UVEITISBirdshot Uveitis is a well-characterized form of autoimmune uveitis mostly known for its ovoid light lesions, which appear ‘shotgun pattern’-like distributed along the vascular arcades in the back of the eye [1]
If we look at publicly available data from the 1000 genomes project, the risk-variant linked to ERAP2 or the risk-variant linked to ERAP1 are observed in HLA-A29positive individuals of non-European ancestry (Figure 4)
The strongest association at 5q15 is linked to the polymorphisms in haplotype A (HapA). We showed that this signal did not influence the splicing or expression of the LNPEP gene, but showed that high ERAP2 expression controlled by this genetic signal embedded in HapA is a risk factor for Birdshot Uveitis (BU) [34, 61]
Summary
Birdshot Uveitis ( known as Birdshot chorioretinopathy or Birdshot retinochoroidopathy) is a well-characterized form of autoimmune uveitis (inflammation of the uveal layer of the eye) mostly known for its ovoid light lesions, which appear ‘shotgun pattern’-like distributed along the vascular arcades in the back of the eye (i.e., the ‘fundus’ of the eye where these lesions are visible by photography) [1]. In contrast to the shared effects of ERAP2 across HLA class I immunopeptidomes, in patient derived cell lines homozygous for the risk ERAP1 allotype Hap, ERAP2 facilitated the increased presentation of peptides with F or Y at P2 for HLAA29 [43, 92] Because this is the same submotif that distinguishes HLA-A29 from other HLA class I alleles, this observation provides a possible explanation for the association of these genes with BU. HLA-A29 can effectively present melanoma epitopes [1], HLAA29 is associated with worse survival compared to HLA-A29negative melanoma patients [110] This could indicate that perhaps similar to the effects of ERAP2, in general, HLA-A29 and ERAP2 may ‘lower’ the immunogenic peptide cargo presented to T cells, but only increase the expression of a very limited (perhaps single) antigen under specific conditions that cause BU. It would be interesting to determine if similar biological mechanisms are linking HLA-A29 to Th17 responses in BU
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