EnRAPtured: Is Endoplasmic Reticulum Aminopeptidase a New Clue to the Pathogenesis and ThERAPy of Uveitis?

Abstract

Baruj Benacerraf and Hugh O. McDevitt are sometimes called the discoverers of immune response genes because their seminal research showed that the immune response was under genetic control. The primary genes identified by this pair are located in the major histocompatibility complex (MHC), known as HLA genes in humans. In 1972, the two wrote a prescient commentary that appeared in Science.1Benacerraf B. McDevitt H.O. Histocompatibility-linked immune response genes.Science. 1972; 175: 273-279Crossref PubMed Scopus (808) Google Scholar In essence, they argued that if genes control the immune response, and if some diseases are triggered by the immune response, then those same genes might influence who receives a diagnosis of diseases like rheumatoid arthritis, systemic lupus erythematosus, or Graves’ disease. Their prediction was validated approximately 1 year later2Brewerton D.A. Hart F.D. Nicholls A. et al.Ankylosing spondylitis and HL-A 27.Lancet. 1973; 1: 904-907Abstract PubMed Scopus (1396) Google Scholar and has been shown to hold true for more than 100 diseases.3Shiina T. Inoko H. Kulski J.K. An update of the HLA genomic region, locus information and disease associations: 2004.Tissue Antigens. 2004; 64: 631-649Crossref PubMed Scopus (269) Google Scholar For most genetically complex immune-mediated diseases, the HLA genes affect the likelihood of disease developing more than any other gene identified in genome-wide association studies. Although Benacerraf and McDevitt made an insightful deduction, their reasoning might have been incorrect. Fifty years ago, many immune-mediated diseases were labelled autoimmune. Rheumatoid arthritis, systemic lupus erythematosus, and Graves’ disease are characterized by autoantibodies, so it makes sense to believe that the immune system is attacking itself, and it is plausible that immune response genes of the major histocompatibility complex affect the magnitude of that response. But this logic has 2 flaws. First, many immune-mediated diseases like sarcoidosis, ankylosing spondylitis, or birdshot chorioretinopathy (BSCR) are not necessarily autoimmune diseases.4McGonagle D. McDermott M.F. A proposed classification of the immunological diseases.PLoS Med. 2006; 3: e297Crossref PubMed Scopus (508) Google Scholar Disease-causing autoantibodies are not characteristic of these diseases. Second and more importantly, even in diseases in which autoantibodies are detectable, rarely, if ever, has a study documented that the HLA genes affect the immune response to the putative autoantigen. In celiac disease, the HLA allele, DQ2.5, does impact the immune response to peptides derived from gluten,5Vader W. Stepniak D. Kooy Y. et al.The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses.Proc Natl Acad Sci U S A. 2003; 100: 12390-12395Crossref PubMed Scopus (290) Google Scholar which is present in diet. An immune response to gluten is causally related to celiac disease, although gluten itself is not an autoantigen. Nevertheless, celiac disease is arguably the disease that best connects disease predisposition to a genetically controlled immune response. The HLA system is the most polymorphic germline genetic system known. The major histocompatibility complex includes class I genes encoded by HLA A, B, and C loci and class II genes encoded by DR, DP, and DQ loci. HLA class I molecules present antigen to CD8 T cells (Fig 1), which perform killer and suppressor functions. HLA class II molecules present antigen to CD4 T cells, which are often labeled helper T cells. For most loci, hundreds of different alleles exist. Considering that an allele is inherited from each parent and some loci have hundreds of allotypes, there are many millions of combinations of different gene products. A teleologic argument is that this genetic diversity helps to protect a species from extinction during a pandemic. Class II genes are most likely to influence susceptibility to a disease. The likelihood of many forms of uveitis developing is known to be affected by HLA alleles.6Davey M.P. Rosenbaum J.T. The human leukocyte antigen complex and chronic ocular inflammatory disorders.Am J Ophthalmol. 2000; 129: 235-243Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Of all the HLA disease associations, the HLA allele that most affects the predisposition to a disease is HLA-A29, which is associated with BSCR, whose likelihood to develop increases roughly 150-fold by virtue of this HLA type.7Kuiper J. Rothova A. de Boer J. Radstake T. The immunopathogenesis of birdshot chorioretinopathy; a bird of many feathers.Prog Retin Eye Res. 2015; 44: 99-110Crossref PubMed Scopus (35) Google Scholar HLA molecules have a pocket that provides the contact with the antigenic peptide that is presented to the T cell. To be presented, the peptide must be a specific size and must include specific amino acids with specific spacing between these amino acids. For HLA class I, the peptide that is loaded into the pocket is trimmed and fitted inside the cell before the HLA complex is transported to the cell surface (Fig 1). Peptide trimming is performed by endoplasmic reticulum aminopeptidase (ERAP).8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google Scholar Two associated genes, ERAP1 and ERAP2, can each be expressed as different isoforms. Furthermore, ERAP1 and ERAP2 have complementary and distinct trimming abilities. Just as HLA molecules affect disease susceptibility, ERAP polymorphisms also affect susceptibility to specific diseases.8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar The contribution of ERAP to disease susceptibility is generally epistatic with HLA class I. Epistasis describes a gene–gene interaction. For example, for ERAP1 to affect susceptibility to ankylosing spondylitis, HLA-B27 must be present as well. The 11 diseases with arguably the best documented association between an ERAP polymorphism and susceptibility are listed in Table 1. The list includes BSCR, a disease that by definition always includes uveitis; acute anterior uveitis associated with HLA-B27, which is reportedly the most common form of uveitis in Europe and North America; and Behçet’s disease, which causes uveitis in most people with this diagnosis. It also includes Kawasaki’s disease, a rare disease whose best-known ocular manifestation is conjunctivitis, but anterior uveitis often is present as well.10Shiari R. Jari M. Karimi S. et al.Relationship between ocular involvement and clinical manifestations, laboratory findings, and coronary artery dilatation in Kawasaki disease.Eye (Lond). 2020; 34: 1883-1887Crossref PubMed Scopus (4) Google Scholar The other 7 diseases included in Table 1 are also associated with uveitis, just not as consistently as the 4 prototypes. Surely, this is a clue to the pathogenesis of uveitis.Table 1Associations with Disease, HLA Class I, and Endoplasmic Reticulum AminopeptidaseDiseaseHLA Association Class IEndoplasmic Reticulum Aminopeptidase AssociationCommentAnkylosing spondylitis8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google ScholarB27rs26653rs2287987rs30187rs10050860∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.rs17482078∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.rs27044Association holds for B27-associated acute anterior uveitis as well as for ankylosing spondylitisEnthesitis-related arthritis11Hinks A. Martin P. Flynn E. et al.Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis.Arthritis Res Ther. 2011; 13: R12Crossref PubMed Scopus (45) Google ScholarB27rs30187Behçet’s disease8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google ScholarB51rs10050860∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.rs17482078∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.Type 1 diabetes9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google ScholarA∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.02:01A∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.24:02rs30187Diabetes is associated weakly with uveitis12Watanabe T. Keino H. Nakayama K. et al.Clinical features of patients with diabetic anterior uveitis.Br J Ophthalmol. 2019; 103: 78-82Crossref PubMed Scopus (7) Google ScholarPsoriasis8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google ScholarC∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.06:02rs26653rs30187rs27044Psoriasis is associated weakly with uveitis13Chi C.C. Tung T.H. Wang J. et al.Risk of uveitis among people with psoriasis: a nationwide cohort study.JAMA Ophthalmol. 2017; 135: 415-422Crossref PubMed Scopus (56) Google ScholarPsoriatic arthritis8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,14Popa O.M. Cherciu M. Cherciu L.I. et al.ERAP1 and ERAP2 gene variations influence the risk of psoriatic arthritis in Romanian population.Arch Immunol Ther Exp (Warsz). 2016; 64: 123-129Crossref PubMed Scopus (18) Google ScholarB27 negativeB27 positivers2248374 (ERAP2)rs30187Multiple sclerosis8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google ScholarC∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.05 (protective)rs30187Inflammatory bowel disease8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google ScholarC∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.07rs30187Birdshot chorioretinopathy8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google Scholar,15Gelfman S. Monnet D. Ligocki A.J. et al.ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for birdshot chorioretinopathy in HLA-A29 carriers. medRxiv, 2021Google Scholar,16Kuiper J.J.W. Setten J.V. Devall M. et al.Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(birdshot) uveitis.Hum Mol Genet. 2018; 27: 4333-4343PubMed Google ScholarA∗ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity.29:02rs10044354 (ERAP2)rs27432rs2287987Kawasaki’s disease8Yao Y. Liu N. Zhou Z. Shi L. Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations.Hum Immunol. 2019; 80: 325-334Crossref PubMed Scopus (18) Google Scholar,17Onouchi Y. Molecular genetics of Kawasaki disease.Pediatr Res. 2009; 65: 46R-54RCrossref PubMed Scopus (63) Google Scholar,18Tsai F.J. Lee Y.C. Chang J.S. et al.Identification of novel susceptibility loci for Kawasaki disease in a Han chinese population by a genome-wide association study.PLoS One. 2011; 6e16853Crossref PubMed Scopus (78) Google ScholarVariousrs149481Uveitis is an accepted association with all the listed diseases, but the association with uveitis is weak for diabetes and cutaneous psoriasis, as referenced. All associations are with ERAP1 polymorphisms except for birdshot chorioretinopathy and psoriatic arthritis, which also have an association with ERAP2. The table indicates 11 diseases (counting ankylosing spondylitis and acute anterior uveitis as diseases that can occur separately) with 3 common traits: an association with HLA class I, an association with an endoplasmic reticulum aminopeptidase polymorphism, and uveitis. Arthritis occurs in most of the listed diseases, but it is not typical of birdshot chorioretinopathy or multiple sclerosis.∗ ERAP1 variants rs100050860 and rs17482078 are in linkage disequilibrium with each other. These variants as well as rs30187 are associated with increased ERAP1 activity. Open table in a new tab Uveitis is an accepted association with all the listed diseases, but the association with uveitis is weak for diabetes and cutaneous psoriasis, as referenced. All associations are with ERAP1 polymorphisms except for birdshot chorioretinopathy and psoriatic arthritis, which also have an association with ERAP2. The table indicates 11 diseases (counting ankylosing spondylitis and acute anterior uveitis as diseases that can occur separately) with 3 common traits: an association with HLA class I, an association with an endoplasmic reticulum aminopeptidase polymorphism, and uveitis. Arthritis occurs in most of the listed diseases, but it is not typical of birdshot chorioretinopathy or multiple sclerosis. Functions beyond antigen presentation have been ascribed to both ERAP and HLA class I. For example, ERAP could modify receptors for cytokines.9Reeves E. James E. The role of polymorphic ERAP1 in autoinflammatory disease.Biosci Rep. 2018; 38BSR20171503https://doi.org/10.1042/BSR20171503Crossref PubMed Scopus (23) Google Scholar Polymorphisms in ERAP affect the immune response to viruses, including the coronavirus responsible for coronavirus disease 2019.19Saulle I. Vicentini C. Clerici M. Biasin M. Antigen presentation in SARS-CoV-2 infection: the role of class I HLA and ERAP polymorphisms.Hum Immunol. 2021; 82: 551-560Crossref PubMed Scopus (4) Google Scholar Viruses are a potential trigger to cause immune-mediated disease. HLA class I could misfold and activate a cascade of biochemical events known as the unfolded protein response.20Colbert R.A. Delay M.L. Layh-Schmitt G. Sowders D.P. HLA-B27 misfolding and spondyloarthropathies.Adv Exp Med Biol. 2009; 649: 217-234Crossref PubMed Scopus (23) Google Scholar HLA class I is recognized by a type of lymphocyte called the natural killer cell, which has been implicated in uveitis. Although it is certainly possible that HLA class I, ERAP, or both affect the likelihood of disease by a mechanism other than antigen presentation, the epistatic effect between the 2 genes strongly suggests that antigen presentation is the key function.21Venema W.J. Hiddingh S. de Boer J.H. ERAP2 increases the abundance of a peptide submotif highly selective for the birdshot uveitis-associated HLA-A29.Front Immunol. 2021; 12: 634441https://doi.org/10.3389/fimmu.2021.634441Crossref PubMed Scopus (1) Google Scholar An additional possibility is that antigen presentation is the critical function, but perhaps the antigen presentation is at the thymic epithelium, where ERAP is known to be active.22Gabrielsen I.S. Viken M.K. Amundsen S.S. et al.Autoimmune risk variants in ERAP2 are associated with gene-expression levels in thymus.Genes Immun. 2016; 17: 406-411Crossref PubMed Scopus (5) Google Scholar The thymic epithelium is responsible for deleting clones of autoreactive T cells. A failure to achieve this central tolerance predisposes a person to uveitis, as is known to occur in a mouse model called autoimmune regulator (AIRE).23DeVoss J. Hou Y. Johannes K. et al.Spontaneous autoimmunity prevented by thymic expression of a single self-antigen.J Exp Med. 2006; 203: 2727-2735Crossref PubMed Scopus (209) Google Scholar Uveitis is not a single disease, so one would not expect that 1 factor contributes to all forms of uveitis. However, it is also reasonable to believe that many forms of uveitis would share common mechanisms.24Rosenbaum J.T. Harrington C.A. Searles R.P. et al.Identifying RNA biomarkers and molecular pathways involved in multiple subtypes of uveitis.Am J Ophthalmol. 2021; 226: 226-234Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Both ERAP1 and ERAP2 are detected in the retina (Brooks MJ, Swaroop A, unpublished data, July 30, 2021; accessed via NEI Commons). Antigen presentation within the eye could represent a simple explanation as to why uveitis is so common in diseases associated with an ERAP polymorphism. Such an antigen could be an autoantigen, that is, endogenous, or it could be a foreign antigen such as one introduced by an infection, diet, or respiration. The peptide VTLGILVSY is contained within S-arrestin, which is uveitogenic. Because this peptide is trimmed by ERAP2, it is a potential contributor to BSCR.7Kuiper J. Rothova A. de Boer J. Radstake T. The immunopathogenesis of birdshot chorioretinopathy; a bird of many feathers.Prog Retin Eye Res. 2015; 44: 99-110Crossref PubMed Scopus (35) Google Scholar One study found that 10 of 10 patients with BSCR harbored autoantibodies to recoverin, a retinal protein,25Gibbs E. Matsubara J. Cao S. Cui J. Forooghian F. Antigen-specificity of antiretinal antibodies in patients with noninfectious uveitis.Can J Ophthalmol. 2017; 52: 463-467Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar although it is unclear if such antibodies are related causally to the disease or merely are epiphenomena secondary to inflammation. The role of ERAP in predisposing an eye to uveitis could involve antigen presentation without invoking a role for an antigen within the eye. The intestinal microbiome, the collection of micro-organisms that coexist within humans, educates the immune system such that laboratory animals that are raised in a germ-free environment have an impoverished immune system.26Hill D.A. Artis D. Intestinal bacteria and the regulation of immune cell homeostasis.Annu Rev Immunol. 2010; 28: 623-667Crossref PubMed Scopus (391) Google Scholar Changes in the microbiome have been implicated in a vast array of immune-mediated diseases. We recently reported that HLA-A29 helps to shape the intestinal microbiome.27Sternes P.R. Martin T.M. Paley M. et al.HLA-A alleles including HLA-A29 affect the composition of the gut microbiome: a potential clue to the pathogenesis of birdshot retinochoroidopathy.Sci Rep. 2020; 10: 17636Crossref PubMed Scopus (3) Google Scholar Other HLA alleles such as HLA-B2728Asquith M. Sternes P.R. Costello M.E. et al.HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome.Arthritis Rheumatol. 2019; 71: 1642-1650Crossref PubMed Scopus (55) Google Scholar and DRB128Asquith M. Sternes P.R. Costello M.E. et al.HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome.Arthritis Rheumatol. 2019; 71: 1642-1650Crossref PubMed Scopus (55) Google Scholar also impact the microbiome. This seems predictable because the microbiome expresses an immense variety of antigens. In any ecosystem, altering the prevalence of a single species inevitably affects other species downstream. Recently, Paun et al29Paun A. Yau C. Meshkibaf S. et al.Association of HLA-dependent islet autoimmunity with systemic antibody responses to intestinal commensal bacteria in children.Sci Immunol. 2019; 4eaau8125https://doi.org/10.1126/sciimmunol.aau8125Crossref PubMed Scopus (23) Google Scholar linked the HLA-controlled immune response to commensal bacteria and the development of juvenile type I diabetes or Crohn’s disease. Pianta et al30Pianta A. Chiumento G. Ramsden K. et al.Identification of novel, immunogenic HLA-DR-presented Prevotella copri peptides in patients with rheumatoid arthritis: patients with rheumatoid arthritis.Arthritis Rheumatol. 2021 May 27; (Online ahead of print)https://doi.org/10.1002/art.41807Crossref PubMed Scopus (2) Google Scholar reported that an HLA-regulated immune response to Prevotella correlates with generating autoantibody to cyclic citrullinated peptide, which is characteristic of rheumatoid arthritis. Furthermore, lymphocytes migrate from the gut to the eye and other target organs.31Ashrafi M. Kuhn K.A. Weisman M.H. The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?.RMD Open. 2021; 7e001558https://doi.org/10.1136/rmdopen-2020-001558Crossref PubMed Scopus (1) Google Scholar,32Nakamura Y.K. Janowitz C. Metea C. et al.Short chain fatty acids ameliorate immune-mediated uveitis partially by altering migration of lymphocytes from the intestine.Sci Rep. 2017; 7: 11745Crossref PubMed Scopus (62) Google Scholar Accordingly, ERAP conceivably could increase the likelihood of uveitis developing via an effect on the microbiome. Although ERAP polymorphisms such as rs10044354 for ERAP2 increase the activity of the enzyme, other polymorphisms such as rs27342 for ERAP1 reduce the activity of the enzyme.15Gelfman S. Monnet D. Ligocki A.J. et al.ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for birdshot chorioretinopathy in HLA-A29 carriers. medRxiv, 2021Google Scholar,16Kuiper J.J.W. Setten J.V. Devall M. et al.Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(birdshot) uveitis.Hum Mol Genet. 2018; 27: 4333-4343PubMed Google Scholar The mechanism by which reduced activity predisposes a person to an autoimmune disease is speculative, but multiple potential explanations exist. For example, if ERAP contributes to tolerance induced by the thymus, reduced activity could lead to a greater immune response. Some reciprocity exists between ERAP1 and ERAP2, so reduced activity of ERAP1 might increase the activity of ERAP2. If the disease results from an immune response to a virus, a hypomorphic allele could result in more viral antigen, and if the mechanism for disease predisposition involves the intestinal microbiome, a reduced immune response could skew the ecosystem within the gut. A recent genome-wide association study of 286 patients with BSCR found that HLA-A29, HLA-Aw19 (a supertype that is detectable in A29, A30, A31, and A33), and polymorphisms in both ERAP1 (rs27342) and ERAP2 (rs10044354) could synergize to increase the risk of BSCR developing well beyond the effect of HLA-A29 alone.15Gelfman S. Monnet D. Ligocki A.J. et al.ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for birdshot chorioretinopathy in HLA-A29 carriers. medRxiv, 2021Google Scholar A prior study found the rs27342 disease-associated polymorphism in 42% of European control participants and 63% of those affected by BSCR.33Kuiper J.J. Van Setten J. Ripke S. et al.A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.Hum Mol Genet. 2014; 23: 6081-6087Crossref PubMed Scopus (73) Google Scholar The same study found the rs10044354 disease-associated polymorphism in 65% of control participants and 83% of patients with BSCR. The rs27342 polymorphism increases the risk of BSCR developing with an odds ratio of 2.46.15Gelfman S. Monnet D. Ligocki A.J. et al.ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for birdshot chorioretinopathy in HLA-A29 carriers. medRxiv, 2021Google Scholar The rs10044354 polymorphism increases the risk with an odds ratio of 1.95.15Gelfman S. Monnet D. Ligocki A.J. et al.ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for birdshot chorioretinopathy in HLA-A29 carriers. medRxiv, 2021Google Scholar Two copies of the Aw19 supertype increase the risk of BSCR with an odds ratio of 4.44.15Gelfman S. Monnet D. Ligocki A.J. et al.ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for birdshot chorioretinopathy in HLA-A29 carriers. medRxiv, 2021Google Scholar All 3 of these risk factors together increase the odds ratio to 13.53.15Gelfman S. Monnet D. Ligocki A.J. et al.ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for birdshot chorioretinopathy in HLA-A29 carriers. medRxiv, 2021Google Scholar However, even when all such genetic risk factors are present, the chance of BSCR developing is still less than 1 in 2000, meaning that ERAP typing currently does not have clinical usefulness. Further research should focus not only on how these genetic factors predispose people to uveitis, but also on why the vast majority of people with these predisposing factors still do not demonstrate uveitis. We find the link relating 11 diseases, ERAP, HLA class I, and uveitis unlikely to represent a mere coincidence. However, it is a coincidence that ERAP exists within therapy and seraphim. We are thus “enraptured” that deciphering the mechanism by which ERAP is linked to uveitis will provide vital clues to several forms of uveitis. The authors thank Kimberly Ogle for contributing her playfulness with words to this editorial.