EULAR study group on MHC-I-opathy: identifying disease-overarching mechanisms across disciplines and borders

887 Kuiper JJW, etal. Ann Rheum Dis 2023;82:887–896. doi:10.1136/annrheumdis-2022-222852 Review EULAR study group on ‘MHCIopathy’: identifying diseaseoverarching mechanisms across disciplines andborders Jonas JW Kuiper ,1 Jörg C Prinz,2 Efstratios Stratikos,3 Piotr Kuśnierczyk,4 Akiko Arakawa,2 Sebastian Springer,5 Dillon Mintoff ,6,7 Ivan Padjen,8,9 Russka Shumnalieva,10 Seçil Vural,11 Ina Kötter,12,13 Marleen G van de Sande,14,15 Ayşe Boyvat,16 Joke H de Boer,1 George Bertsias,17,18 Niek de Vries,14,15 Charlotte LM Krieckaert ,19,20 Inês Leal,21,22 Nataša Vidovič Valentinčič,23,24 Ilknur TugalTutkun,25 Hanane el Khaldi Ahanach,26,27 Félicie Costantino,28,29 Simon Glatigny,30,31 Danijela Mrazovac Zimak,32 Fabian Lötscher,33 Floor G Kerstens,19,20 Marija Bakula,8 Elsa Viera Sousa ,34,35 Peter Böhm,36 Kees Bosman,37 Tony J Kenna,38 Simon J Powis,39 Maxime Breban ,28,29 Ahmet Gul,40 John Bowes ,41,42 Rik JU Lories ,43,44 Johannes Nowatzky,45,46 Gerrit Jan Wolbink,19,47 Dennis G McGonagle,48,49 Franktien Turkstra ,19,20 EULAR studygroup MHCIopathies To cite: KuiperJJW, PrinzJC, StratikosE, etal. Ann Rheum Dis 2023;82:887–896. Handling editor Josef S Smolen ►Additional supplemental material is published online only. To view, please visit the journal online (http:// dx. doi. org/ 10. 1136/ ard2022222852). For numbered affiliations see end of article. Correspondence to Dr Franktien Turkstra, Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam 1105, The Netherlands; f. turkstra@ reade. nl Received 21 July 2022 Accepted 25 January 2023 Published Online First 27March2023 © Author(s) (or their employer(s)) 2023. Reuse permitted under CC BYNC. No commercial reuse. See rights and permissions. Published by BMJ. ABSTRACT The ’MHCI (major histocompatibility complex class I)- opathy’ concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHCI antigen presentation pathway. Classical MHCIopathies such as spondyloarthritis, Behçet’s disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHCI alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHCI peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHCI pathway. Here, we discuss new insights into the biology of MHCIopathies that strongly advocate for diseaseoverarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHCIopathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHCImediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHCIopathies towards improving patient treatment and prognostication. THE INCEPTION OF THE MHC-I-OPATHY FAMILY Inflammation against self is orchestrated by a continuum of incompletely understood innate and adaptive immune mechanisms. The term ‘autoinflammatory’ refers to inflammation against self, caused by abnormal innate immunity, whereas ‘autoimmunity’ is caused by aberrant adaptive immunity.1 2 Since this dichotomous definition overlooked conditions such as psoriasis (PsO) and Behçet’s disease (BD), the concept of ‘mixedpattern’ or ‘intermediate’ diseases was proposed.3 Genomewide association studies (GWAS) of MHCIassociated diseases, such as BD (associated with HLAB*51),4 5 PsO (associated with HLAC*06:02),6–8 HLAB*27associated spondyloarthritis (SpA)9–11 HLAB*27associated anterior uveitis (AU)12 and HLAA*29associated birdshot uveitis (BU),13 14 revealed that these ‘intermediate diseases’ share a distinguishable genetic background defined by MHCI genes, the antigen processing genes ERAP1 and ERAP2, and the IL17 pathway gene IL23R. Such genetic overlap implicates MHCI peptide presentation as the key mechanistic commonality. Furthermore, it substantiates the idea that BD, PsO, SpA and BU belong to a distinct disease cluster known as ‘MHCIopathies’.15 There is ongoing debate and incomplete evidence regarding underlying mechanisms of MHCIopathies.16–18 MHCI proteins (also called HLAA, HLAB and HLAC) bind short peptides from degraded or pathogenic proteins, which have been proteolysed inside the cell by the proteasome.19–21 Most MHCI peptides are derived from proteins from the host. ERAP1 and ERAP2 are endoplasmic reticulum aminopeptidases associated with antigen processing that trim a certain fraction of these peptides if they are not short enough before loading them onto MHCI molecules.22 This process enables MHCI to present tens of thousands of peptides on the cell surface, collectively referred to as the ‘immunopeptidome’.23 CD8+T cells read out the immunopeptidome by binding to the peptideMHCI complexes with their T cell receptors (TCR) (figure 1). MHCI molecules can Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from 888 Kuiper JJW, etal. Ann Rheum Dis 2023;82:887–896. doi:10.1136/annrheumdis-2022-222852 Review also bind to killercell immunoglobulinlike receptors (KIRs) and other receptors on natural killer (NK) cells.24 There is much conjecture about the cause(s) of MHCIopathies15 25 26 and several popular hypotheses have been proposed which are not necessarily mutually exclusive. The primary hypothesis for the cause of MHCIopathies is that diseaseassociated MHCI alleles present specific immunogenic peptides that trigger ‘autoimmune’ reactions (ie, the arthritogenic peptide theory).27 The genetic association with ERAP genes also supports this hypothesis since the activity of these enzymes can modify the immunopeptidome.28 Proof of concept has been shown in PsO and recently in SpA and HLAB*27+AU.29 The identification of CD8+T cells in PsO react against melanocytes in the context of HLAC06:02 as skinspecific target cells of the psoriatic autoimmune response,30–32 while CD8+T cells from synovial and eye fluid of SpA and AU patients recognise both self and microbial peptides presented by HLAB*27.29 There is still no conclusive evidence that this mechanism underlies other MHCIopathies since mechanistic studies are technically challenging to conduct, owing to multiorgan involvement having complex tissues, which requires labourintensive technology to screen for many epitopes. Consequently, several alternative theories for MHCIopathies have been proposed, one of which suggests that MHCI protein misfolding directly leads to inflammation. According to this theory, predisposing MHCI molecules may exhibit properties which could cause excessive misfolding and accumulation in the ER, promoting the ‘unfolded protein response’.33–38 Studies of (HLAB*27) transgenic animals and cellular models support this hypothesis, but there is a paucity of translational evidence.39–43 A third popular hypothesis suggests that the predisposing MHCI alleles are recognised by KIRs or leucocyte immunoglobulinlike receptors (LILRs) on the cell surface of NK cells.44 45 In our opinion, the first hypothesis applies to the majority of MHCIopathies (with the most robust evidence for PsO and SpA), but definitive proof for CD8+T cellmediated pathologies is lacking for several other conditions. Hypotheses 2 and 3 may also apply to certain conditions. For example, in BD, ERAP1 may mediate HLAB51 recognition via NK cells,17 46 47 and pathogens that can cause reactive arthritis induce unfolded protein responses in HLAB*27positive individuals.48 While these other pathways and mechanisms are implicated, including the very interesting interactions of altered microbiomes in patients,49 we focus our discussion on the MHCI pathway as the key determinant for this family of complex conditions. THE MANY FACES AND CHALLENGES OF MHC-I-OPATHIES Several conditions are considered to be ‘classical’ MHCIopathies (PsO, psoriatic arthritis (PsA), SpA, B*27AU, BD and BU) and share strikingly similar clinical symptoms (table 1). BU is a rare and severe type of uveitis, leading to retinal damage and vision loss that exclusively affects HLAA*29positive individuals.50 51 Although it is unclear which other clinical features are shared between BU and other MHCIopathies, 1 study of 118 cases revealed that many patients also suffer from arthralgia and PsO.52 We also discuss PsA because it shares many characteristics with PsO, including strong association with MHCI alleles and IL23R.7 8 53–55 While some patients with inflammatory bowel disease may have similar symptoms,56 we will only discuss classical MHCIopathies here. MHCIopathies overlap in their pattern of organ involvement (table 1). Uveitis, for instance, is a disease feature reported in every classical MHCIopathy, although with different prevalence and anatomical location (anterior/posterior).57 58 Sacroiliitis is present in patients with SpA, PsA as well as BD.59–61 Cutaneous involvement is also a shared feature of MHCIopathies (table 1). However, not every patient exhibits the symptomatic hallmarks of every clinical entity. For example, arterial, venous and neurological complications are common in BD, but infrequent in other MHCIopathies.18 62 For several MHCIopathies, patients with the associated risk MHCI alleles are more likely to manifest earlyonset disease and a worse prognosis.63–66 Furthermore, substantial clinical and geographical variation in disease phenotypes exists, for example, the prevalence of gastrointestinal involvement in BD in Asian versus European populations.67 68 WHAT YOU (DO NOT) SEE IS WHAT YOU (DO NOT) GET! The clinical management of MHCIopathy patients is complicated by heterogeneity in age of onset, symptoms and disease course. Unlike cases with commonly recognised symptoms (e.g., Figure 1 An overview of the role of the MHCI pathway in MHCIopathies. The proteasome produces peptide fragments that are transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) and trimmed by ERAP1 and ERAP2 (ERAP) to a length of 811 amino acids before binding to MHCI molecules. After trafficking to the cell surface the MHCIpeptide complex is “read out” by surveying immune cells, triggering antigenspecific CD8+ T cell responses or natural killer (NK) cell activation. MHCIopathies are genetically associated with functionally distinct variants of MHCI and ERAP which alter the peptide repertoire presented by MHCI. Autoreactive T cells in the periphery that escape tolerance mechanisms and promote inflammation against selfpeptide epitopes. Biorender software was used to create elements from this figure under an academic license. Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from 889 Kuiper JJW, etal. Ann Rheum Dis 2023;82:887–896. doi:10.1136/annrheumdis-2022-222852 Review uveitis in SpA patients), asymptomatic or atypical involvement of the skin, bowel or other comorbidities in patients may be overlooked (table 1). For example, reexamination of SpA patients revealed that up to onethird may have comorbid PsO.69 In the DUET study, over 40% of patients with B*27AU were diagnosed with SpA or PsA on reevaluation by a rheumatologist,70 which was confirmed by other studies.71 Large populationlevel data also correlate disease manifestations of MHCIopathies such as uveitis, PsO, PsA and BD.58 72 73 Observations from wellpowered cohort studies substantiate that oral disease, which is a hallmark of BD, is also linked to SpA.74–76 Despite considerable phenotypic heterogeneity, these studies support that MHCIopathies are interconnected conditions that cannot be understood in isolation and require a multidisciplinary approach. The human phenotype ontology (HPO) provides a framework for standardised nomenclature of disease symptoms, which can facilitate improved classification of disease phenotypes.77 Although originally designed to systematically capture the clinical manifestations of rare, monogenic conditions, HPO has more recently been used to successfully infer several rare phenotypes of the UK Biobank.78 In its current form, the HPO may not be optimal for the annotation of the clinical spectrum of patients with MHCIopathies. As a result, the EULAR study group aims to evaluate the HPO and adapt it to fit the symptoms of MHCIopathies. The spectrum of MHCIopathies will benefit from standardisation of disease manifestations, allowing existing cohorts to be merged into a wellpowered study. The precise delineation of clinical phenotypes will allow us to relate them to molecular endotypes. We expect that this process will facilitate the discovery (and validation) of better diagnostic, prognostic and therapeutic biomarkers. A COMMON GENETIC ARCHITECTURE MHC-I, the tip of the iceberg Strong genetic association with certain MHCI alleles is the hallmark of the MHCIopathy cluster: MHCI association studies date back to 1973 with the discovery of the association of HLAB*27 and SpA as well as HLAB*51 and BD (formerly ‘HLA5’),79–81 followed by reports on HLAC*06:02 (previously known as ‘HLACw6’) and PsO in 1977,82 83 and the association between HLAA*29 and BU in 198284 (table 2). In comparison to genes associated with complex inflammatory conditions, the effect size of MHCI alleles accounts for a disproportionate amount of genetic risk. For almost 50 years, researchers have struggled to understand the role these class I alleles play in their disease biology. Interestingly, recent finemapping studies showed that statistical adjustment for HLAB*27 in SpA revealed independent associations for other MHCI alleles, including HLAA*02:01, HLAB*07, HLAB*57 and HLAB*4085 86 (table 2). This is significant because it also implicates the MHCI pathway for cases lacking the primary MHCI risk allele and strongly incriminates peptide presentation rather than alternative mechanisms. Association with several of these alleles was also found after correcting for the primary risk MHCI allele in PsO (HLAA*02:01, HLAB*27 and HLAB*07), BD (eg, HLAB*27 and HLAB*57), PsA (eg, HLAB*07 and HLAA*02) and AU.7 12 87–90 To date, small GWAS in the rare BU had limited power to detect HLAA*29independent loci in detail, but also reported independent risk MHCI alleles.13 14 These findings raise the possibility that an ensemble of diseaseoverarching MHCI alleles contribute to MHCIopathy susceptibility. Table 1 Summary of tissue involvement per MHCIopathy, organised per clinical specialty (references underlying the summarised data and scores can be found in online supplemental table 1 Disease PsO* PsA† SpA B*27 AU BD BU Medical specialty Primary risk MHCIallele(s) C*06 C*06/B*27 B*27 B*27 B*51 A*29 Prognosis worse when primary MHCI allele present 3 0 3 n.a 3 0 Ophthalmology Uveitis‡ 1 1 3 3 3 3 Dermatology Oral ulcerations 0 1 1 0 3 0 Dermatology Genital ulcerations 0 0 0 0 3 0 Dermatology Psoriasiform dermatitis§ 3 3 2 2 1 1 Dermatology Pustular lesions¶ 2 2 1 0 3 0 Dermatology Erythema nodosumlike lesions 0 0 0 0 3 0 Rheumatology Spondylitis 1 3 3 3 1 0 Rheumatology Arthritis 2 3 3 2 3 0 Rheumatology Enthesitis 2 3 3 3 1 0 Rheumatol/immunol Vasculitis** 1 1 1 0 3 0 Gastroenterology Inflammatory bowel disease 1 1 2 1 2 0 Internal medicine Comorbid hypertension 1 2 2 0 0 2 Neurol/Int Med/cardiol Comorbid cardiovasc disease 2 2 2 0 1 0 Legend: 3 part of the disease ectrum 2 regularly reported 1 infrequently reported 0 3 part of the disease spectrum. 2 regularly report. 1 infrequently reported. 0 either unknown / no reports / not present. *Psoriasis: besides plaque psoriasis. This encompasses other forms of psoriatic disease like psoriasis guttate and (several types of) pustular psoriasis. †PsA: both axial and peripheral disease. ‡Uveitis anterior is the main subtype reported in PsO, PsA, SpA, whereas in Behçet’s multiple anatomical subtypes of uveitis are reported. BU manifests as posterior uveitis. §Psoriasiform lesions: refers to the several types of psoriasis; classical plaque psoriasis, guttate, nail lesions and erythematous as well as pustular lesions. ¶Pustular lesions: covers acneiform, papulopustular and nonfollicular pustules. **Vasculitis in PsO as well as in PsA and SpA vasculitis is in the large vessels (aortitis); in B27AU and BU not reported outside the eye; in Behçet’s vasculitis is in all types of vessels, arteries and veins. BU, birdshot uveitis; PsA, psoriatic arthritis; PsO, psoriasis; SpA, spondyloarthritis. Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from 890 Kuiper JJW, etal. Ann Rheum Dis 2023;82:887–896. doi:10.1136/annrheumdis-2022-222852 Review Therefore, functional studies that consider only one MHCI allele may not capture the complexity of the MHCI pathway in patients. This emphasises the need to use primary patient tissues to investigate disease mechanisms. It remains to be determined whether the full MHC haplotype (including ‘secondary’ risk MHCI alleles) improves patient stratification. Large populationbased studies (ie, UK Biobank) support that MHCI alleles are associated with a variety of health biomarkers.91 A first step into this direction could be the conduction of a multiancestral MHCIopathy GWAS analysis by combining several available largescale genomewide datasets and interrogating the MHC for different phenotypic states. The devil is in the ERAP1 and ERAP2 details Perhaps one of the major accomplishments for the progress in the understanding of MHCIopathies was the discovery of the association with the ERAP1 and/or ERAP2 genes.4 6 7 9 12–14 92–95 These genes encode two ERresident enzymes specialised in trimming peptides to facilitate or prevent their binding in the groove of MHCI.96 97 By generating and destroying peptide epitopes, ERAPs can affect CD8+T cell and NK cell responses.98–101 Genetic variants in ERAP1 and ERAP2 affect the enzymatic activity and expression levels of these enzymes.93 102 Consequently, a change in ERAP activity may expose CD8+T cells to altered peptide repertoires (self or nonself) via MHCI risk alleles, which can be harmful.28 Genetic association between ERAP1 and MHCIopathies is typically observed in individuals carrying the primary risk MHCI.4 6 11 13 85 93 Coding variants in ERAP1 organise into several common haplotypes often referred to as ERAP1 ‘allotypes’103 104 that exhibit a wide range of enzymatic activities towards peptide substrates and differentially shape the immunopeptidome of MHCI.28 105 Risk polymorphisms in ERAP1 (and ERAP2) are also strongly associated with mRNA and protein expression levels of these aminopeptidases.50 102 106 Haplotypebased analyses have singled out specific ERAP1 allotypes as risk factors for MHCIopathies. While several terms have been proposed for ERAP1 allotypes, standardised nomenclature has yet to be widely adopted. One functionally distinct ERAP1 allotype (often referred to as Haplotype 10 (hap10)) is a risk factor for BD and BU,93 107 but protective for SpA, AU and PsO.28 108 Interestingly, in PsO, the protective hap10 was less effective in generating the autoantigenic epitope than the risk haplotypes of ERAP1, leading to lower HLAC expression and immunogenicity of melanocytes.31 ERAP1 may also influence NK cell responses via inhibitory receptors NKG2A/CD94 (also expressed by CD8+T cells109) to nonclassical MHCI molecule HLAE.46 The inhibitory activity of HLAE requires the presentation of a signal sequence from MHCI molecules, which are also present in HLAA29, HLAB27 and HLAB51.110–112 Therefore, ERAPs may also affect NK cells and CD8+T cells via MHCIrelated molecules, as was previously shown in cancer models.46 113 Although KIR receptors can recognise immunopeptidome changes caused by ERAP1, KIR genes do not influence HLAB*27 and ERAP1mediated ankylosing spondylitis risk.114 115 This suggests that the disease mechanisms mediated by ERAP1 and MHCI are less dependent on KIRs. In contrast to ERAP1, ERAP2 genetic variants are not associated with all MHCIopathies (eg, BD). Also, ERAP2 is associated with SpA regardless of HLAB*27 status. Because there is also epistasis between ERAP1 and HLAB*40 in SpA (independent of HLAB*27),85 it is possible that ERAP2 modifies disease in SpA via alternative risk MHCI alleles. Functional studies support that ERAP2 significantly affects the immunopeptidome of many MHCI alleles, including HLAB*40115 116 Note that ERAP2 allotypes cooccur nonrandomly with ERAP1 allotypes.93 105 Furthermore, although HLAA*29 is common in many regions, HLAA*29positive individuals who carry both ERAP1 and ERAP2 risk alleles are only observed in countries where BU is prevalent.93 Therefore, an individual’s ERAP1 and ERAP2 allotypes along with their MHCI profile (and T cell repertoire) are most likely to determine their susceptibility to MHCIopathies.117 Studies linking ERAP genotypes with clinical end points may have potential,118 119 but we would like to emphasise that these studies should be carefully controlled and well powered. Both ERAP1 and ERAP2 are common denominators of MHCIopathies, which place antigenic peptide presentation at the heart of their pathogenesis. IL23R and T cells There are many other genes associated with conditions within the MHCIopathy spectrum that have been discovered through GWAS. While they are important to disease biology, we only briefly discuss IL23R, a receptor for IL23 expressed by T cells (and Table 2 Reported HLA class I associations in four MHCIopathies MHCIopathy Prevalence Primary HLA class I association % cases negative for primary HLA class I allele Independent* HLA class I associations Birdshot uveitis 15/500 000 HLAA*29:02 0HLAA*3013 14 HLAA*3314 Spondyloarthritis† 0.5% HLAB*27 ~ <30 HLAB*4085 86 HLAA*0285 HLAB*0785 HLAB*5785 HLAC*1586 Behçet’s Disease 0.19120/100 0009HLAB*51 ~30–70 HLAA*0287 HLAB*2787 HLAB*5787 HLAA*0387 HLAB*1587 HLAB*4987 HLAA*2687 89 HLAC*0789 Psoriasis 2–4% HLAC*06:02 ~30–70 HLAA*02122 HLAB*27122 HLAB*07122 HLAC*07176 *Identified by statistical adjusting for primary associated HLA class I allele. †Majority of data are from genetic studies in ankylosing spondylitis. Includes both risk and protective alleles. Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from 891 Kuiper JJW, etal. Ann Rheum Dis 2023;82:887–896. doi:10.1136/annrheumdis-2022-222852 Review innate lymphocytes), because it is common to MHCIopathies and is associated with disease severity and phenotypes.8 118 120–122 Fascinatingly, despite IL23R expression by CD4+T cells, epigenetic analyses implicate CD8+T cells as major perpetrators of MHCIopathies.88 Interleukin17producing CD8+T cells (termed ‘Tc17’) infiltrating skin and synovial lesions in PsO, BD, SpA and PsA patients express IL23R.123–125 Tc17 cells are also more abundant in patients with BU.126 127 IL23R’s role in the pathophysiology of MHCIopathies is incompletely understood, but likely to be tissuedependent.128 This may explain why patients with PsO129 and PsA130 exhibit clinical response to therapy that disrupts T cell IL23 signalling, while initial trials were less successful in SpA.131 132 A better understanding of clinical and molecular features will help overcome challenges posed by patient heterogeneity as well as identify therapeutic biomarkers which will guide the selection of candidates eligible for treatment with IL23 inhibitors.21 128 131–134 UNMET NEEDS IN MHC-I-OPATHY PATHOPHYSIOLOGY UNDERSTANDING Evidence for autoreactive CD8+ T cell involvement A number of immunopeptidome studies in cell models have shown that polymorphisms in ERAP cause change in the peptides presented by HLAB27, HLAB51, HLAA29 and other MHCI alleles.28 115 116 Circumstantial evidence suggests that these enzymes introduce or remove peptides that bind to risk MHCI alleles and signal CD8+T cells to attack healthy tissues. The fact that CD8+T cells are clonotypically expanded in patients with SpA, PsO and PsA supports this concept.135–138 In BD, carriers of the diseaseassociated ERAP1 allotype107 show enrichment for circulating antigenexperienced effector CD8+T cells and ERAP1 modulation influenced CD8+T cell responses.107 The lack of identification of causative autoantigens or indeed alloantigens has resulted in discussion about whether CD8+T cells drive pathology in MHCIopathies.17 Regardless, autoantigenderived peptide recognition by CD8+T cells in patients has previously been reported, including an HLAB51presented peptide derived from a stressinducible autoantigen in BD,139 HLAC06:02 presented peptide from innate host defence protein LL37 in PsO,140 and HLAB27restricted epitope from a peptide hormone receptor and cartilagederived peptides in SpA.141 142 To date, the most compelling conceptual proof that CD8+T cells mediate autoimmune inflammation is based on studies of PsO, and very recently in HLAB*27positive SpA and AU patients.29 30 Skin lesional CD8+T cells in PsO can recognise an HLAC06:02restricted autoantigen epitope from ADAMTSL5 highly expressed in skin melanocytes.30 31 ADAMTSL5specific CD8+T cells secrete PsOpromoting cytokines (eg, IL17) specifically after recognising melanocytepeptide processed by ERAP1 and presented by the diseaseassociated MHCI HLAC06:02.30–32 Here, the immunogenicity of melanocytes for selfreactive CD8+T cell responses was increased by diseaseassociated ERAP1 haplotypes through greater supply of the peptide autoantigen.30 It has, therefore, been suggested that pharmacological modulation of ERAP activity towards precursor peptides specifically presented by MHCI alleles could reverse inflammation in MHCIassociated diseases.143 144 Researchers recently found that tissueinfiltrating CD8+T cells shared TCRs in eye liquid as well as synovial fluid of HLAB*27positive patients with AS and AU.29 These CD8+T cells specifically recognise microbial (eg, YEIH protein from reactive arthritistriggering pathogens) and selfantigens (eg, peptides from GPER1 or PRPF3 proteins) specifically within the context of HLAB27. According to these findings, environmental pathogens may trigger autoimmunity via CD8+T cell activation in MHCIopathies, thus supporting the primary hypothesis of the MHCIopathy pathogenesis. Future research might explore whether HLAB27 presentations of these peptides are affected by risk allotypes of ERAP1 and whether pharmacological targeting of ERAPs interferes with these responses. It remains unclear why of the thousands of selfpeptides in the immunopeptidome only a minority become immunogenic, while the majority remain tolerable. However, T cell autoantigens often have posttranslational modifications or show altered binding conformation.145–147 What triggers CD8+T cell selfreactivity in MHCIopathies remains unknown. The classical view is that negative selection in the thymus eliminates autoreactive T cells. Some selfreactive CD8+T cells manage to escape this filtering process and are reintroduced into the circulation (sometimes at high frequencies) but kept in check by tolerance mechanisms.148–150 Interestingly, recent work suggests that thymic regulatory Tcells, rather than negative selection of autoreactive T cells, enforce protection against autoimmunity.148 151 Here, the cytokine IL23 eliminates thymic regulatory T cells in an IL23Rdependent manner,152 while selectively enriching IL23Rexpressing CD8+T cells.153 Moreover, there is no sharp affinity threshold for the recognition of MHCpeptide complex by TCRs, and CD8+T cells with otherwise low affinity TCRs can be activated by a large increase in presented autoantigen.154 155 This also fits with the recently proposed ‘autoimmune surveillance of hypersecreting mutants’ theory that links high autoantigen levels to Tcell autoimmunity.156 Crosspresentation of extracellular antigens in dendritic cells can also lead to the entry of extracellular antigens into the MHC class I pathway, thereby greatly expanding the potential pool of immunogenic peptides. Conceptually, this integrates the possibility of microbial agents causing disease, as demonstrated for SpA, and AU.29 Virustriggered Box 1 The aims of the EULAR study group on "MHCIopathy" 1. Multidisciplinary collaboration between rheumatologists, dermatologists and ophthalmologists for consensus and standardised annotation of disease symptoms. 2. Detailed phenotypic evaluation by patientreported symptoms/outcomes. 3. Integration of GWAS data of MHCIopathyrelated diseases, across a larger number of existing cohorts, to facilitate fine mapping of the genetic basis. 4. Harmonisation of the nomenclature (eg, ERAP allotypes) and provide expert synthesis of current best practice for the study of key aspects of the biology in MHCIopathies. 5. Establishment of a panEuropean consortium with standardised clinicopathological disease phenotypes from aim 1 and 2, (complemented by molecular data on ERAP and MHCI haplotypes and possibly other biological data such as metagenomics to assess microbiome involvement and TCRrepertoire data) for improved disease classification, diagnostic criteria and prognostic biomarkers for prediction of disease progression and efficacy of (type of) therapy. 6. Evaluation of MHCIopathies in different ethnic backgrounds, given the massive heterogeneity within class1 antigens. 7. Patient participation: involvement of patient research partners. Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from 892 Kuiper JJW, etal. Ann Rheum Dis 2023;82:887–896. doi:10.1136/annrheumdis-2022-222852 Review clonal CD8+T cell responses are processed through MHC class I, and some of these responses are controlled by ERAP1.157 Recent technological advancements which have increased the sensitivity and scale of analysing immunopeptidomes of primary patient tissues (ideally sampled at the affected organs) aswell as highthroughput profiling of (auto)antigenspecific Tcell repertoires (ie, singlecell TCR sequencing) may help identify CD8+T cellmediated disease mechanisms in MHCIopathies in greater detail.158–161 Towards MHC-I pathway therapy This study group’s ultimate goal is to improve disease outcome of MHCIopathies. Although definite disease mechanisms need to be established, available clinical and molecular evidence allow us to outline several potential strategies. Given that MHCI is considered a root cause for MHCIopathies, therapeutic targeting of antigen processing and presentation seems selfevident. This may be achieved by interventions aimed at disrupting cytokine signalling (see section IL23R and T cells) or strategies that facilitate restoration of the microbiome.48 Patients with MHCIopathies may have an altered microbiota,162–164 but healthy individuals may also show microbiota compositions that cluster according to their HLA alleles (eg, HLAB*27, HLAA*29).165 Emerging T cellantigen discovery approaches within the microbiome may provide an exciting field for upcoming studies.166 In case of autoantigenmediated pathology, it may be possible to specifically negate T cell interaction by antibodies or small compounds that specifically block access to MHCIpeptide complexes. Tcell engagement may also be blocked by preventing or changing the abundance of target peptide presentation by manipulation upstream of MHCI, including the cellular proteome (eg, chemotherapy), or pharmacological inhibition or modulation of the proteasome, TAP or the antigen loading complex,167–171 although with limitations in specificity at the cost of potential adverse effects. Inhibiting or, depending on the disease, enhancing the action of ERAP1 and ERAP2 may be a promising approach, since these enzymes are highly specialised for antigen presentation, and much is known about their structure and function to allow the development of inhibitors or enhancers.143 144 172 The fact that their impact on antigen presentation may be limited to a part of the immunopeptidome,173 may constitute a middle ground between single antigen strategies (antibodies for MHC/peptide complex) and general suppression of the MHCI pathway. Most of these therapeutic ‘options’ are still in their infancy and require translational studies in suitable preclinical models. Although the HLAB*27transgenic rodent models,174 have provided valuable insights into the disease mechanisms of MHCIopathies, there remains an unmet need for additional transgenic MHCI models. To determine if it is possible to target the MHCI pathway therapeutically in patients, these models should be ‘fully’ humanised and capture a broader spectrum of clinical and molecular characteristics. Mission of the EULAR study group on MHC-I-opathies As a result of the complexity of the clinical phenotypes and the lack of knowledge about the underlying mechanisms of MHCIopathies, international crossdisciplinary collaborations and complementary scientific expertise are urgently needed. The EULAR study group on MHCIopathies provides an international network that brings medical specialists, translational and fundamental scientists under one umbrella with the aim of cooperatively overcoming longstanding unmet needs in the disease management and understanding of the biology of MHCIopathies. The study group (currently >50 participants: dermatologists, ophthalmologists, rheumatologist, scientists and patient representatives from >15 countries) was founded in 2020 amidst the COVID19 pandemic. The global pandemic restricted initial discussion to online meetings. An inaugural meeting took place in May 2022, in Amsterdam, followed by a meeting during EULAR in June 2022 in Copenhagen. Study group research and collaborations will focus on the pathophysiology of MHCI pathway in these conditions. Briefly, the study group aims are summarised in box 1 and the objective is to harmonise, facilitate and improve research methodology and terminology, study disease mechanisms more collectively; foster basic and translational knowledge exchange in an interdisciplinary fashion through meetings via symposia during EULAR meetings(https://www.eular.ch/myUploadData/files/study_group_aims_ mhc_i_opathy_for_web.pdf) and disseminate progress via social media (eg, an open Linkedin page for interested colleagues, https:// www.linkedin.com/groups/12722534/). To accomplish these objectives, the Study Group formed several multidisciplinary task forces composed of clinicians, biologists and patient representatives to prioritise unmet research needs that would require crossEuropean collaboration. For example, one of the task forces aims to conduct metaanalysis of GWAS data of the MHCIopathies to fine map the MHC and identify novel risk loci in relation to clinical features. Another task force currently works on evaluation of a patientreported symptom infrastructure, which has already been successfully employed in COVID19 studies.175 Although currently all work within the study group is contributed in kind by its members, the rapidly growing study group aims to apply for external funding for research. This will also be required to achieve more ambitious goals, such as the collection of biomaterials to foster innovative research by deep immunoprofiling (eg, Tcell repertoires, MHCI immunopeptidomes) and translational studies (eg, ERAP modulation in patient tissues). The EULAR study group will complement their scientific objectives with the organisation of interactive workshops and symposia connected to EULAR to exchange basic, translational and clinical knowledge in an interdisciplinary fashion and further facilitate the growth of the study group by inclusion of physicians and scientists active in this field. In conclusion, the EULAR study group on MHCIopathies bridges a variety of medical scientific disciplines with the ambitious joint objective to conduct an integrated investigation of MHCIopathies to discover the cause and cure for a variety of complex inflammatory conditions. Author affiliations 1Department of Ophthalmology, Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands 2University Hospital, department of Dermatology and Allergy, Ludwig Maximilians University Munich, Munchen, Germany 3Laboratory of Biochemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece 4Laboratory of Immunogenetics and Tissue Immunology, Institute of Immunology and Experimental Therapy Ludwik Hirszfeld Polish Academy of Sciences, Wroclaw, Poland 5School of Science, Constructor University Bremen gGmbH, Bremen, Germany 6Department of Dermatology, Mater Dei Hospital, Msida, Malta 7Department of Pathology, University of Malta Faculty of Medicine and Surgery, Msida, Malta 8Division of Clinical Immunology and Rheumatology, University Hospital Centre Zagreb Department of Internal Medicine, Zagreb, Croatia 9University of Zagreb School of Medicine, Zagreb, Croatia 10Clinic of Rheumatology, Department of Rheumatology, Medical University of Sofia, Sofia, Bulgaria 11School of Medicine, Department of Dermatology, Koç University, Istanbul, Turkey 12Clinic for Rheumatology and Immunology, Bad Bramdsted Hospital, Bad Bramstedt, Germany 13Division of Rheumatology and Systemic Inflammatory Diseases, University Medical Center HamburgEppendorf, Hamburg, Germany Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from 893 Kuiper JJW, etal. Ann Rheum Dis 2023;82:887–896. doi:10.1136/annrheumdis-2022-222852 Review 14University of Amsterdam, Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity, Amsterdam UMC Location AMC, Amsterdam, The Netherlands 15Amsterdam Rheumatology and Immunology Center (ARC) | Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands 16Department of Dermatology, Ankara University Faculty of Medicine, Ankara, Turkey 17Department of Rheumatology and Clinical Immunology, University of Crete School of Medicine, Iraklio, Greece 18Laboratory of AutoimmunityInflammation, Institute of Molecular Biology and Biotechnology, Heraklion, Greece 19Amsterdam Rheumatology and immunology Center (ARC)| Reade, Amsterdam, The Netherlands 20Department of Rheumatology, Reade Hoofdlocatie Dr Jan van Breemenstraat, Amsterdam, The Netherlands 21Department of Ophthalmology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte EPE, Lisboa, Portugal 22Centro de Estudeos das Ciencias da Visão, Universidade de Lisboa Faculdade de Medicina, Lisboa, Portugal 23University Eye Clinic, University Medical Centre Ljubljana, Ljubljana, Slovenia 24Faculty of medicine, University of Ljubljana, Ljubljana, Slovenia 25Department of Ophthalmology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey 26Departement of Ophthalmology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands 27Department of Ophthalmology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands 28Service de Rheumatology, Hospital AmbroisePare, BoulogneBillancourt, France 29Infection & Inflammation, UMR 1173, Inserm, UVSQ, University ParisSaclay, MontignyleBretonneux, France 30Infection & Inflammation, UMR 1173, Inserm, UVSQ/Université Paris Saclay, MontignyleBretonneux, France 31Laboratoire d’Excellence Inflamex, Paris, France 32Department of Ophthalmology, University Hospital Centre Zagreb, Zagreb, Croatia 33Department of Rheumatology and Immunology, Inselspital University Hospital Bern, University of Bern, Bern, Switzerland 34Rheumatology Research Unit Molecular João Lobo Antunes, University of Lisbon Medical Faculty, Lisboa, Portugal 35Rheumatology DepartmentSanta Maria Centro Hospital, Academic Medical Centre of Lisbon, Lisboa, Portugal 36Patientpartner, German League against Rheumatism, Bonn, Germany 37Patientpartner, Nationale Vereniging ReumaZorg, Nijmegen, The Netherlands 38Translational Research Institute, Queensland University of Technology, Brisbane, Queensland, Australia 39School of Medicine, University of St Andrews School of Medicine, St Andrews, UK 40Division of Rheumatology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey 41Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Center, The University of Manchester, Manchester, UK 42NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester, UK 43Department of Rheumatology, KU Leuven University Hospitals Leuven, Leuven, Belgium 44Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium 45Department of Medicine, Division of Rheumatology, NYU Langone Behçet’s Disease Program, NYU Langone Ocular Rheumatology Program, New York University Grossman School of Medicine, New York University, New York, New York, USA 46Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA 47Department Immunopathology, Sanquin Research, Amsterdam, The Netherlands 48Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK 49NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK Twitter Jonas JW Kuiper @jonas_kuiper and Tony J Kenna @tonykenna3 Contributors The final version was approved by all authors. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or notforprofit sectors. Competing interests JCP: Grants or contracts from any entity German Research Foundation grants PR 241/52Consulting fees Boehringer IngelheimPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events paid activities as a speaker for Almirall, Boehringer Ingelheim, JanssenCilag, Novartis and Pfizer PK Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid All unpaid: Human Immunology (Elsevier) Editorial Board, Frontiers in Immunology Guest associate, Editor and review editor. Editorial board of International Journal of Immunogenetics SS: all support for the present manuscript (eg, funding, provision of study materials, medical writing, article processing charges, etc. Deutsche Forschungsgemeinschaft (DFG) to Jacobs University Bremen DM Grants or contracts from any entity Government of MaltaPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Sanofi, UriageSupport for attending meetings and/or travel Avene, Bioderma, UriageLeadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid Maltese Association of Dermatologists and VenereologistsIvan IP Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Novartis, Eli Lilly, Pfizer, Abbvie, Honoraria for lectures, payments directly to me RS Support for attending meetings and/or travel Abbvie and PfizerIna IK Consulting fees Amgen, Boehringer,GSK, SobiPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Abbvie, Amgen. Boehringer, GSK, Janssen, Lilly, MSD, Novartis, Pfizer, Sobi MvdS Grants or contracts from any entity Novartis, UCB, EliLillyPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events UCBSupport for attending meetings and/or travel UCBParticipation on a Data Safety Monitoring Board or Advisory Board Novartis, UCB, Abbvie GB Grants or contracts from any entity GSK, PfizerPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events GSK, AstraZeneca, Pfizer, Abbvie, Aenorasis, Novartis, Lilly IL Consulting fees Novartis, Alimera lTT Consulting fees AbbVie, Turkey, NovartisPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events AbbVie, Turkey FC Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events LillySupport for attending meetings and/or travel UCB, NovartisParticipation on a data safety monitoring board or Advisory Board UCB, Novartis DMZ Grants or contracts from any entity European Society of OphthalmologyPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Zentiva, Alkaloid d.o.o., Inspharma d.o.o. MB Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Pfizer, Viatris, Lilly, MSD TJK All support for the present manuscript (eg, funding, provision of study materials, medical writing, article processing charges, etc). National Health & Medical Research Council GNT2011115Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid President, Australian Society for Medical Research MB Grants or contracts from any entity PFIZERConsulting fees PFIZERPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events FRENESIUS KABI, LILLYSupport for attending meetings and/or travel BIOGEN, PFIZER, JANSSEN RJUL Consulting fees UCB, Novartis, Abbvie, EliLillyPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events UCB, Novartis, Abbvie, EliLilly, Amgen JN All research funding support for the present manuscript: NEINIH R01EY033495—research funds and R01EY031383— research fundsHonoraria for lectures: Harvard University, Northwestern University, Massachusetts General Hospital.Support for attending meetings and/or travel: NYU Department of Medicine, NIHNEIParticipation Medical Advisory Board: ABDA (American Behçet’s Disease Association) DGMcG Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Janssen, Abbvie, Novartis, UCB, BMS, Lilly. 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ORCID iDs Jonas JWKuiper http://orcid.org/0000-0002-5370-6395 DillonMintoff http://orcid.org/0000-0003-3705-0119 Charlotte LMKrieckaert http://orcid.org/0000-0001-6591-7838 ElsaViera Sousa http://orcid.org/0000-0002-7170-8802 MaximeBreban http://orcid.org/0000-0002-6932-9395 JohnBowes http://orcid.org/0000-0003-4659-031X Rik JULories http://orcid.org/0000-0002-5986-3092 FranktienTurkstra http://orcid.org/0000-0002-8055-9036 Protected by copyright. on June 27, 2023 at Faculty of Medicine, University of Lisbon.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/ard-2022-222852 on 27 March 2023. Downloaded from 894 Kuiper JJW, etal. Ann Rheum Dis 2023;82:887–896. doi:10.1136/annrheumdis-2022-222852 Review REFERENCES 1 Medzhitov R. The spectrum of inflammatory responses. Science 2021;374:1070–5. 2 Szekanecz Z, McInnes IB, Schett G, etal. Autoinflammation and autoimmunity across rheumatic and musculoskeletal diseases. 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Presse Medicale (Paris, France: 1983), 39(5), e97–e102. doi:10.1016/j.lpm.2009.12.005 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/ard-2022-222852–10.:10 2023;Ann Rheum Dis, et al. Kuiper JJW