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Review
. 2023 Jul;82(7):887-896.
doi: 10.1136/ard-2022-222852. Epub 2023 Mar 27.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching 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 Tugal-Tutkun  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  50   20 ; EULAR studygroup MHC-I-opathies
Affiliations
Review

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

Jonas Jw Kuiper et al. Ann Rheum Dis. 2023 Jul.

Abstract

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I 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 MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies 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 MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Keywords: Arthritis, Psoriatic; Behcet Syndrome; Immune System Diseases; Spondylitis, Ankylosing.

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Conflict of interest statement

Competing interests: JCP: Grants or contracts from any entity German Research Foundation grants PR 241/5-2Consulting fees Boehringer IngelheimPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events paid activities as a speaker for Almirall, Boehringer Ingelheim, Janssen-Cilag, 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 lT-T 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, Eli-LillyPayment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events UCB, Novartis, Abbvie, Eli-Lilly, Amgen JN All research funding support for the present manuscript: NEI-NIH 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, NIH-NEIParticipation 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.

Figures

Figure 1
Figure 1
An overview of the role of the MHC-I pathway in MHC-I-opathies. 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 8-11 amino acids before binding to MHC-I molecules. After trafficking to the cell surface the MHC-I-peptide complex is “read out” by surveying immune cells, triggering antigen-specific CD8+ T cell responses or natural killer (NK) cell activation. MHC-I-opathies are genetically associated with functionally distinct variants of MHC-I and ERAP which alter the peptide repertoire presented by MHC-I. Autoreactive T cells in the periphery that escape tolerance mechanisms and promote inflammation against self-peptide epitopes. Biorender software was used to create elements from this figure under an academic license.
See this image and copyright information in PMC

References

    1. Medzhitov R. The spectrum of inflammatory responses. Science 2021;374:1070–5. 10.1126/science.abi5200 - DOI - PubMed
    1. Szekanecz Z, McInnes IB, Schett G, et al. . Autoinflammation and autoimmunity across rheumatic and musculoskeletal diseases. Nat Rev Rheumatol 2021;17:585–95. 10.1038/s41584-021-00652-9 - DOI - PubMed
    1. McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med 2006;3:e297. 10.1371/journal.pmed.0030297 - DOI - PMC - PubMed
    1. Kirino Y, Bertsias G, Ishigatsubo Y, et al. . Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 2013;45:202–7. 10.1038/ng.2520 - DOI - PMC - PubMed
    1. Takeuchi M, Mizuki N, Meguro A, et al. . Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet’s disease susceptibility. Nat Genet 2017;49:438–43. 10.1038/ng.3786 - DOI - PMC - PubMed

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