{"doi":"10.1002/art.42327","title":"Paradoxical Effects of Endoplasmic Reticulum Aminopeptidase 1 Deficiency on <scp>HLA</scp>–<scp>B27</scp> and Its Role as an Epistatic Modifier in Experimental Spondyloarthritis","abstract":"OBJECTIVE: We undertook this study to examine the functional basis for epistasis between endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 in experimental spondyloarthritis (SpA). METHODS: -microglobulin-transgenic (HLA-B27-Tg) rats and HLA-B7-Tg rats. The effects of ERAP1 deficiency on HLA allotypes were determined using immunoprecipitation and immunoblotting, flow cytometry, allogeneic T cell proliferation assays, and gene expression analyses. Animals were examined for clinical features of disease, and tissue was assessed by histology. RESULTS: m-free) HLA-B27 heavy chains, while having the opposite effect on HLA-B7. Furthermore, in rats with ERAP1 deficiency, HLA-B27 misfolding was reduced, while free HLA-B27 heavy chain dimers on the cell surface and monomers were increased. The effects of ERAP1 deficiency persisted during up-regulation of HLA-B27 and led to a reduction in endoplasmic reticulum stress. ERAP1 deficiency reduced the prevalence of arthritis in HLA-B27-Tg rats by two-thirds without reducing gastrointestinal inflammation. Dendritic cell abnormalities attributed to the presence of HLA-B27, including reduced allogeneic T cell stimulation and loss of CD103-positive/major histocompatibility complex class II-positive cells, were not rescued by ERAP1 deficiency, while excess Il23a up-regulation was mitigated. CONCLUSION: ERAP1 deficiency reduced HLA-B27 misfolding and improved folding while having opposing effects on HLA-B7. The finding that HLA-B27-Tg rats had partial protection against SpA in this study is consistent with genetic evidence that loss-of-function and/or reduced expression of ERAP1 reduces the risk of ankylosing spondylitis. Functional studies support the concept that the effects of ERAP1 on HLA-B27 and SpA may be a consequence of how peptides affect the biology of this allotype rather than their role as antigenic determinants.","journal":"Arthritis & Rheumatology","year":2022,"id":245414,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9668,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":697090,"name":"Tejpal Gill","orcid":"0000-0002-9567-3827","position":1,"is_corresponding":false},{"id":859702,"name":"Joshua Bennett","orcid":null,"position":2,"is_corresponding":false},{"id":880019,"name":"So‐Hee Hong","orcid":"0000-0002-2833-8025","position":3,"is_corresponding":false},{"id":708400,"name":"Vance Holt","orcid":null,"position":4,"is_corresponding":false},{"id":822579,"name":"Anders Lindstedt","orcid":"0000-0003-1988-5163","position":5,"is_corresponding":false},{"id":880480,"name":"Sufia Bakshi","orcid":null,"position":6,"is_corresponding":false},{"id":218220,"name":"Keith A. Sikora","orcid":null,"position":7,"is_corresponding":false},{"id":880481,"name":"Joel D. Taurog","orcid":null,"position":8,"is_corresponding":false},{"id":293023,"name":"Maxime Bréban","orcid":"0000-0002-6932-9395","position":9,"is_corresponding":false},{"id":470058,"name":"Fatemeh Navid","orcid":"0000-0002-1964-7635","position":10,"is_corresponding":false},{"id":218261,"name":"Robert A. Colbert","orcid":"0000-0001-6237-4575","position":11,"is_corresponding":false},{"id":880018,"name":"Tri Tran","orcid":"0009-0006-5770-5572","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T00:23:34.974895Z","pmid":"36577442","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}