{"doi":"10.1093/brain/awae048","title":"HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease","abstract":"Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.","journal":"Brain","year":2024,"id":419213,"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":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":661382,"name":"Sergio Muñiz‐Castrillo","orcid":"0000-0001-5958-3288","position":1,"is_corresponding":false},{"id":900896,"name":"Lídia Sabater","orcid":"0000-0001-8556-6166","position":2,"is_corresponding":false},{"id":1209196,"name":"Vicente Peris-Sempere","orcid":null,"position":3,"is_corresponding":false},{"id":233138,"name":"Vamsee Mallajosyula","orcid":"0000-0002-0658-3652","position":4,"is_corresponding":false},{"id":1209197,"name":"Luo Guo","orcid":null,"position":5,"is_corresponding":false},{"id":439352,"name":"Han Yan","orcid":"0000-0003-0401-9676","position":6,"is_corresponding":false},{"id":347907,"name":"Eric Yu","orcid":"0000-0003-3525-4564","position":7,"is_corresponding":false},{"id":225067,"name":"Jing Zhang","orcid":"0000-0001-8549-3286","position":8,"is_corresponding":false},{"id":1208586,"name":"Ling Lin","orcid":"0000-0002-3146-8648","position":9,"is_corresponding":false},{"id":1209198,"name":"Flavia Fagundes Bueno","orcid":null,"position":10,"is_corresponding":false},{"id":411585,"name":"Xuhuai Ji","orcid":"0000-0002-1768-6403","position":11,"is_corresponding":false},{"id":1208587,"name":"Géraldine Picard","orcid":"0000-0003-1282-267X","position":12,"is_corresponding":false},{"id":1208588,"name":"Véronique Rogemond","orcid":"0000-0003-2098-920X","position":13,"is_corresponding":false},{"id":1209199,"name":"Anne Laurie Pinto","orcid":null,"position":14,"is_corresponding":false},{"id":301069,"name":"Anna Heidbreder","orcid":"0000-0002-9552-7619","position":15,"is_corresponding":false},{"id":231248,"name":"Romana Höftberger","orcid":"0000-0002-5769-1100","position":16,"is_corresponding":false},{"id":1208589,"name":"Francesc Graus","orcid":"0000-0002-8924-8322","position":17,"is_corresponding":false},{"id":404629,"name":"Josep Dalmau","orcid":"0000-0001-5856-2813","position":18,"is_corresponding":false},{"id":907061,"name":"Joan Santamaría","orcid":"0000-0003-0879-4135","position":19,"is_corresponding":false},{"id":1209200,"name":"Alex Iranzo","orcid":null,"position":20,"is_corresponding":false},{"id":1208590,"name":"Bettina Schreiner","orcid":"0000-0002-3830-6991","position":21,"is_corresponding":false},{"id":1208591,"name":"Maria Pia Giannoccaro","orcid":"0000-0003-2208-376X","position":22,"is_corresponding":false},{"id":1029646,"name":"Rocco Liguori","orcid":"0000-0002-1815-1013","position":23,"is_corresponding":false},{"id":1208592,"name":"Takayoshi Shimohata","orcid":"0000-0002-8788-9089","position":24,"is_corresponding":false},{"id":1208593,"name":"Akio Kimura","orcid":"0000-0003-0383-2008","position":25,"is_corresponding":false},{"id":1208594,"name":"Yoya Ono","orcid":"0000-0001-6777-4252","position":26,"is_corresponding":false},{"id":1208595,"name":"Sophie Binks","orcid":"0000-0003-0991-5998","position":27,"is_corresponding":false},{"id":761766,"name":"Sara Mariotto","orcid":"0000-0002-7806-3103","position":28,"is_corresponding":false},{"id":840204,"name":"Alessandro Dinoto","orcid":"0000-0002-3249-4792","position":29,"is_corresponding":false},{"id":1208596,"name":"Michael Bonello","orcid":"0000-0002-0080-3976","position":30,"is_corresponding":false},{"id":1066563,"name":"Christian Hartmann","orcid":"0009-0004-3700-3536","position":31,"is_corresponding":false},{"id":1208597,"name":"Nicola Tambasco","orcid":"0000-0003-1497-4482","position":32,"is_corresponding":false},{"id":1208598,"name":"Pasquale Nigro","orcid":"0000-0002-2736-0095","position":33,"is_corresponding":false},{"id":230505,"name":"Harald Prüß","orcid":"0000-0002-8283-7976","position":34,"is_corresponding":false},{"id":315042,"name":"Andrew McKeon","orcid":"0000-0001-6856-8143","position":35,"is_corresponding":false},{"id":3343,"name":"Mark M. 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