{"doi":"10.1172/jci161170","title":"Autoimmunity to synovial extracellular matrix proteins in patients with postinfectious Lyme arthritis","abstract":"BACKGROUNDAutoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked upregulation of HLA-DR molecules, including in postinfectious Lyme arthritis (LA). However, the identity of HLA-DR-presented peptides, and therefore the reasons for these associations, has frequently remained elusive.METHODSUsing immunopeptidomics to detect HLA-DR-presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with postinfectious LA, identified potential Borreliella burgdorferi-mimic (Bb-mimic) epitopes, and characterized T and B cell responses to these peptides or proteins.RESULTSOf 24 postinfectious LA patients, 58% had CD4+ T cell responses to at least 1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to at least 1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or -DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb-mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4+ T cells in synovial fluid were T-bet-expressing Th1 cells, a small percentage were RoRγt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Tregs.CONCLUSIONAutoreactive, proinflammatory CD4+ T cells and autoantibodies develop to ECM proteins in a subgroup of postinfectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.FUNDINGSupported by National Institute of Allergy and Infectious Diseases R01-AI101175, R01-AI144365, and F32-AI125764; National Institute of Arthritis and Musculoskeletal and Skin Diseases K01-AR062098 and T32-AR007258; NIH grants P41-GM104603, R24-GM134210, S10-RR020946, S10-OD010724, S10-OD021651, and S10-OD021728; and the G. Harold and Leila Y. Mathers Foundation, the Eshe Fund, and the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital.","journal":"Journal of Clinical Investigation","year":2023,"id":333985,"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":0.9585,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":482773,"name":"Klemen Strle","orcid":"0000-0002-0109-6791","position":1,"is_corresponding":false},{"id":744999,"name":"Robert B. Lochhead","orcid":"0000-0001-7726-0466","position":2,"is_corresponding":false},{"id":685866,"name":"Annalisa Pianta","orcid":null,"position":3,"is_corresponding":false},{"id":4835,"name":"Laura M. Mateyka","orcid":null,"position":4,"is_corresponding":false},{"id":307818,"name":"Qi Wang","orcid":"0000-0002-5287-6050","position":5,"is_corresponding":false},{"id":685091,"name":"Sheila L. Arvikar","orcid":"0000-0002-0224-9681","position":6,"is_corresponding":false},{"id":1061902,"name":"David E. Kling","orcid":"0000-0002-0624-1046","position":7,"is_corresponding":false},{"id":1062342,"name":"Cameron A. Deangelo","orcid":null,"position":8,"is_corresponding":false},{"id":1062343,"name":"Lucy Curham","orcid":null,"position":9,"is_corresponding":false},{"id":411393,"name":"Alan G. Barbour","orcid":"0000-0002-0719-5248","position":10,"is_corresponding":false},{"id":391253,"name":"Catherine E. Costello","orcid":"0000-0003-1594-5122","position":11,"is_corresponding":false},{"id":281386,"name":"James J. Moon","orcid":"0000-0001-8246-931X","position":12,"is_corresponding":false},{"id":311008,"name":"Allen C. Steere","orcid":"0000-0002-5268-9853","position":13,"is_corresponding":false},{"id":1061901,"name":"Korawit Kanjana","orcid":"0000-0003-2533-9804","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T01:09:44.297718Z","pmid":"37471146","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":[]}