{"doi":"10.3389/fimmu.2023.1106537","title":"Autoantibody repertoire characterization provides insight into the pathogenesis of monogenic and polygenic autoimmune diseases","abstract":"Autoimmune diseases vary in the magnitude and diversity of autoantibody profiles, and these differences may be a consequence of different types of breaks in tolerance. Here, we compared the disparate autoimmune diseases autoimmune polyendocrinopathy-candidiasis-ecto-dermal dystrophy (APECED), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS) to gain insight into the etiology of breaks in tolerance triggering autoimmunity. APECED was chosen as a prototypical monogenic disease with organ-specific pathology while SjS and SLE represent polygenic autoimmunity with focal or systemic disease. Using protein microarrays for autoantibody profiling, we found that APECED patients develop a focused but highly reactive set of shared mostly anti-cytokine antibodies, while SLE patients develop broad and less expanded autoantibody repertoires against mostly intracellular autoantigens. SjS patients had few autoantibody specificities with the highest shared reactivities observed against Ro-52 and La. RNA-seq B-cell receptor analysis revealed that APECED samples have fewer, but highly expanded, clonotypes compared with SLE samples containing a diverse, but less clonally expanded, B-cell receptor repertoire. Based on these data, we propose a model whereby the presence of autoreactive T-cells in APECED allows T-dependent B-cell responses against autoantigens, while SLE is driven by breaks in peripheral B-cell tolerance and extrafollicular B-cell activation. These results highlight differences in the autoimmunity observed in several monogenic and polygenic disorders and may be generalizable to other autoimmune diseases.","journal":"Frontiers in Immunology","year":2023,"id":358194,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"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":1108323,"name":"Pan Du","orcid":"0000-0001-7335-4078","position":1,"is_corresponding":false},{"id":1108324,"name":"Satyendra Kumar","orcid":"0000-0001-7392-7120","position":2,"is_corresponding":false},{"id":1108685,"name":"Shinji L. Okitsu","orcid":null,"position":3,"is_corresponding":false},{"id":1108686,"name":"Mark Schuette","orcid":null,"position":4,"is_corresponding":false},{"id":1108325,"name":"Qi An","orcid":"0000-0002-6444-7157","position":5,"is_corresponding":false},{"id":1108326,"name":"Jinyang Zhang","orcid":"0009-0002-1683-2795","position":6,"is_corresponding":false},{"id":1108687,"name":"Evgeni P. Tzvetkov","orcid":null,"position":7,"is_corresponding":false},{"id":413451,"name":"Mark A. Jensen","orcid":"0000-0001-7081-8586","position":8,"is_corresponding":false},{"id":287624,"name":"Timothy B. Niewold","orcid":"0000-0003-3532-6660","position":9,"is_corresponding":false},{"id":285926,"name":"Elise M. N. Ferré","orcid":"0000-0002-3285-7768","position":10,"is_corresponding":false},{"id":1108688,"name":"Julie Nardone","orcid":null,"position":11,"is_corresponding":false},{"id":104225,"name":"Michail S. Lionakis","orcid":"0000-0003-4994-9500","position":12,"is_corresponding":false},{"id":1108327,"name":"Jaromir Vlach","orcid":"0000-0002-2804-2224","position":13,"is_corresponding":false},{"id":1108689,"name":"Julie A. DeMartino","orcid":null,"position":14,"is_corresponding":false},{"id":334739,"name":"Andrew T. Bender","orcid":"0000-0003-4349-4488","position":15,"is_corresponding":false},{"id":757539,"name":"Thomas Clarke","orcid":"0009-0002-7880-6445","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:13:43.629667Z","pmid":"36845162","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":[]}