{"doi":"10.3389/fimmu.2023.1114808","title":"Contribution of S100A4-expressing fibroblasts to anti-SSA/Ro-associated atrioventricular nodal calcification and soluble S100A4 as a biomarker of clinical severity","abstract":"Background Fibrosis and dystrophic calcification disrupting conduction tissue architecture are histopathological lesions characterizing cardiac manifestations of neonatal lupus (cardiac-NL) associated with maternal anti-SSA/Ro antibodies. Objectives Increased appreciation of heterogeneity in fibroblasts encourages re-examination of existing models with the consideration of multiple fibroblast subtypes (and their unique functional differences) in mind. This study addressed fibroblast heterogeneity by examining expression of α-Smooth Muscle Actin (myofibroblasts) and of S100 Calcium-Binding Protein A4 (S100A4). Methods Using a previously established model of rheumatic scarring/fibrosis in vitro , supported by the evaluation of cord blood from cardiac-NL neonates and their healthy (anti-SSA/Ro-exposed) counterparts, and autopsy tissue from fetuses dying with cardiac-NL, the current study was initiated to more clearly define and distinguish the S100A4-positive fibroblast in the fetal cardiac environment. Results S100A4 immunostaining was observed in 4 cardiac-NL hearts with positional identity in the conduction system at regions of dystrophic calcification but not fibrotic zones, the latter containing only myofibroblasts. In vitro , fibroblasts cultured with supernatants of macrophages transfected with hY3 (noncoding ssRNA) differentiated into myofibroblasts or S100A4 + fibroblasts. Myofibroblasts expressed collagen while S100A4 + fibroblasts expressed pro-angiogenic cytokines and proteases that degrade collagen. Cord blood levels of S100A4 in anti-SSA/Ro-exposed neonates tracked disease severity and, in discordant twins, distinguished affected from unaffected. Conclusions These findings position the S100A4 + fibroblast alongside the canonical myofibroblast in the pathogenesis of cardiac-NL. Neonatal S100A4 levels support a novel biomarker of poor prognosis.","journal":"Frontiers in Immunology","year":2023,"id":374549,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9504,"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":235989,"name":"Marc K. Halushka","orcid":"0000-0002-7112-7389","position":1,"is_corresponding":false},{"id":934019,"name":"Nicola Fraser","orcid":"0000-0001-5608-3659","position":2,"is_corresponding":false},{"id":319181,"name":"Mala Masson","orcid":null,"position":3,"is_corresponding":false},{"id":355543,"name":"Bettina F. Cuneo","orcid":"0000-0001-9085-0882","position":4,"is_corresponding":false},{"id":317646,"name":"Amit Saxena","orcid":"0000-0003-0098-1083","position":5,"is_corresponding":false},{"id":285330,"name":"Robert M. Clancy","orcid":"0000-0003-1151-0084","position":6,"is_corresponding":false},{"id":255416,"name":"Jill P. Buyon","orcid":"0000-0002-3852-7129","position":7,"is_corresponding":false},{"id":106334,"name":"Christina E. M. Firl","orcid":null,"position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:16:15.380731Z","pmid":"37090702","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":[]}