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Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>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 \u03b1-Smooth Muscle Actin (myofibroblasts) and of S100 Calcium-Binding Protein A4 (S100A4).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using a previously established model of rheumatic scarring\/fibrosis <jats:italic>in vitro<\/jats:italic>, 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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. <jats:italic>In vitro<\/jats:italic>, fibroblasts cultured with supernatants of macrophages transfected with hY3 (noncoding ssRNA) differentiated into myofibroblasts or S100A4<jats:sup>+<\/jats:sup> fibroblasts. Myofibroblasts expressed collagen while S100A4<jats:sup>+<\/jats:sup> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings position the S100A4<jats:sup>+<\/jats:sup> fibroblast alongside the canonical myofibroblast in the pathogenesis of cardiac-NL. Neonatal S100A4 levels support a novel biomarker of poor prognosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1114808","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T06:29:17Z","timestamp":1680762557000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Contribution of S100A4-expressing fibroblasts to anti-SSA\/Ro-associated atrioventricular nodal calcification and soluble S100A4 as a biomarker of clinical severity"],"prefix":"10.3389","volume":"14","author":[{"given":"Christina E. 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