Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, United States.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
Front Immunol. 2023 Apr 6;14:1114808. doi: 10.3389/fimmu.2023.1114808. eCollection 2023.
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.
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).
Using a previously established model of rheumatic scarring/fibrosis , 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.
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. , 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.
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.
纤维化和破坏性钙化破坏了传导组织的结构，这是母体抗 SSA/Ro 抗体相关的新生儿狼疮（心脏 NL）的心脏表现的组织病理学病变。
对成纤维细胞异质性的认识不断提高，鼓励在考虑多种成纤维细胞亚型（及其独特的功能差异）的情况下，重新检查现有的模型。本研究通过检查α-平滑肌肌动蛋白（成肌纤维细胞）和 S100 钙结合蛋白 A4（S100A4）的表达来研究成纤维细胞的异质性。
利用以前建立的风湿性瘢痕/纤维化模型，结合心脏 NL 新生儿及其健康（抗 SSA/Ro 暴露）对照的脐血评估，以及死于心脏 NL 的胎儿尸检组织，本研究旨在更清楚地定义和区分胎儿心脏环境中的 S100A4 阳性成纤维细胞。
在 4 例心脏 NL 心脏中观察到 S100A4 免疫染色，其位置在传导系统的位置与营养不良性钙化区域一致，但不在纤维化区域，后者仅含有成肌纤维细胞。用转染 hY3（非编码 ssRNA）的巨噬细胞上清液培养的成纤维细胞分化为成肌纤维细胞或 S100A4 成纤维细胞。成肌纤维细胞表达胶原蛋白，而 S100A4 成纤维细胞表达促血管生成细胞因子和降解胶原蛋白的蛋白酶。抗 SSA/Ro 暴露新生儿脐带血中的 S100A4 水平与疾病严重程度相关，在不一致的双胞胎中，区分了受影响和未受影响的。
这些发现将 S100A4 成纤维细胞与心脏 NL 发病机制中的经典成肌纤维细胞并列。新生儿 S100A4 水平支持预后不良的新型生物标志物。
