Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE ( Institute for Translational Research) in Inflammation, Lille, France.
CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France, Lille, France.
Front Immunol. 2022 Jun 29;13:904631. doi: 10.3389/fimmu.2022.904631. eCollection 2022.
Autoantibodies (Aabs) are frequent in systemic sclerosis (SSc). Although recognized as potent biomarkers, their pathogenic role is debated. This study explored the effect of purified immunoglobulin G (IgG) from SSc patients on protein and mRNA expression of dermal fibroblasts (FBs) using an innovative multi-omics approach. Dermal FBs were cultured in the presence of sera or purified IgG from patients with diffuse cutaneous SSc (dcSSc), limited cutaneous SSc or healthy controls (HCs). The FB proteome and transcriptome were explored using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and microarray assays, respectively. Proteomic analysis identified 3,310 proteins. SSc sera and purified IgG induced singular protein profile patterns. These FB proteome changes depended on the Aab serotype, with a singular effect observed with purified IgG from anti-topoisomerase-I autoantibody (ATA) positive patients compared to HC or other SSc serotypes. IgG from ATA positive SSc patients induced enrichment in proteins involved in focal adhesion, cadherin binding, cytosolic part, or lytic vacuole. Multi-omics analysis was performed in two ways: first by restricting the analysis of the transcriptomic data to differentially expressed proteins; and secondly, by performing a global statistical analysis integrating proteomics and transcriptomics. Transcriptomic analysis distinguished 764 differentially expressed genes and revealed that IgG from dcSSc can induce extracellular matrix (ECM) remodeling changes in gene expression profiles in FB. Global statistical analysis integrating proteomics and transcriptomics confirmed that IgG from SSc can induce ECM remodeling and activate FB profiles. This effect depended on the serotype of the patient, suggesting that SSc Aab might play a pathogenic role in some SSc subsets.
自身抗体（Aabs）在系统性硬化症（SSc）中很常见。尽管被认为是有效的生物标志物，但它们的致病作用仍存在争议。本研究采用创新的多组学方法，探讨了来自弥漫性皮肤型 SSc（dcSSc）、局限性皮肤型 SSc 或健康对照者（HCs）患者的纯化免疫球蛋白 G（IgG）对真皮成纤维细胞（FB）蛋白和 mRNA 表达的影响。用患者血清或纯化 IgG 培养真皮成纤维细胞，探讨 FB 蛋白质组和转录组分别采用液相色谱-串联质谱（LC-MS/MS）和微阵列分析。蛋白质组分析鉴定了 3310 种蛋白质。SSc 血清和纯化 IgG 诱导了独特的蛋白谱模式。这些 FB 蛋白质组的变化取决于 Aab 血清型，与来自抗拓扑异构酶-I 自身抗体（ATA）阳性患者的纯化 IgG 相比，HC 或其他 SSc 血清型观察到单一效应。ATA 阳性 SSc 患者的 IgG 诱导了与粘着斑、钙粘素结合、细胞质部分或溶酶体相关的蛋白的富集。多组学分析采用两种方式进行：首先，将转录组数据的分析限制在差异表达的蛋白上；其次，通过整合蛋白质组学和转录组学进行全局统计分析。转录组分析区分了 764 个差异表达基因，并揭示了 dcSSc 的 IgG 可以诱导 FB 中细胞外基质（ECM）重塑改变基因表达谱。整合蛋白质组学和转录组学的全局统计分析证实，SSc 的 IgG 可以诱导 ECM 重塑并激活 FB 谱。这种效应取决于患者的血清型，提示 SSc Aab 可能在某些 SSc 亚群中发挥致病作用。
