AUTHOR=Chepy Aurélien , Vivier Solange , Bray Fabrice , Ternynck Camille , Meneboo Jean-Pascal , Figeac Martin , Filiot Alexandre , Guilbert Lucile , Jendoubi Manel , Rolando Christian , Launay David , Dubucquoi Sylvain , Marot Guillemette , Sobanski Vincent 

TITLE=Effects of Immunoglobulins G From Systemic Sclerosis Patients in Normal Dermal Fibroblasts: A Multi-Omics Study

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.904631

DOI=10.3389/fimmu.2022.904631

ISSN=1664-3224

ABSTRACT=Autoantibodies (Aab) are frequent in systemic sclerosis (SSc). While recognized as potent biomarkers, their pathogenic role is debated. This study explored the effect of purified immunoglobulins G (IgG) from SSc patients on protein and mRNA expression of dermal fibroblast (FB) using an innovative multi-omics approach. Dermal FB were cultured in the presence of sera or purified IgG from patients with diffuse cutaneous SSc (dcSSc), limited cutaneous SSc or healthy controls (HC). 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 were dependent on Aab serotype, with a singular effect observed with purified IgG from anti-topoisomerase-I autoantibodies (ATA) positive patients compared to HC or other SSc serotypes. IgG from ATA positive SSc patients induced an 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 of gene expression profiles in FB. Global statistical analysis integrating proteomics and transcriptomics confirmed that IgG from SSc can induce ECM remodeling and activated FB profiles. This effect was dependent on the patient serotype, suggesting that SSc Aab might have a pathogenic role in some SSc subsets.