Biology subjects

Gottenberg, J.-E.

Publications and source records attributed to Gottenberg, J.-E..

4 recordsLinked to original sources

bioRxiv2025

The SjD Map: An interactive pathway tour into Sjogren's disease signalling mechanisms

ObjectivesSjogrens disease (SjD) remains a major unmet medical challenge, marked by biological complexity, patient heterogeneity, and a lack of curative treatments. To advance the understanding of its pathogenesis and support therapeutic discovery, we developed a comprehensive knowledgebase in the form of a Molecular Interaction Map (MIM). MethodsDifferential expression analysis was performed on peripheral blood samples from SjD patients and healthy controls across three datasets: GSE51092 (190 SjD vs 32 controls), UKPSSR (151 SjD vs 29 controls) and PRECISESADS (304 SjD vs 341 controls). Pathway enrichment analyses provided guidance for MIM construction, which was further refined through literature mining to integrate data-driven results with curated knowledge. ResultsA total of 1,625 differentially expressed genes (DEGs) were identified: 725 from PRECISESADS, 1,162 from GSE51092, and 239 from UKPSSR, with 25 DEGs shared across all three datasets. Among these, nine common DEGs were associated with interferon signalling, reinforcing experimental evidence pointing to its pivotal role in SjD. Enrichment analyses revealed 146 pathways, 43 of which were successfully incorporated into the MIM. The resulting SjD Map freely accessible at https://sjdmap.elixir-luxembourg.org/, comprises 829 molecular entities connected by 598 interactions, with 45% of the information depicted supported by transcriptomic data and 47% derived from literature. The map also includes overlays of experimental data and clinical trial information. ConclusionThis first comprehensive Sjogrens Disease Map, developed through a hybrid data-driven and literature-based approach, offers an integrative view of SjD pathogenesis. It supports visualisation of mechanistic pathways, omics-based data overlays, enables incorporation of user data and drug queries. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/674876v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1bdc517org.highwire.dtl.DTLVardef@1d68077org.highwire.dtl.DTLVardef@18c079forg.highwire.dtl.DTLVardef@487b64_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG Key messagesO_LIThis is the first molecular interaction map specific of Sjogrens Disease C_LIO_LIIt enables comprehensive visualisation of affected pathways through integrated transcriptomic and literature-based evidence, following systems biology graphical notation schemes C_LIO_LIThe map may support therapeutic discovery by linking molecular mechanisms to clinical data and drug targets C_LI

systems biology↗

bioRxiv2024

LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

Autophagy is a fundamental catabolic process performed by a network of autophagy related (ATG) proteins. Some ATG proteins coordinate parallel roles in so-called "noncanonical" autophagy such as LC3-associated phagocytosis (LAP). Both autophagy and LAP share key functions in immunity and inflammation and have been linked to autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by excessive fibrosis in skin and multiple internal organs linked with an aberrant immune activation. Several polymorphisms of genes coding for ATG proteins, particularly in ATG5, are more frequent in SSc patients. We hypothesized that autophagy and/or LAP could be dysregulated in immune cells from SSc patients. No defect of canonical autophagy was found in lymphocytes and monocytes isolated from peripheral blood mononuclear cells of SSc patients. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess LAP activity. While M0 macrophage polarization appears similar than in healthy donors, we showed that LAP is downregulated in SSc patients. We now need to understand the molecular mechanisms underlying LAP dysregulations. Future investigations leading to the discovery of LAP modulating drugs could then open new therapeutic options for SSc treatment. Key messagesO_LIPolymorphisms of autophagy-related genes are associated with several autoimmune and autoinflammatory diseases, including SSc and SLE C_LIO_LIWhile autophagy has been shown to be dysregulated in circulating cells from SLE patients, no information is available for SSc C_LIO_LIWe show here that autophagy is comparable between PBMCs from patients and matched controls C_LIO_LIWe find a strong impartment of LAP, another ATG-dependent mechanism, in monocyte-derived macrophages from SSc patients C_LIO_LIAs LAP is involved in efferocytosis and the regulation of inflammation, we propose that restoring LAP activity could be a therapeutic option to limit fibrosis and inflammation C_LI

immunology↗

bioRxiv2023

Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjogrens Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6, CXCR5, and lnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.

genetics↗

bioRxiv2021

Differential levels of IFNα subtypes in autoimmunity and viral infection

Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFN (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease. We developed a digital ELISA with specificity and high sensitivity for the IFN2 subtype. Application of this assay, in parallel with our previously described pan-IFN assay, allowed us to study different IFN protein responses following cellular stimulation and in diverse patient cohorts. We observed different ratios of IFN protein responses between viral infection and autoimmune patients. This analysis also revealed a small percentage of autoimmune patients with high IFN2 protein measurements but low pan-IFN measurements. Correlation with an ISG score and functional activity showed that in this small sub group of patients, IFN2 protein measurements did not reflect its biological activity. This unusual phenotype was partly explained by the presence of anti-IFN auto-antibodies in a subset of autoimmune patients. This study reports ultrasensitive assays for the study of IFN proteins in patient samples and highlights the insights that can be obtained from the use of multiple phenotypic readouts in translational and clinical studies.

immunology↗