Biology subjects

Pers, J.-O.

Publications and source records attributed to Pers, J.-O..

6 recordsLinked to original sources

bioRxiv2025

BiomiX-Driven Multi-Omics Integration of PRECISESADS Data Reveals Lysophosphatidic Acid and Metabolic Pathway Signatures in B Cells and Immune Macroenvironment in Sjogren's Disease

ObjectiveSjogrens disease (SjD) is a systemic autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, resulting in xerostomia, keratoconjunctivitis sicca, fatigue, arthralgia, and systemic organ involvement. This study aimed to characterize the metabolic and immune dysregulation of SjD using a multi-omics approach, focusing on the metabolic environment and B-cell transcriptomic responses. MethodsTranscriptomic, methylomic, and metabolomic datasets from whole blood, plasma, and urine of 293 SjD patients and 508 controls were analyzed from the PRECISESADS study. B-cell transcriptomes were included to link systemic metabolic alterations to cell-intrinsic immune programs. Multi-omics factor analysis (MOFA) was used to integrate data and identify discriminant molecular drivers. ResultsMulti-omics integration revealed metabolic rewiring involving the urea cycle, glutamine/arginine metabolism, and NAD depletion linked to interferon signaling. Among the strongest contributors, plasma lysophosphatidic acids (LPA) emerged as key discriminants associated with interferon-driven activation. B-cell transcriptomes showed upregulation of LPA-related genes (CERS6, INPP1, TRIP6), and its receptor LPAR6. Importantly, in this study LPAR6 protein expression was confirmed in B cells for the first time. Secondary findings included alterations in sphingosine-1-phosphate (S1P) metabolism, suggesting a broader lysophospholipid signaling axis. ConclusionsThis study identifies the LPA-LPAR6 signaling axis as a potential metabolic driver of B-cell activation and interferon-associated inflammation in SjD, highlighting a previously unrecognized immunometabolic pathway. These findings highlight LPA-LPAR6 as a candidate target for therapeutic modulation in SjD, while also implicating S1P signaling as a complementary regulatory mechanism.

immunology↗

bioRxiv2025

Assessing the Molecular Validity of Spontaneous Lupus Mouse Models and Its Implication for Human Studies

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by a loss of self-tolerance, causing inflammation and tissue damage in multiple organs. Animal models have advanced our understanding of SLEs molecular basis, but the FDAs recent elimination of animal testing requirements for drug approval has raised concerns about their validity, prompting a reevaluation of their role in basic research, especially for heterogeneous diseases like SLE. MethodsFour different spontaneous SLE mouse models were studied: MRLlpr/lpr, NZB/W, BXSB.Yaa, and Tlr7.Tg6. Transcriptome sequencing from blood, spleen, and kidney, flow cytometry from the spleen, and cytokines and autoantibody measurement in plasma were performed at four time points. Similar molecular data from human SLE patients was used for the integration. ResultsThe study identified specific molecular pathways driving the phenotype in each mouse model and established optimal time points for future experimental designs. By comparing these pathways to human SLE, the most similar ones and their relationship with disease activity were identified, providing crucial insight into translational relevance. Importantly, disease severity across models was linked to the extent and timing of molecular dysregulations. As expected, MRLlpr/lpr showed the most aggressive phenotype with early immune activation and apoptosis dysregulation, while Tlr7.Tg6 presented late-onset signatures associated with interferon and inflammation. Shared molecular features with human SLE included interferon responses, T and B cell depletion, and neutrophil activation. Integration analysis revealed distinct yet overlapping immune pathways between models and species, with some signatures such as age-associated B cells and double-negative memory T cells being model-specific but potentially relevant to early disease processes. ConclusionsThese findings build a valuable framework for future SLE research, reinforcing the utility of mouse models in studying specific molecular pathways related to human SLE pathogenesis and heterogeneity. The integration of longitudinal mouse data with human transcriptomes highlights the models that best recapitulate key aspects of human disease, offering guidance for the study of specific immunopathological mechanisms or therapeutic targets.

immunology↗

bioRxiv2024

B-Cell Involvement in Immune Checkpoint Inhibitor-Induced Lichen Planus: A Comparative Analysis with Non-Drug-Related Lichen Planus.

BackgroundImmune checkpoint inhibitors (ICI) have significantly improved cancer prognosis but can lead to immune-related adverse events (irAE), including cutaneous manifestations affecting 30% to 60% of ICI-treated patients. However, the physiopathology of cutaneaous irAE remains unclear. ObjectiveThis study investigated the immune infiltration in tissues affected by cutaneous irAE to elucidate their contribution to the pathogenesis of these toxicities. MethodsSkin biopsies from 6 patients with ICI-induced lichenoid eruptions were compared using imaging mass cytometry to samples from 7 controls with non-drug-related lichen planus. ResultsT cells were the predominant cell type within the inflammatory infiltrate in all samples, but we observed a reduced T-cell infiltration and an increased B-cell frequency in ICI-induced lichen planus compared to non-drug related lichen planus. Among B cells, we observed a significant decrease in IgD-CD27-double-negative B cells and an increase in IgD+CD27-naive B cells. Spatial analysis demonstrated that infiltrating B cells were organized in aggregates close to T cells in ICI-induced lichen planus. LimitationsThis is a retrospective single-center study with a relatively small sample size. ConclusionThis study sheds light on the involvement of B cells in the pathogenesis of ICI-induced lichen planus, suggesting distinct immunological mechanisms from non-drug-related lichen planus. CAPSULE SUMMARYO_LILichenoid manifestations are a common but understudied side effect occurring in patients receiving anti-PD-1 antibodies. C_LIO_LIICI-induced lichen planus displays distinct physiopathology from non-drug-related lichen planus, with a decrease of T-cell infiltration concomitantly to the increase of B cells organized in aggregates. 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↗

bioRxiv2022

Deciphering the maturation of tertiary lymphoid structures in cancer and inflammatory diseases of the digestive tract using imaging mass cytometry: from high-level data to a simple architectural and functional grading

ObjectivePersistent inflammation can promote the development of tertiary lymphoid structures (TLS) within tissues resembling the secondary lymphoid organs (SLO) as lymph nodes (LN). The composition of the TLS across different organs and diseases could be of pathophysiological and medical interest. In this work, we compared TLS to SLO and between cancer and inflammatory diseases of the digestive tract. DesignColorectal and gastric tissues with different inflammatory diseases and cancers from the department of pathology of CHU Brest were analyzed based on 39 markers using imaging mass cytometry (IMC). Unsupervised and supervised clustering analyses of IMC images were used to compare SLO and TLS. ResultsUnsupervised analyses tended to group TLS per patient but not per disease. Supervised analyses of IMC images revealed that LN had a more organized structure than TLS and non-encapsulated SLO Peyers patches. TLS followed a maturation spectrum with close correlations between germinal cell (GC) markers evolution. The correlations between organizational and functional markers made relevant the previously proposed TLS division into three stages: lymphoid-aggregates (LA) (CD20+CD21-CD23-) had neither organization nor GC functionality, non-GC TLS (CD20+CD21+CD23-) were organized but lacked GCs functionality and GC-like TLS (CD20+CD21+CD23+) had GCs organization and functionality. This architectural and functional maturation grading of TLS pointed to differences across diseases. ConclusionTLS architectural and functional maturation grading is accessible with few markers allowing future diagnostic, prognostic, and predictive studies on the value of TLS grading, quantification and location within pathological tissues in cancers and inflammatory diseases. KEY MESSAGES- What is already known on this topic: Tertiary lymphoid structures (TLS) arise in organs under various pathological conditions and can be of prognostic significance. - What this study adds: This study deciphers the composition of TLS in digestive cancers and inflammatory diseases using massively multiplexed (39 markers) imaging mass cytometry (IMC). Beyond the term TLS, this study points to the heterogeneity of these structures in terms of composition and maturation but also the relevance of a simple architectural and functional three-stage grading of TLS. - How this study might affect research, practice, or policy: This preliminary study paves the way for future studies evaluating the diagnostic, prognostic and theranostic values of TLS maturation grading, quantification and location within tissues as novel biomarkers in inflammatory diseases and cancers.

immunology↗

bioRxiv2021

IL-21 and IFN-α have both opposite and redundant role on human innate precursors and memory B-cell differentiation.

Immunological memory is essential for effective immune protection upon antigen rechallenge. Memory B cells encompass multiple subsets, heterogeneous in terms of phenotypes, origins and precursors, anatomical localization, and functional responses. B-cell responses are conditioned by micro-environmental signals, including cytokines. Here, we analyzed in vitro the effects of two cytokines implicated in B-cell differentiation, interferon-alpha (IFN-) and interleukin (IL)-21, on the early functional response of four different mature B-cell subsets (IgD- CD27- naive, IgD+ CD27+ unswitched, IgD- CD27+ switched and double-negative B cells). The dual response of naive and memory B cells to IL-21 allowed us to uncover a unique IgD+ CD27- CD10- B-cell population (referred to as NARB+) characterized by the expression of marginal zone B-cell markers CD45RB and CD1c. Similar to memory B cells, NARB+ cells were in a pre-activated state, allowing them to rapidly differentiate into plasmablasts upon innate signals while maintaining their susceptibility to IL-21 activation-induced apoptosis as observed for the naive compartment. Both in-depth phenotypic analysis of circulating B cells, and identification of these cells in spleen, tonsil and gut-associated lymphoid tissues, supported that NARB+ are uncommitted precursors of human marginal zone B cells.

immunology↗