Biology subjects

Binvignat, M.

Publications and source records attributed to Binvignat, M..

3 recordsLinked to original sources

bioRxiv2024

Immunological Profiling in Knee Osteoarthritis: Treg Dysfunction as Key Driver of Pain

Pain is the hallmark symptom of osteoarthritis (OA) and its biological drivers remain poorly understood. While the role of innate immunity in OA has been extensively studied, the involvement of adaptive immunity, in particular regulatory T cells (Tregs), is not well understood. Using a comprehensive multi-omic approach on the peripheral blood from 46 knee OA patients with similar radiographic stage, including deep immunophenotyping, cytokine profiling, transcriptomic and T-cell receptor analysis on sorted CD4 Tregs and effector T cells (Teff), we identified an immunological signature associated with OA-related pain. Cytokines promoting Treg expansion and activation (with increases of sIL2-RA, sTNFR1, sTNFR2) were correlated with the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscore, suggesting a potential Treg dysfunction. Nineteen T cell subsets were correlated with WOMAC pain. Notably, we found a negative correlation of cell subsets associated with Treg expansion and activation (FoxP3+CTLA4+, CD4+CD57+, Treg CD95+, CD4 Treg CD45RA-). Differential gene expression analysis between patients with low and high WOMAC pain intensity (threshold [≥] 40/100) revealed an upregulation of inflammasome-related genes such as IL1RL1, IL31RA, IFITM3, NLRP3, IFNG in Tregs. Functional enrichment analysis highlighted an overrepresentation of innate immune response, IL-8, and interferon activation pathways suggesting a pro-inflammatory state in Tregs of patients with high pain intensity. Collectively, our systems immunology approach highlights multiple associations between Treg dysfunctionality and OA-related pain, providing new insights into the adaptive immune systems contribution to OA-related pain.

immunology↗

bioRxiv2024

IL-1β Signaling Modulates T Follicular Helper and Regulatory Cells in Human Lymphoid Tissues

BackgroundDysregulation of the T follicular helper (Tfh) and T follicular regulatory (Tfr) homeostasis in the germinal center (GC) can result in antibody-mediated autoimmunity. While interleukin-1{beta} (IL-1{beta}) has been shown to be an important modulator of the GC response in animal models via the expression of IL-1 agonist (IL-1R1) and antagonist (IL-1R2) receptors on follicular T cells, such regulation has not yet been studied in humans. MethodsWe investigated Tfh and Tfr phenotypes in human secondary lymphoid organs -- namely tonsils, spleens, and mesenteric lymph nodes -- using flow cytometry, single-cell transcriptomics, and in vitro cell culture. We also benchmarked our findings with a cohort of patients with autoimmune and inflammatory diseases. ResultsWe found that Tfh and Tfr cells exhibit organ-specific phenotypes related to their activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 was linked to the emergence of a unique activated Tfr subset that combines features of both Treg and GC-Tfh cells. Single-cell transcriptomics and in vitro studies showed that IL-1{beta} signaling through IL-1R1 promotes follicular T-cell activation. Inhibiting IL-1{beta} resulted in upregulation of IL-1R1 expression, showing a fine-tuned regulation. In autoimmune patients, high IL-1{beta} and circulating Tfr levels correlated with higher autoantibody levels, linking inflammation, IL-1{beta} signaling, and the Tfr/Tfh balance. ConclusionsOur study underscores the pivotal role of IL-1{beta} in follicular T-cell activation, contributing to pathological antibody production in humans. Targeting IL-1{beta} signaling in Tfh and Tfr cells could offer new treatment strategies for antibody-mediated autoimmune diseases.

immunology↗

bioRxiv2023

Deciphering Cell-types and Gene Signatures Associated with Disease Activity in Rheumatoid Arthritis using Single Cell RNA-sequencing

ObjectiveSingle cell profiling of synovial tissue has previously identified gene signatures associated with rheumatoid arthritis (RA) pathophysiology, but synovial tissue is difficult to obtain. This study leverages single cell sequencing of peripheral blood mononuclear cells (PBMCs) from patients with RA and matched healthy controls to identify disease relevant cell subsets and cell type specific signatures of disease. MethodsSingle-cell RNA sequencing (scRNAseq) was performed on peripheral blood mononuclear cells (PBMCs) from 18 RA patients and 18 matched controls, accounting for age, gender, race, and ethnicity). Samples were processed using standard CellRanger and Scanpy pipelines, pseudobulk differential gene expression analysis was performed using DESeq2, and cell-cell communication analysis using CellChat. ResultsWe identified 18 distinct PBMC subsets, including a novel IFITM3+ monocyte subset. CD4+ T effector memory cells were increased in patients with moderate to high disease activity (DAS28-CRP [≥] 3.2), while non-classical monocytes were decreased in patients with low disease activity or remission (DAS28-CRP < 3.2). Differential gene expression analysis identified RA-associated genes in IFITM3+ and non-classical monocyte subsets, and downregulation of pro-inflammatory genes in the V{delta} subset. Additionally, we identified gene signatures associated with disease activity, characterized by upregulation of pro-inflammatory genes TNF, JUN, EGR1, IFIT2, MAFB, G0S2, and downregulation of HLA-DQB1, HLA-DRB5, TNFSF13B. Notably, cell-cell communication analysis revealed upregulation of immune-associated signaling pathways, including VISTA, in patients with RA. ConclusionsWe provide a novel single-cell transcriptomics dataset of PBMCs from patients with RA, and identify insights into the systemic cellular and molecular mechanisms underlying RA disease activity.

immunology↗