Biology subjects

Mauri, C.

Publications and source records attributed to Mauri, C..

9 recordsLinked to original sources

bioRxiv2026

B-cell SIGLEC-5 engages T-cell components of the elastin receptor complex (ERC) to suppress inflammatory T-cell cytokines

SIGLECs remain poorly defined in human B-cell biology beyond SIGLEC-2/CD22 and SIGLEC-10. Here, we identify a previously unrecognized regulatory pathway involving the paired receptors SIGLEC-5 and SIGLEC-14 at the human B-T-cell interface. We show that activated B-cells differentially regulate these receptors: SIGLEC-5 is predominantly surface-expressed and induced by CD40 engagement, whereas SIGLEC-14 is primarily secreted and upregulated after both CD40 and TLR9 stimulation. We further identify EBP (elastin binding protein) and CTSA (cathepsin A) components of the elastin receptor complex (ERC), expressed by activated T-cells, as a novel ligand for both SIGLEC-5 and SIGLEC-14. Functionally, ERC-associated engagement of SIGLEC-5 on B-cells suppresses T-cell IFN-{gamma} and IL-17 expression, establishing SIGLEC-5 as a B-cell-expressed inhibitory SIGLEC that restrains inflammatory T-cell cytokine responses. SIGLEC-14 does not alter this suppression, as SIGLEC-5{square} B-cells from SIGLEC-14-sufficient and -null individuals show comparable inhibitory activity. These findings broaden SIGLEC-mediated adaptive immune regulation, with relevance to inflammatory and autoimmune disease.

immunology↗

bioRxiv2026

VesSynth: Tubes Are All You Need for Robust Cross-Scale Cross-Modal 3D Vessel Segmentation

The cerebral vasculature is central to brain function, with alterations linked to numerous cerebrovascular and neurological disorders. Yet, no single imaging modality can capture the entire cerebral vascular network in humans. Instead, an array of techniques are sensitized to different spatial scales, while trading off resolution for coverage. Magnetic Resonance Imaging (MRI) typically resolves only large pial vessels, while high-resolution microscopy allows micrometer-scale vessels to be mapped over limited spatial extents. These techniques must therefore be combined to obtain a complete mapping of the cerebral angioarchitecture, which underscores the need for automatic, cross-modal vessel segmentation. Here, we introduce VesSynth, a flexible vessel segmentation framework that achieves state-of-the-art accuracy across multiple modalities and spatial resolutions (MR, optical and X-ray imaging), despite being trained entirely on synthetic data. By enabling consistent vascular mapping across scales, this framework paves the way to comprehensive investigation of cerebrovascular organization and its role in health and disease.

bioengineering↗

bioRxiv2026

Hierarchical X-ray microscopy and mesoscopic diffusion MRI in the same brain reveal the human connectome across scales

We present a multimodal pipeline for 3D imaging of cerebral white-matter archi-tecture across scales, from whole-brain axonal projections down to individual myelinated axons. After diffusion MRI, an adult ex vivo human hemisphere undergoes label-free imaging with Hierarchical Phase-Contrast Tomography (HiP-CT) from 20 {micro}m/voxel in the whole hemisphere to 2 {micro}m/voxel in areas of interest, with intrinsic cross-scale alignment. A 4 cm tissue block extracted from the hemisphere is reimaged with HiP-CT at 0.857 {micro}m/voxel, enabling direct visualisation of single myelinated axons. After osmium staining, micro-CT at 0.364 {micro}m/voxel and electron microscopy at 4 nm/voxel are acquired in biop-sies from the tissue block to validate the presence of myelinated axons in the label-free HiP-CT contrast. Spanning three orders of magnitude in resolution, these co-registered multimodal datasets bridge microscopic wiring and macro-scopic brain organisation, providing a foundation for anatomically grounded whole-brain connectomics.

neuroscience↗

bioRxiv2026

Neutrophils impair B cell differentiation via mitochondrial and lipid metabolism in lupus.

Systemic lupus erythematosus (SLE) is characterised by aberrant neutrophil activation and pathogenic B-cell responses that drive organ damage, particularly in lupus nephritis (LN). Here, we identify neutrophil-derived mitochondrial DNA (mtDNA) as a metabolic driver of B-cell dysregulation in LN. Using single-cell transcriptomics of human blood and kidney tissue together with functional co-culture assays, we show that neutrophils from patients with active LN release extracellular traps enriched in mtDNA that induce mitochondrial oxidative stress in B cells. NET-derived mtDNA suppresses IL-10-producing regulatory B cells while promoting pro-inflammatory and plasmablast differentiation through nucleic acid-dependent signalling. Mechanistically, oxidative stress drives maladaptive NADPH utilisation, diverting NADPH from cholesterol biosynthesis toward antioxidant defence, resulting in altered lipid trafficking, mitochondrial dysfunction, and impaired regulatory B-cell differentiation. Consistent with this model, kidney B cells from patients with LN exhibit transcriptional signatures of disrupted redox and lipid metabolism, and NADPH deficiency is associated with reduced regulatory B-cell differentiation in humans. These findings identify a neutrophil-driven metabolic checkpoint that governs B-cell fate in lupus nephritis.

immunology↗

bioRxiv2025

Tumor-infiltrating CD27-IgD- regulatory B cells suppress cytotoxic CD8+T cell responses in renal cell carcinoma

B cells play a pivotal role in shaping the tumor microenvironment (TME) and tertiary lymphoid structures (TLS), but the functions of specific B cell subsets in cancer pathogenesis remain unclear. Using a novel tissue-centric single cell RNA-sequencing (scRNA-seq) bioinformatic workflow aimed at unraveling cancer-specific clusters, combined with flow cytometry and high-plex spatial imaging, we identify a renal cell carcinoma (RCC)-specific enrichment of CD27-IgD-CD21+CD11c- double negative 1 (DN1) B cells associated with worse prognosis and regulatory function. Spatial profiling localizes DN1 Bregs within immature TLSs, in close proximity to IL-10 and TGF{beta}CD8T cells. RCC-resident DN1 B cells are enriched for endosomal Toll-like receptor (TLR) signaling pathways and stimulation of tumor-infiltrating lymphocytes (TILs) with TLR agonists induces the differentiation of IL-10+ and TGF{beta}+DN Bregs suppressing CD8+T cell cytotoxicity, partially via IL-10 and TGF{beta}. These findings identify a pro-tumorigenic B cell population with potential diagnostic and therapeutic relevance in RCC.

immunology↗

bioRxiv2025

Multi-step antibody class switching in a primary human response is restricted after IGHG2 and dependent on B cell maturation stage.

Class switch recombination (CSR) allows the formation of functionally specialized antibodies. Understanding of CSR dynamics is key for better design and prediction of vaccines to protect mucosal surfaces. To investigate CSR in a primary human immune response under a controlled setting, we sampled healthy volunteers without COVID-19 history every other day during the first three weeks after SARS-CoV-2 vaccination, with additional time points up to six months. Leveraging bulk and single-cell B cell receptor repertoires, single-cell transcriptomics, and immunophenotyping, we uncover paradigm-shifting insights into CSR. Newly activated B cells produce sterile transcripts of all antibody isotype constant regions (IGHC) simultaneously up to IGHG2, challenging the view that sterile transcription occurs for only a single IGHC gene at a time. CSR follows a multistep progression along the IGHC locus; in this challenge vaccine-induced B cells switch from IGHM to IGHG3 and IGHG1, followed by a subsequent switching to IGHA1 and IGHG2 after secondary immunization. IGHA2 clones require pre-switching to IGHA1 clones. Notably, switching tendency, measured by IGHC sterile transcription, is memory B cell subtype dependent, particularly beyond IGHG2. Contrary to other vaccines, antigen-specific B cells are enriched in DN2, Cmem2 and DN4 subtypes after immunization. We also observe a temporal decoupling of CSR and somatic hypermutation (SHM), with the latter detectable only after six months post-immunization. Our data describes the dynamics between CSR, SHM, sterile transcription and B cell memory development during a human primary response, challenges textbook models of CSR and offers new insights to aid control of CSR direction. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/652638v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@785769org.highwire.dtl.DTLVardef@b2c54eorg.highwire.dtl.DTLVardef@b78c72org.highwire.dtl.DTLVardef@65b5aa_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryClass switch recombination occurs independently of somatic hypermutation and in a multistep fashion up to IGHG2 during a primary response in humans.

immunology↗

bioRxiv2024

Auto-antibodies against interferons are common in people living with chronic hepatitis B virus infection and associate with PegIFN non-response

Background and aimsType one (T1) and three interferons (T3IFNs) are implicated in Chronic Hepatitis B (CHB) immunopathogenesis. IFN remains the only licenced immune modulating therapy for CHB. We measured the prevalence of auto-antibodies (auto-Abs) against T1 and T3IFNs to examine the hypothesis that they impact Hepatitis B Virus (HBV) control and treatment response, as highlighted by COVID-19. MethodsOur multi-centre retrospective longitudinal study accessed two CHB cohorts, auto-Ab levels and neutralisation status were measured against T1IFN and T3IFN. Associations were tested against HBV clinical parameters. ResultsOverall, 11.9% (33/276) of CHB patients had any detectable anti-IFN auto-Abs and 9.8% (27/276) anti-T3IFN auto-Abs, with high incidence of PegIFN-induced de novo auto-Ab (25.7%, 9/35). However, only a minority of auto-Ab-positive sera demonstrated neutralisation in vitro (3/33, 9.1%). Auto-Ab-positivity correlated with higher median HBsAg levels (p=0.0024). All individuals with detectable auto-Ab were PegIFN non-responders including those without auto-Ab against IFN specifically. ConclusionsNon-neutralising anti-IFN auto-Abs are common in CHB and associate with higher median HBsAg levels. Further prospective study of anti-cytokine auto-Ab in CHB are required to characterise association with long-term outcomes. Impact and implicationsHBV and PegIFN individually may induce broad auto-reactivity associated with dysregulated anti-viral immune responses. Auto-Ab screening pre-PegIFN and other immunotherapies may have a critical role in stratifying patient selection.

immunology↗

bioRxiv2023

sciCSR infers B cell state transition and predicts class-switch recombination dynamics using single-cell transcriptomic data

Class-switch recombination (CSR) is an integral part of B cell maturation. Steady-state analyses of isotype distribution (e.g. B cell receptor [BCR] repertoire analysis of snapshots during an immune response) do not directly measure CSR dynamics, which is crucial in understanding how B cell maturation is regulated across time. We present sciCSR (pronounced scissor, single-cell inference of class switch recombination), a computational pipeline which analyses CSR events and dynamics of B cells from single-cell RNA-sequencing (scRNA-seq) experiments. sciCSR re-analyses transcriptomic sequence alignments to differentiate productive heavy-chain immunoglobulin transcripts from germline "sterile" transcripts. From a snapshot of B cell scRNA-seq data, a Markov state model is built by the pipeline to infer the dynamics and direction of CSR. Applying sciCSR on SARS-CoV-2 vaccination time-course scRNA-seq data, we observe that sciCSR predicts, using data from an earlier timepoint in the collected time-course, the isotype distribution of BCR repertoires of subsequent timepoints with high accuracy (cosine similarity [~] 0.9). sciCSR also recapitulates CSR patterns in mouse models where B cell maturation was perturbed using gene knockouts. sciCSR infers cell state transitions using processes specific to B cells, identifies transitions which are often missed by conventional RNA velocity analyses, and can reveal insights into the regulation of CSR and the dynamics of B cell maturation during an immune response.

bioinformatics↗

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↗