Biology subjects

Svensson, C.

Publications and source records attributed to Svensson, C..

9 recordsLinked to original sources

bioRxiv2026

Netrin-1 inhibition does not attenuate cancer-induced bone pain in three translational models

1.Cancer-induced bone pain (CIBP) occurs in a majority of patients when primary or metastatic cancer develops within the bone. This pain has a significant impact on quality of life, yet there are limited effective treatment options available. Nerve sprouting is a complex mechanism that has been implicated in CIBP. Netrin-1 is a neuronal guidance molecule that is produced by numerous cell types, including cancer cells. In this study we aimed to determine whether netrin-1 inhibition (with NP137 - a humanized IGg1 monoclonal antibody) could ameliorate nerve sprouting, and nociception by extension, in three models of CIBP - osteosarcoma, metastatic breast cancer, and metastatic prostate cancer. Sustained administration of NP137 failed to produce an anti-nociceptive effect in these models, but a delayed onset was observed in the osteosarcoma model. NP137 did not produce a disease-modifying effect, as micro-computed tomography did not reveal reduced bone destruction in the NP137-treated groups. Additionally, there was no nerve fibre density reduction in any of the groups at the late-stage of the disease, suggesting that nerve sprouting occurs in early- to mid-stage CIBP development. Investigation of NP137 exposure indicated that serum levels of NP137 were comparable between the sham and cancer groups. Our study indicates that netrin-1 may play a role in early-stage CIBP development, but inhibition of this mechanism does not produce robust anti-nociception.

pharmacology and toxicology↗

bioRxiv2026

Tissue-to-Analysis Framework Enables Multiscale Mapping of the Architectural and Cellular Organization in the Human Dorsal Root Ganglion

Transcriptomic studies have helped us understand the dorsal root ganglias cellular milieu, yet our knowledge of protein expression and spatial organization/architecture remains less defined. Here we establish a comprehensive resource from processing through analysis of hDRG tissue. We optimize tissue-handling strategies and evaluate 114 antibodies targeting neuronal and non-neuronal cell types, identifying protocols that preserve neuronal morphology and antigen retain specificity. Integrating these workflows with our Deep Learning-assisted image analysis pipelines, we quantify size, expression, and spatial organization across 35,721 neurons from 15 donors. Female donors exhibited significantly larger neuronal somata, indicating sexual dimorphism. Neuronal subpopulations display clear spatial clustering. We further characterized the perineuronal niche, marked by dense vascularization, nuclear remodeling in perineuronal cells, and age-related increased turnover of neuron-associated macrophages. Together, this resource provides standardized methodologies and quantitative frameworks for reproducible protein-level interrogation of human sensory biology and pain mechanisms.

neuroscience↗

bioRxiv2026

Leveraging TNFR2 for antitumour immunity: T reg depletion and myeloid reprogramming versus T cell costimulation

Although checkpoint inhibitors have revolutionized cancer treatment, responses are largely restricted to targeting CTLA-4 and PD-(L)1. TNFR2 has been identified as a target of interest, but a lack of understanding of whether agonists or blockers should be used, and whether Fc{gamma}R interactions promote effcacy, has hampered therapeutic antibody development. Here, we engineered two distinct -TNFR2 types: ligand-blocking Fc{gamma}R-engaging versus non-ligand-blocking agonist antibodies. Both showed potent anti-tumor effcacy across multiple syngeneic mouse tumor models and combined effectively with -PD-1. The ligand-blocking antibody depleted intratumoral T regs and reprogrammed the myeloid compartment, directing monocytes towards a pro-inflammatory macrophage and dendritic cell trajectory. Surprisingly, this effect depended on both inhibitory and activating Fc{gamma}Rs. In contrast, the agonist directly co-stimulated T and NK cells, through partially Fc{gamma}R-independent mechanisms. Both antibodies converged on activating tumor-specific CD8+ T cells mediating tumor rejection. Clinical assessment of both ligand-blocking (BI-1808) and agonist (BI-1910) -TNFR2 antibodies is currently ongoing. Graphical abstractO_LILigand-blocking anti-TNFR2 mAbs (BI-1808 and 3F10) deplete CCR8+ T regs and activate myeloid cells, remodeling the TME and leading to CD8+ T cell killing of cancer cells. T reg depletion and myeloid activation are mediated through interaction with activating Fc{gamma}Rs and the inhibitory Fc{gamma}RIIB, respectively. C_LIO_LIAgonist anti-TNFR2 mAbs (BI-1910 and 5A05) intrinsically agonize TNFR2 on T cells and NK cells, which is enhanced by Fc{gamma}RIIB crosslinking. The resulting broad lymphocyte activation mediates cancer cell killing. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/697572v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@3ecc17org.highwire.dtl.DTLVardef@c936a7org.highwire.dtl.DTLVardef@23189aorg.highwire.dtl.DTLVardef@243a05_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Exploring the neuroimmune cellular landscape in the skin of subjects with fibromyalgia.

Fibromyalgia (FM) is a chronic disorder involving widespread pain, fatigue, and cognitive impairment. Although its pathogenesis remains uncertain, FM patients exhibit hypersensitivity, reduced intraepidermal nerve fiber density (IENFD), and more recently shown, skin immune dysregulation, possibly manifesting in cutaneous alterations in various cell populations. To characterize the cutaneous cellular landscape in FM, we assessed the sensory profile and skin cell populations across different layers within the same cohort. FM patients, compared to healthy controls (HC), showed lower pain thresholds across multiple body areas, with no differences in thermal detection. While our findings confirm previous reports for reduced PGP9.5+ IENF and increased density in mast cells in FM, we also identified novel changes, particularly in the dermis. We observed elongated thinly myelinated NF200+ fibers and reduced density in non-nerve-associated S100B+ Schwann cells in FM compared to HC. Notably, dermal CD68+ and CD163+ populations were significantly reduced in FM, accompanied by morphological changes. The CD163+ population correlated negatively and significantly against IENFD. These findings suggest that, beyond intraepidermal nerve loss, FM involves broader neuroimmune alterations in the skin, particularly within the dermis, offering new insights into its pathophysiology and establishing a foundation for future studies exploring the functional implications of these changes. SUMMARYAmong the alterations observed in patients with fibromyalgia (FM) are changes in skin innervation and differences in the density of certain immune cell populations. To better characterize FM from an integral perspective, we examined both the sensory profile and the cutaneous cellular landscape of FM patients in comparison with healthy controls (HC). FM patients exhibited lower pain thresholds across multiple body areas, with no differences in thermal detection. Consistent with previous findings, FM skin biopsies revealed reduced intraepidermal nerve fiber density and increased mast cell numbers. Beyond these known alterations, our study identified novel dermal changes, including elongated thinly myelinated NF200+ fibers, reduced density of non-nerve-associated S100B+ Schwann cells, and decreased CD68+ and CD163+ macrophage populations exhibiting morphological alterations. Notably, CD163+ cell density correlated negatively with intraepidermal nerve fiber density, highlighting potential neuroimmune mechanisms underlying the pathophysiology of FM.

immunology↗

bioRxiv2024

Androgens modulate the immune profile in a mouse model of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with a low-grade inflammation, but it is unknown how hyperandrogenism, the hallmark of PCOS, affects the immune system. Using a well-established PCOS-like mouse model, we demonstrate that androgen exposure affects immune cell populations in reproductive, metabolic, and immunological tissues differently in a site-specific manner. Co-treatment with flutamide, an androgen receptor antagonist, prevents most of these alterations, demonstrating that these effects are mediated through androgen receptor activation. Dihydrotestosterone (DHT)-exposed mice display a drastically reduced eosinophil population in uterus compared to controls, coupled with lower levels of eotaxin (CCL11), suggesting a reduced recruitment from blood. Decreased frequencies of eosinophils were also seen in visceral adipose tissue (VAT). A higher expression level of CD69, a marker of activation or tissue residency, was consistently found on natural killer (NK) cells in all analyzed tissues. However, a higher frequency of NK cells and elevated levels of IFN-{gamma} and TNF- were only seen in uteri of androgen-exposed mice, while NK cell frequencies were unaffected in all other analyzed compartments. Distinct alterations of macrophages in ovaries, uterus and VAT were also found in DHT-exposed mice and could potentially be linked to PCOS-like traits of the model. Indeed, androgen-exposed mice were insulin resistant and displayed an aberrant immune profile in VAT, albeit unaltered fat mass. Collectively, we demonstrate that hyperandrogenism causes tissue-specific alterations of immune cells in reproductive organs and VAT, which could have considerable implications on tissue function and contribute to the reduced fertility and metabolic comorbidities associated with PCOS.

immunology↗

bioRxiv2023

The role of B cells in immune cell activation in polycystic ovary syndrome

Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knock-out mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS. SummaryAndrogen receptor activation alters B cell frequencies and functionality as the transfer of human PCOS IgG increase weight in female mice. Lack of B cells does not protect from the development of a PCOS phenotype, suggesting an unrecognized role for B cells in PCOS autoimmune comorbidities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/525671v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@15802fborg.highwire.dtl.DTLVardef@12bd154org.highwire.dtl.DTLVardef@1bc14a9org.highwire.dtl.DTLVardef@f08d2b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

eEF2 improves dense connective tissue repair and healing outcome by regulating cellular death, autophagy, apoptosis, proliferation and migration

Outcomes following human dense connective tissue (DCT) repair are often variable and suboptimal, resulting in compromised function and development of chronic painful degenerative diseases. Moreover, biomarkers and mechanisms that guide good clinical outcomes after DCT injuries are mostly unknown. Here, we characterize the proteomic landscape of DCT repair following human tendon rupture and its association with long-term patient-reported outcome. Moreover, the regulatory mechanisms of relevant biomarkers were assessed partly by gene silencing experiments. A Mass-Spectrometry based proteomic approach quantified a large number (769) of proteins, including 51 differentially expressed proteins among 20 good versus 20 poor outcome patients. A novel biomarker, elongation factor-2 (eEF2) was identified as being strongly prognostic of the 1-year clinical outcome. Further bioinformatic and experimental investigation revealed that eEF2 positively regulated autophagy, cell proliferation and migration, as well as reduced cell death and apoptosis, leading to improved DCT repair and outcomes. Findings of eEF2 as novel prognostic biomarker could pave the way for new targeted treatments to improve healing outcomes after DCT injuries.

cell biology↗

bioRxiv2022

Fibromyalgia patients with high levels of anti-satellite glia cell IgG antibodies present with more severe symptoms

ObjectiveTransferring fibromyalgia patient IgG to mice induces pain-like behaviour and fibromyalgia IgG binds mouse and human satellite glia cells (SGCs). These findings suggest that autoantibodies could be part of fibromyalgia pathology. However, it is unknown how frequently fibromyalgia patients have anti-SGC antibodies and how anti-SGC antibodies associate with disease severity. MethodsWe quantified serum or plasma anti-SGC IgG levels in two fibromyalgia cohorts from Sweden and Canada using an indirect immunofluorescence murine cell culture assay. Fibromyalgia serum IgG binding to human SGCs in human dorsal root ganglia tissue sections was assessed by immunofluorescence (n=14/group). ResultsIn the cell culture assay anti-SGC IgG levels were increased in both fibromyalgia cohorts compared to controls. Elevated anti-SGC IgG was associated with higher levels of self-reported pain in both cohorts, and higher fibromyalgia impact questionnaire scores and increased pressure sensitivity in the Swedish cohort. Anti-SGC IgG levels were not associated with fibromyalgia duration. Swedish FM patients were clustered into FM-severe and FM-mild groups and the FM-severe group had elevated anti-SGC IgG compared to the FM-mild and controls. Anti-SGC IgG levels detected in culture were positively correlated with increased binding to human SGCs. Moreover, the FM-severe group had elevated IgG binding to human SGCs compared to the FM-mild and control groups. ConclusionsA subset of fibromyalgia patients have elevated levels of anti-SGC antibodies, and the antibodies are associated with more severe fibromyalgia severity. Screening fibromyalgia patients for anti-SGC antibodies could provide a path to personalized treatment options that target autoantibodies and autoantibody production.

neuroscience↗

bioRxiv2019

Passive transfer of fibromyalgia pain from patients to mice.

Fibromyalgia syndrome (FMS) is a chronic pain condition characterized by widespread pain and tenderness1,2. The etiology and pathophysiology of fibromyalgia are unknown and there are no effective treatments. Here we show that sensory hypersensitivity in FMS is caused by autoantibodies that act by sensitizing nociceptive sensory neurons. Administration of IgG from FMS patients increased mouse pain sensitivities to stimulation with mechanical pressure and cold. In contrast, transfer of IgG depleted samples from FMS patients or IgG from healthy control subjects had no effect on pain sensitivity. Sensory nerve fibres in ex vivo skin-nerve preparations from mice treated with FMS IgG were hypersensitive to mechanical stimulation. Immunohistochemical analysis revealed that IgG from FMS patients specifically labeled satellite glial cells and myelinated fibre tracts, as well as a small number of macrophages and endothelial cells in mouse dorsal root ganglia but not skin, muscle, spinal cord and brain. Our results demonstrate that fibromyalgia pain is caused by IgG autoantibodies that sensitize peripheral nociceptive afferents neurons and suggest that therapies that reduce patient IgG titres may be effective treatments of fibromyalgia pain.

neuroscience↗