Biology subjects

Yazdanbakhsh, M.

Publications and source records attributed to Yazdanbakhsh, M..

10 recordsLinked to original sources

bioRxiv2026

Enhancing Supercooled Red Blood Cell Storage: The Membrane-Stabilizing Effect of Ethanol

Hypothermic storage is constrained by the progressive depletion of energy reserves, curtailing the shelf-life of organs, cell therapies, and blood products. High sub-zero supercooling helps preserve energy homeostasis by slowing catabolic processes; however, the resulting injury in this setting is not primarily driven by energy depletion. Here, we investigated whether low-dose ethanol could prevent forms of injury that arise independently of disrupted energy homeostasis and remain unaddressed in supercooled storage. Human red blood cells treated with 4% (v/v) ethanol were stored 4 {degrees}C, -4 {degrees}C, or -8 {degrees}C and subject to a series of functional assessments and integrated metabolomic/lipidomic profiling after 21 and 42 days of storage. Metabolomics data showed that energy homeostasis was better preserved at lower temperatures, yet these supercooled conditions simultaneously intensified hemolysis and caused a marked depletion of lysophospholipid species that did not occur at 4 {degrees}C. Ethanol blunted these effects, cutting hemolysis by [~]50 % at -4 {degrees}C, by [~]85 % at -8 {degrees}C, and attenuating lysophospholipid depletion. These results uncover a previously unrecognized, lipid-centric injury that arises during supercooled storage and establish low-dose ethanol as a simple, readily deployable countermeasure that could help extend storage intervals of diverse biological systems. SUMMARYCellular preservation has traditionally focused on maintaining energy metabolism during hypothermic storage, but whether this is sufficient at high sub-zero temperatures remains unclear. Human red blood cells were stored for up to 42 days at 4{degrees}C, -4{degrees}C, or -8{degrees}C with or without 4% ethanol and evaluated using functional assays and integrated metabolomic and lipidomic profiling. Although supercooling preserved energy homeostasis, it increased hemolysis and caused pronounced lysophospholipid depletion. Ethanol reduced hemolysis by approximately 50% at -4{degrees}C and 85% at -8{degrees}C, attenuated lysophospholipid loss, and produced comparatively modest changes in cellular metabolism. These findings identify membrane integrity as a critical determinant of preservation outcome and support strategies that protect membrane stability alongside metabolic homeostasis.

cell biology↗

bioRxiv2026

Ageing of the Upper Airway Epithelial Niche Limits Tissue-Resident T Cell Immunity

Respiratory tract infections are a major cause of morbidity and mortality among older adults worldwide. Yet, how ageing shapes protective immunity within the upper respiratory tract (URT) remains poorly understood. Here, we profiled the nasal immune landscape of young adults and older adults with and without frailty, using high-dimensional cytometry, proteomics, single-cell transcriptomics and T cell receptor (TCR) sequencing. Ageing was associated with a selective reduction of tissue-resident memory T (Trm) cells, independent of effector T cell numbers, inflammageing levels or frailty and was accompanied by a decline in T cell receptor repertoire stability. Trm cells from older adults also showed decreased steady-state IFN{gamma} expression, accompanied by reduced antiviral transcriptional programs in the mucosa. Mechanistically, in vitro PBMC-epithelium co-culture models revealed that older adults have a reduced capacity for Trm differentiation, which was associated with a diminished epithelial TGF-{beta} secretion, driven by reduced expression in ciliated epithelial cells. Together, these findings reveal that URT immunity deteriorates with age due to disrupted epithelial-immune crosstalk. This identifies the epithelial niche as a key regulator of mucosal immune ageing and suggests that enhancing TGF{beta} signaling may improve the effectiveness of mucosal airway vaccination strategies in older populations.

immunology↗

bioRxiv2026

A cell surface proteomic atlas reveals socioeconomic status associated immune diversity

Socioeconomic status (SES) is a potent determinant of immune variation, yet unbiased approaches to holistically map the effect of SES on the immune system are lacking. We developed a high-dimensional flow cytometry-based profiling approach to analyse 331 cell surface proteins across 33 immune cell subsets within an SES-stratified Senegalese cohort, alongside a European cohort (Netherlands). We identified 108 SES-related markers across the immune system, revealing that lower SES individuals exhibited downregulation of surface proteins, affecting in particular adhesins, chemokine and complement receptors. Conversely, lower SES was associated with hallmarks of chronic activation and exhaustion including upregulation of immune checkpoints. Metabolic profiling demonstrated that while lower SES individuals displayed elevated baseline RNA transcription, higher SES individuals exhibited superior protein translation rates. We validated these SES-related immune trends in an independent cohort and provide an interactive online resource for exploring this surface protein atlas on immune cell subsets. Taken together, these findings provide a global overview of how the cell surface proteome varies by SES, and identify molecular changes that can affect vaccine efficacy and disease outcomes.

immunology↗

bioRxiv2025

Mass cytometry data integration methods reveal rural-urban gradient of immune profiles across geography

The human immune system strongly varies across populations and is shaped by a wide range of host and environmental factors. As such, a rural compared to urban lifestyle has previously been associated with baseline differences in immune profiles, which can impact outcome of vaccination. The question whether there is a immune signature that associates with rural living irrespective of ancestry or geography has been addressed here along with which analytical methods are most suitable. Using three mass cytometry datasets, we studied shared and population-specific immune characteristics of healthy rural- or urban-living Indonesian, Senegalese and Tanzanian adults and urban-living Europeans. After harmonized preprocessing and quality control, 75.4 million cells were integrated using four different data-integration methods. Among these, CytoNorm with in silico references performed best, revealing shared differences in the differentiation state within the lymphocyte compartment that distinguishes rural from urban-living individuals. Differentiated CD4+ T cells expressing CTLA-4, PD-1 and ICOS characterized rural living, as did CD4+ T cells with high CD161 expression in combination with CRTH2 and GATA3. In the innate compartment, CD56- CD16 NK cells with low CD38 and CD11c expression were expanded in rural living subjects. Together, our results demonstrate that, using a harmonized analytical pipeline and machine learning-based integration, large-scale mass cytometry data can be combined across diverse cohorts to identify shared immunological hallmarks of rural living. These signatures may provide targets for modulating immune responses in future vaccine studies.

immunology↗

bioRxiv2025

Phage-display immunoprecipitation sequencing reveals distinct antibody repertoire patterns across a rural-urban gradient

Environmental microbial exposures are hypothesized to drive immune profile differences across rural-urban gradients, yet direct evidence linking exposures to immune phenotypes remains limited. Here, we employed phage-displayed immunoprecipitation sequencing (PhIP-seq) to profile antibody repertoires against 357,192 epitopes from >700 organisms in 62 age-matched healthy adults from rural Senegal (n=29), urban Senegal (n=20), and urban Netherlands (n=13). PhIP-Seq analysis identified two major patterns of antibody repertoire variation: geographically restricted signatures distinguishing Senegal from the Netherlands, and a trajectory associated with rural-urban gradients spanning from rural Senegal to urban Netherlands. Integration of PhIP-seq data with high-dimensional immunological profiling revealed immune signatures correlated with the rural-urban antibody repertoire trajectory. Our findings demonstrate that antibody repertoire profiling captures distinct microbial exposure histories across both geographic regions and rural-urban gradients and correlates with variation in immune signatures. This work establishes PhIP-seq as a powerful tool for linking environmental exposure histories to population-level immune landscapes and provides insights into immune adaptation across diverse environments.

immunology↗

bioRxiv2025

Immuno-functionomics reveals geographical variation and a role for TLR8 in mRNA vaccine responses

The innate immune system plays a pivotal role in pathogen defense via pattern recognition receptor sensing, initiating responses upon infection or vaccination. Understanding its functional capacity is crucial for deciphering correlates of vaccine efficacy and understanding responses to infection. In this study, we developed a holistic approach to study immune function, generating >3100 readouts across 16 cell types, 18 pattern recognition receptors and 11 produced cytokines using spectral flow cytometry. To explore geographical variation, we studied the immune system of Europeans, urban, and rural Indonesians. We found differences in immune responses, such as increased IL1{beta} production in rural Indonesians and impaired IFN{gamma} production by innate lymphocytes after TLR8 stimulation. In Europeans vaccinated with mRNA-1273, baseline IFN{gamma} production by innate lymphocytes correlated with SARS-CoV-2 Spike-specific immune responses. In vitro mRNA vaccine stimulation also induced IFN{gamma} production, which was TLR8-dependent and reduced in rural Indonesians. This study highlights functional immune diversity and TLR8s potential role in mRNA vaccine responses. SummaryWe developed an approach to study the function capacity of the immune system, exploring geographical variation and mRNA vaccine responses. This revealed TLR8s potential role in responding to mRNA vaccines, and an impairment in this pathway in rural Indonesians.

immunology↗

bioRxiv2021

LKB1 signalling in dendritic cells controls whole-body metabolic homeostasis by limiting T helper 17 priming

Obesity-associated metaflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of dendritic cells (DCs). Here, we report that hepatic DCs from high-fat diet (HFD)-fed obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11c{Delta}LKB1) worsened HFD-driven hepatic steatosis, systemic insulin resistance and glucose intolerance. Loss of LKB1 in DCs was associated with increased cellular expression of Th17-polarizing cytokines and increased hepatic CD4+ IL-17A+ Th17 cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11c{Delta}LKB1 mice. Mechanistically, disrupted metabolic homeostasis was independent of the canonical LKB1-AMPK axis. Instead, we provide evidence for involvement of the AMPK-related salt-inducible kinase(s) in controlling Th17-polarizing cytokine expression in LKB1-deficient DCs. Altogether, our data reveal a key role for LKB1 signalling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 differentiation.

immunology↗

bioRxiv2020

Soluble mannose receptor induces pro-inflammatory macrophage activation andobesity-associated metaflammation

Pro-inflammatory activation of macrophages in metabolic tissues is critically important in induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct, functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to a Src/Akt/NF-{kappa}B-mediated cellular reprogramming towards an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Additionally, MR deficiency lowers pro-inflammatory macrophages in metabolic tissues and protects against hepatic steatosis and whole-body metabolic dysfunctions in high-fat diet-induced obese mice. Conversely, administration of sMR in lean mice increases serum pro-inflammatory cytokines, activates tissue macrophages and promotes insulin resistance. Altogether, our results reveal sMR as novel regulator of pro-inflammatory macrophage activation which could constitute a new therapeutic target for metaflammation and other hyperinflammatory diseases.

immunology↗

bioRxiv2020

The helminth glycoprotein omega-1 improves metabolic homeostasis in obese mice through type-2 immunity-independent inhibition of food intake

Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) can induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega-1 (ω1), one of the major S. mansoni immunomodulatory glycoproteins, on metabolic homeostasis. Male C57Bl6/J mice were fed a high-fat diet for 12 weeks followed by bi-weekly injection of SEA, ω1 or vehicle for 4 additional weeks. Whole-body metabolic homeostasis and energy expenditure were assessed by glucose/insulin tolerance tests and indirect calorimetry, respectively. Tissue-specific immune cell phenotypes were determined by flow cytometry. We show that treatment of obese mice with plant-produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass and improved systemic insulin sensitivity and glucose tolerance in a time-and dose-dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils and alternatively-activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6-deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole-body energy expenditure, an effect also occurring in leptin receptor-deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole-body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6-independent mechanism.Author summary The obesity-induced chronic low-grade inflammation, notably in adipose tissue, contributes to insulin resistance and increased risk of type 2 diabetes. We have previously shown that infection with parasitic helminth worms was associated with protection against obesity-related metabolic dysfunctions both in mice and humans. We have also reported that treatment of obese mice with an extract of Schistosoma mansoni eggs (SEA) improves insulin sensitivity and glucose tolerance, a beneficial effect that was associated with a helminth-specific type 2 immune response in metabolic organs. Here, we studied the effects of omega-1 (ω1), a single immunomodulatory molecule from SEA, on metabolic health in obese mice, and investigated the role of the host immune response elicited. We found that ω1 induced a helminth-characteristic type 2 immune response in adipose tissue and improved both insulin sensitivity and glucose tolerance in obese mice. Yet, in contrast to SEA, ω1’s immunomodulatory properties were dispensable for its metabolic effects. Instead, we show that ω1 inhibited food intake, a feature accounting for most of the improvements in metabolic health. Together, our findings indicate that helminth molecules may improve metabolic health through multiple distinct mechanisms, and further characterization of such molecules could lead to new therapeutic strategies to combat obesity.List of abbreviationsAAMAlternatively activated macrophageALATAlanine aminotransferaseBATBrown adipose tissueDCDendritic cellEEEnergy expenditureGTTGlucose tolerance testHEKHuman embryonic kidneyHFDHigh-fat dietHOMA-IRHomeostatic model assessment of insulin resistanceIFN-γInterferon gammaILInterleukinILCInnate lymphoid cellITTInsulin tolerance testLBMLean body massLFDLow-fat dietNAFLDNon-alcoholic fatty liver diseaseNASHNon-alcoholic steatohepatitispLeX-ω1Recombinant omega-1 from LeX-glyco-engineered Nicotiana benthamiana plantsPMAPhorbol myristate acetatepWT-ω1Recombinant omega-1 from wild-type N. benthamiana plantsSEASchistosoma mansoni soluble egg antigensSTATSignal transducer and activator of transcriptionSVFStromal vascular fractionThT helperTNFTumor necrosis factorUCP1Uncoupling protein 1WATWhite adipose tissueWTWild-typeView Full Text

immunology↗

bioRxiv2019

Defining mucosal immunity using mass cytometry following experimental human pneumococcal challenge

Streptococcus pneumoniae (Spn) is a common cause of respiratory infection, but also frequently colonises the nasopharynx in the absence of disease. We used mass cytometry to study immune cells from nasal biopsy samples, collected following experimental human pneumococcal challenge, in order to identify immunological changes that follow and control spn colonisation. Using 37 markers, we characterized 293 nasal immune cell clusters, of which 7 were associated with Spn colonisation. B cell and CD8+CD161+ T cell clusters were significantly higher in non-colonised than in colonised subjects. Spn colonization led to recirculation of not only Spn-specific but also aspecific nasal B cells. This associated with increased numbers of circulating plasmablasts and increased antibody levels against the unrelated bacterium Haemophilus influenzae. In addition, we demonstrated that baseline functionality of blood mucosal associated invariant T (MAIT) cells associated with protection against Spn. These results identify new host-pathogen interactions at the mucosa upon Spn colonisation.

immunology↗