Biology subjects

Parthasarathy, V.

Publications and source records attributed to Parthasarathy, V..

7 recordsLinked to original sources

bioRxiv2026

Multi-omic profiling of human antibody-secreting cells reveals diverse subsets sustain durable humoral immunity

Antibody-secreting cells (ASCs) provide humoral immunity that can mediate lifelong protection against pathogens. Current classifications cannot delineate the heterogenous functionalities, tissue residencies, and lifespans of human ASC subsets, impeding clinical translation. We applied multi-omic sequencing, spatial proteomics, and functional assays to discover and characterize human bone marrow (BM) ASC subsets. We identified two peripheral subsets (ASCp) also present in blood and three BM-resident subsets (ASCr), comprising a maturation continuum associated with increased mitochondrial networking, diminished antibody secretion, differential transcription factor motif accessibility, and preferential co-localization in homotypic niches. CD19+9+ASCr and CD19-ASCr exhibited poor recovery years after BM transplantation, indicating a strong dependence on supportive niches. Childhood vaccine antigens were recognized by long-lived ASCr subsets in adults and by immature HLA-DR+ASCp, implying ASCs can differentiate without recent antigen exposure. Our results provide new insights into ASC identity, maturation, and longevity and a generalizable framework for study and manipulation of human ASCs.

immunology↗

bioRxiv2026

Myeloma and therapy reshape the bone marrow niche to durably constrain immune reconstitution and vaccine responsiveness

Infections are the most common cause of non-relapse mortality in multiple myeloma (MM), but the basis of persistent immune dysfunction is obscured by patient heterogeneity and complex treatment regimens, including autologous stem cell transplant (ASCT). We performed longitudinal multi-omic profiling of matched bone marrow and peripheral blood from MM patients across diagnosis, induction, ASCT, and recovery. We found the tumor imposes a compartment-specific immune program where the marrow exhibits metabolic and inflammatory changes that bias hematopoiesis and alter cytotoxic effector programs not mirrored in blood. Adaptive immune reconstitution is impaired up to two years post-ASCT. Half of patients fail to mount IgG responses to high-dose non-adjuvanted influenza vaccine, a defect overcome by the lipid nanoparticle (LNP) adjuvanted COVID mRNA vaccine, which elicited responses in all patients, supporting adjuvanted influenza vaccine strategies in MM. Together these findings define how myeloma and its treatment durably reshape immunity from the marrow outward. HighlightsO_LIMultiple Myeloma marrow and blood show opposing metabolic and inflammatory states C_LIO_LIInduction therapy selects durable myeloma plasma-cell transcriptional states C_LIO_LIB cell and follicular helper T deficits blunt antigen responses after transplant C_LIO_LICOVID-19 vaccination builds immune memory with variable responses to flu vaccination C_LI eTOCMultiple myeloma and its treatment leave a lasting imprint on the bone marrow niche. By profiling bone marrow and blood longitudinally at diagnosis, through induction, autologous transplant, and recovery, we show that marrow-local metabolic and inflammatory constraints persist and help explain why influenza vaccination often fails while mRNA vaccination succeeds.

cancer biology↗

bioRxiv2024

Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination. The resulting resource includes scRNA-seq datasets of >16 million PBMCs, interrogating 71 immune cell subsets from our new Immune Health Atlas. This study allows unique insights into the composition and transcriptional state of immune cells at homeostasis, with vaccine perturbation, and across age. We find that T cells specifically accumulate age-related transcriptional changes more than other immune cells, independent from inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination are linked to a Th2-like state shift in older adults memory CD4 T cells, revealing possible mechanisms of immune dysregulation during healthy human aging. This extensive resource is provided with a suite of exploration tools at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ to enhance data accessibility and further the understanding of immune health across age.

immunology↗

bioRxiv2024

Tumor localization strategies of multi-cancer early detection tests: a quantitative assessment

IntroductionBlood-based multi-cancer early detection (MCED) tests may expand the number of "screenable" cancers. Defining an optimal approach to diagnostic resolution for individuals with positive MCED test results is critical. Two prospective trials employed distinct diagnostic resolution approaches; one employed a molecular signal to predict tissue of origin (TOO) and the other used an imaging-based diagnostic strategy. Using mathematical modeling, we compared the diagnostic burden of each approach and characterized the risk of excess cancer incidence that may be attributable to radiation exposure associated with a false positive (FP) MCED test result and an imaging-based diagnostic strategy. MethodsA mathematical expression for diagnostic burden was derived using MCED test positive predictive value (PPV), molecular TOO localization accuracy, and the expected number of imaging procedures associated with each diagnostic outcome. Imaging and molecular TOO strategies were compared by estimating diagnostic burden across a wide range of MCED PPVs and TOO accuracies. Organ-specific radiation dose for diagnostic imaging was extracted from the literature and used as input to National Cancer Institute RADRat tool for estimating excess lifetime cancer risk due to radiation exposure. ResultsFor the molecular TOO diagnostic approach, an average of 2.1 procedures are required to reach diagnostic resolution for correctly-localized TPs, 4.4 procedures for incorrectly-localized TPs, and 4 procedures for FPs, vs. an average of 2.75 procedures for TPs and 2.4 for FPs with an imaging-based diagnostic strategy. Across the entire range of possible PPV and localization performance, a molecular TOO strategy resulted in a higher mean diagnostic burden: 3.6 procedures (SD 0.445) vs. 2.6 procedures (SD 0.1) for the imaging strategy. Predicted diagnostic burden was higher for molecular TOO in 95.5% of all possible PPV and TOO accuracy combinations; 79% or higher PPV would be required for a 90% accurate molecular TOO strategy to be less burdensome than imaging. The maximum rate of excess cancer incidence from radiation exposure for FP results from MCED screening between the ages of 50-84 was estimated at 64.6 per 100,000 (annual testing, 99% specificity), 48.5 per 100,000 (biennial testing, 98.5% specificity), and 64.6 per 100,000 (biennial testing, 98% specificity). ConclusionsThis analysis demonstrates that an imaging-based diagnostic strategy is more efficient than a molecular TOO-informed approach across 95.5% of all possible MCED PPV and TOO accuracy combinations. The use of an imaging-based approach for cancer localization can be efficient and low risk compared to a molecular-based approach.

cancer biology↗

bioRxiv2023

Single-cell RNA sequencing reveals dysregulated fibroblast subclusters in prurigo nodularis

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory skin disease that disproportionately affects black patients. However, the pathogenesis of PN is poorly understood. We performed single-cell transcriptomic profiling, ligand receptor analysis and cell trajectory analysis of 28,695 lesional and non-lesional PN skin cells to uncover disease-identifying cell compositions and genetic characteristics. We uncovered a dysregulated role for fibroblasts (FBs) and myofibroblasts as a key pathogenic element in PN, which were significantly increased in PN lesional skin. We defined seven unique subclusters of FBs in PN skin and observed a shift of PN lesional FBs towards a cancer-associated fibroblast (CAF)-like phenotype, with WNT5A+ CAFs increased in the skin of PN patients and similarly so in squamous cell carcinoma (SCC). A multi-center PN cohort study subsequently revealed an increased risk of SCC as well as additional CAF-associated malignancies in PN patients, including breast and colorectal cancers. Systemic fibroproliferative diseases were also upregulated in PN patients, including renal sclerosis and idiopathic pulmonary fibrosis. Ligand receptor analyses demonstrated increased FB1-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV, suggesting a fibroblast-neuronal axis in PN. Type I IFN responses in immune cells and increased angiogenesis/permeability in endothelial cells were also observed. As compared to atopic dermatitis (AD) and psoriasis (PSO) patients, increased mesenchymal dysregulation is unique to PN with an intermediate Th2/Th17 phenotype between atopic dermatitis and psoriasis. These findings identify a pathogenic role for CAFs in PN, including a novel targetable WNT5A+ fibroblast subpopulation and CAF-associated malignancies in PN patients.

bioinformatics↗

bioRxiv2022

Dermal nerve growth factor is increased in prurigo nodularis compared to atopic dermatitis

BackgroundPrurigo nodularis (PN) is a chronic, pruritic, inflammatory skin disease characterized by hyperkeratotic nodules on the trunk and extremities. While there is growing research on the immunological basis of PN, the neuropathic and structural components of PN lesions are unknown. ObjectiveTo determine the inflammatory, neuropathic, and structural pathways in PN compared to atopic dermatitis (AD). MethodsLesional and non-lesional skin biopsies were collected from 13 PN and 6 AD patients. mRNA and protein expression in biopsies was determined using RNA-Sequencing and immunohistochemistry (IHC), respectively. Differentially expressed genes (DEGs) were identified using the DESeq2 R package and pathway level enrichment was determined using Gene Set Enrichment Analysis. IHC expression was quantified with QuPath followed by statistical comparison with the Students t-test and Mann-Whitney U. ResultsCompared to lesional AD, lesional PN had greater mRNA expression of MMPs, OSM, NGF, IL1{beta}, CXCL2, CXCL5, CXCL8, and insulin-like growth factors, and lower expression of CCL13, CCL26, EPHB1, and collagens. Compared to non-lesional AD, non-lesional PN showed upregulation of keratin-family genes. GSEA revealed that lesional PN had greater keratinization, cornified envelope, myelin sheath, TGF-beta signaling, extracellular matrix disassembly, metalloendopeptidase activity, and neutrotrophin-TRK receptor signaling, while non-lesional PN had higher keratin filament, extracellular structure organization, extracellular matrix disassembly, and angiogenesis. IHC showed increased dermal nerve growth factor (NGF) expression in lesional PN compared to lesional AD (p=0.038), and greater epidermal NGF compared to dermal NGF in non-lesional PN (p=0.014). LimitationsSingle, tertiary care center. ConclusionsPN demonstrated increased neurotrophic and extracellular matrix (ECM) remodeling signatures compared to AD, possibly explaining the morphological differences in their lesions. These signatures may therefore be important components of the PN pathogenesis and may serve as therapeutic targets.

pathology↗

bioRxiv2022

Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: a cluster analysis

BackgroundPrurigo nodularis (PN) is a chronic inflammatory skin disease characterized by severe pruritus and notable disease heterogeneity. There is evidence of systemic inflammation in PN, including dysregulation observed in type 2 inflammation in subsets of patients. We aimed to elucidate which components of type 2 inflammation are dysregulated in PN patients using plasma immunoassay cytokine profiling. Materials and MethodsWhole blood was obtained from PN patients with uncontrolled disease and control patients without pruritus. Plasma samples were isolated from whole blood and assayed for IL-4, IL-5, IL-13, IgE, and periostin. For statistical analysis, ANOVA was utilized to compare PN and control patients. For multiple hypothesis, adjusted p-value was calculated with a Benjamini-Hochberg procedure with the significance threshold at 0.05. Clustering was performed using K-means clustering in R version 4.0.3. ResultsSingle-plex assays of the Th2 biomarkers demonstrated significantly elevated circulating plasma IL-13 (0.13 vs. 0.006 pg/mL, p=0.0008) and periostin (80.3 vs. 60.2 ng/mL, p=0.012) in PN patients compared to controls. IL-4 (0.11 vs. 0.02 pg/mL, p=0.30) and IL-5 (0.75 vs. 0.40 pg/mL, p=0.10) were not significantly elevated, while IgE approached significance in PN (1202.0 vs. 432.7 ng/mL, p=0.08). Clustering of PN and control patients together revealed mean silhouette maximization at two clusters. Cluster 1 (n=36) consisted of 18 PN patients and 18 controls. Cluster 2 (n=11) consisted entirely of PN patients (p<0.01) (Figure 1b). When comparing the two clusters, cluster 2 had higher levels of IL-13 (0.33 vs. 0.008 pg/mL, p=0.0001) and IL-5 (1.22 vs. 0.43 pg/mL, p=0.03) compared to cluster 1. There were no significant differences in any of the biomarkers between PN patients from cluster 1 and the healthy control patients in this cluster. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/495051v1_fig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@101432dorg.highwire.dtl.DTLVardef@1e16d01org.highwire.dtl.DTLVardef@bb8edborg.highwire.dtl.DTLVardef@19fd785_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Single-plex plasma immunoassays of prurigo nodularis vs. controls (a) Plasma single-plex immunoassays (b) Heatmap of Z-scored biomarker levels for each patient, delineated by cluster. PN, prurigo nodularis; HC, healthy control C_FIG ConclusionsThis study demonstrates elevation of IL-13 and periostin in PN patients with distinct clusters with varying degrees of type 2 inflammation. Given this heterogeneity, further biomarker studies with single-cell resolution will provide better guidance towards future precision medicine approaches in the treatment of PN.

immunology↗