Biology subjects

Gustafson, C. E.

Publications and source records attributed to Gustafson, C. E..

6 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↗

bioRxiv2025

PULSAR: a Foundation Model for Multi-scale and Multicellular Biology

Biology emerges from interactions across physical scales, where molecular interactions drive cellular states, which in turn orchestrate multicellular tissue functions that collectively define health and disease. However, current computational models are often constrained to single scales in isolation, failing to integrate the biology that emerges from lower to higher levels [1]. Here we present PULSAR (Patient Understanding Leveraging Single-cell universAl Representation), a multi-scale and multicellular foundation model architecture that explicitly enables information flow from genes to cells to multicellular systems. Applied to the human peripheral immune system, PULSAR extracts a unified donor representation that supports rapid disease classification, biomarker prediction, and forecasting of future clinical events, such as Rheumatoid arthritis onset. As a generative model, PULSAR enables the simulation of cytokine perturbation response across physical resolutions, while its interpretability reveals the key cell types driving disease. Overall, PULSAR opens new avenues for precision medicine by enabling computational reasoning that connects molecular biology to clinical phenotypes.

bioinformatics↗

bioRxiv2024

Systemic inflammation and lymphocyte activation precede rheumatoid arthritis

Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical at-risk state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity. We provide a suite of tools at https://apps.allenimmunology.org/aifi/insights/ra-progression/ to facilitate exploration and enhance accessibility of this extensive dataset. One Sentence SummaryACPA+ at-risk individuals show RA-like inflammation and multi-compartment immune dysregulation during transition to clinically active RA

immunology↗

bioRxiv2024

Comprehensive multi-site profiling of the malignant pleural mesothelioma micro-environment identifies candidate molecular determinants of histopathologic type

Pleural mesothelioma (PM) comprises sarcomatoid, epithelioid and biphasic histologic subtypes. Bulk PM RNA-sequencing identifies a histology-associated molecular gradient with features of epithelial-mesenchymal (EM) transition but cannot parse malignant, stromal, and immune tumor components. The mechanisms driving PM malignant cell phenotype and associated histology is not well-characterized. Here, we use single-cell RNA-sequencing (scRNA-seq) paired with exome, bulk RNA-sequencing, and histologic analysis of adjacent samples to characterize malignant cell EM state, parse the tumor microenvironment (TME), and identify candidate drivers of PM cell fate. We observe EM variation in malignant cells analogous to bulk samples. We characterize epithelioid and sarcomatoid malignant cell programs and identify a new uncommitted malignant cell EM phenotype enriched in biphasic histology samples. Using inferred CNVs we observe that single individual PM clones consist of cells exhibiting all three EM cell states. We find that distinct non-malignant microenvironments associated with tumors consisting of mostly cells in each state, and identify WNT inhibition, GAS6-AXL, and HBEGF-EGFR signaling as pathways associated with distinct EM cell states. These findings provide deeper insight into the molecular drivers of PM malignant cells and identify non-malignant cell signals as potential EMT and growth drivers in PM.

cancer biology↗

bioRxiv2024

SPARROW reveals cell states and functions influenced by microenvironment zones in complex tissues.

Spatially resolved transcriptomics technologies have significantly enhanced our ability to understand cellular characteristics within tissue contexts. However, they present a trade-off between spatial resolution and transcriptome coverage. This limitation, compounded with analytical tools treating cell type inference and cellular neighbourhood identification as separate processes, hinders a unified understanding of tissue features across scales. Our computational framework, SPARROW, infers cell types and delineates cellular organization patterns as microenvironment zones using an interconnected architecture. SPARROW algorithmically achieves single cell spatial resolution and whole transcriptome coverage by integrating spatially resolved transcriptomics and scRNA-seq data. Using SPARROW, we identified established and novel microenvironment zone-specific ligand-receptor mediated interactions in human tonsils, discoveries that would not be possible using either modality alone. Moreover, SPARROW uncovered novel cell states in the mouse hypothalamus, underscoring the influence of microenvironment zones on cell identities. Lastly, through its common latent spaces that facilitate cross-tissue comparisons, SPARROW revealed distinct inflammation states between different lymph node tissues. Overall, SPARROW integrates cellular gene expression with spatial organization, providing a comprehensive characterization of tissue features across scales and samples.

bioinformatics↗

bioRxiv2022

Distinct Heterogeneity in the Naive T cell Compartments of Children and Adults

AbstractThe naive T cell compartment undergoes multiple changes across age that associate with altered susceptibility to infection and autoimmunity. In addition to the acquisition of naive-like memory T cell subsets, mouse studies describe substantial molecular reprogramming of the naive compartment in adults compared with adolescents. However, these alterations are not well delineated in human aging. Using a new trimodal single cell technology (TEA-seq), we discovered that the composition and transcriptional and epigenetic programming of the naive T cell compartment in children (11-13 yrs) is distinct from that of older adults (55-65 yrs). Naive CD4 T cells, previously considered relatively resistant to aging, exhibited far more pronounced molecular reprogramming than naive CD8 T cells, in which alterations are preferentially driven by shifts in naive-like memory subsets. These data reveal the complex nature of the naive T cell compartment that may contribute to differential immune responses across the spectrum of human age. One Sentence SummaryThe naive CD8 and CD4 T cell compartments in humans are heterogeneous and impacted differently with age, in which naive CD8 T cell subsets dramatically shift in composition and true naive CD4 T cells display significant molecular re-programming.

immunology↗