Biology subjects

Lipsky, P. E.

Publications and source records attributed to Lipsky, P. E..

5 recordsLinked to original sources

bioRxiv2026

Comprehensive Transcriptomic Analysis of Atopic Dermatitis Patients Documents the Spectrum of Molecular Abnormalities and the Response to Treatment

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by immune dysregulation and barrier dysfunction. To define the molecular architecture of AD in greater detail, we integrated lesional (LES) and non-lesional (NLS) transcriptomic data from multiple datasets using gene expression data from normal skin and psoriasis (PSO) and nummular eczema (NME) cohorts as reference. Gene set variation analysis revealed that adult AD exhibits broad immune activation and consistent barrier impairment in both LES and NLS skin, whereas pediatric AD is dominated by IL-1-driven inflammation with minimal barrier alteration. Comparative analyses showed stronger Th2 and myeloid activity in AD, metabolic enrichment in PSO, and complement and NK cell activation in NME. Longitudinal profiling identified temporal variation in Th1, Th2 and IFN pathways in AD skin. An eczema immune and cellular score, ECZECIS, was developed to quantify transcriptomic abnormalities and correlated with clinical improvement following dupilumab therapy. Among all treatments analyzed, dupilumab produced the most extensive reduction of immune and cytokine pathway activity in skin and attenuated systemic immune activation in blood. These findings delineate distinct immune and barrier signatures across age groups and disease types and establish ECZECIS as a quantitative biomarker for monitoring molecular treatment response in AD.

bioinformatics↗

bioRxiv2024

Obesity-Associated Changes in Immune Cell Dynamics During Alphavirus Infection Revealed by Single Cell Transcriptomic Analysis

Obesity induces diverse changes in host immunity, resulting in worse disease outcomes following infection with various pathogens, including arthritogenic alphaviruses. However, the impact of obesity on the functional landscape of immune cells during arthritogenic alphavirus infection remains unexplored. Here, we used single-cell RNA sequencing (scRNA-seq) to dissect the blood and tissue immune responses to Mayaro virus (MAYV) infection in lean and obese mice. Footpad injection of MAYV caused significant shifts in immune cell populations and induced robust expression of interferon response and proinflammatory cytokine genes and related pathways in both blood and tissue. In MAYV-infected lean mice, analysis of the local tissue response revealed a unique macrophage subset with high expression of IFN response genes that was not found in obese mice. This was associated with less severe inflammation in lean mice. These results provide evidence for a unique macrophage population that may contribute to the superior capacity of lean mice to control arthritogenic alphavirus infection. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/617696v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@11e9cbdorg.highwire.dtl.DTLVardef@c44512org.highwire.dtl.DTLVardef@192da94org.highwire.dtl.DTLVardef@4c5ea5_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIObesity worsens disease outcomes following arthritogenic alphavirus infection. C_LIO_LIArthritogenic alphavirus infection causes significant shifts in immune cell populations in the blood and footpad. C_LIO_LIBlood monocytes from lean mice had higher expression of interferon response genes at the later stage of infection. C_LIO_LIFootpads in lean mice have an expanded population of F4/80lo macrophages with an intense interferon response gene signature before and after alphavirus infection that is not found in obese mice. C_LIO_LIMacrophages in obese mice express lower levels of interferon response genes, have a unique necroptosis signature, and higher F4/80 expression. C_LI

immunology↗

bioRxiv2022

Augmented glucose dependency of autoreactive B cells provides a treatment target forlupus

Heightened glycolysis is inherent to immune/inflammatory disorders, but little is known of its role in the pathogenesis of systemic lupus erythematosus (lupus). Here, we profile key autoimmune populations in acute and chronic lupus-prone models and their response to glycolytic inhibition. We demonstrate that glycolysis is specifically required for autoreactive germinal center B cells (GCB), but not for T follicular helper cells (Tfh) to survive. This augmented reliance on glucose oxidation to maintain ATP production in pathogenic GCB renders them highly susceptible to oxidative stress-induced apoptosis triggered by glycolysis blockade via 2-deoxyglucose (2DG). We show that 2DG can preferentially reduce GCB in lupus-prone mice, while sparing other autoreactive populations, including Tfh, but still significantly improving lifespan and kidney function. Furthermore, the subset of GCB expressing B-cell maturation antigen (BCMA) exhibits an exaggerated dependence on glycolysis to sustain their growth. Depletion of these cells with a proliferation-inducing ligand-based CAR T-cells leads to greatly prolonged lifespan of mice with severe autoimmune activation. These results reveal that glycolysis dependent GCB, especially those expressing BCMA, are key lupus mediators and highlight that they can be selectively targeted to improve disease outcomes for lupus patients.

immunology↗

bioRxiv2020

Analysis of Gene Expression from Systemic Lupus Erythematosus Synovium Reveals a Profile of Activated Immune Cells and Inflammatory Pathways

Arthritis is a common manifestation of systemic lupus erythematosus (SLE) yet understanding of the underlying pathogenic mechanisms remains incomplete. We, therefore, interrogated gene expression profiles of SLE synovium to gain insight into the nature of lupus arthritis (LA), using osteoarthritis (OA) and rheumatoid arthritis (RA) as comparators. Knee synovia from SLE, OA, and RA patients were analyzed for differentially expressed genes (DEGs) and also by Weighted Gene Co-expression Network Analysis (WGCNA) to identify modules of highly co-expressed genes. Genes upregulated and/or co-expressed in LA revealed numerous immune/inflammatory cells dominated by a myeloid phenotype, whereas OA was characteristic of fibroblasts and RA of T- and B-cells. Upstream regulator analysis identified CD40L and inflammatory cytokines as drivers of the LA gene expression profile. Genes governing trafficking of immune cells into the synovium by chemokines were identified, but not in situ generation of germinal centers. GSVA confirmed activation of specific myeloid and lymphoid cell types in LA. Numerous therapies were predicted to target LA, including TNF, NF{kappa}B, MAPK, and CDK inhibitors. Detailed gene expression analysis identified a unique pattern of cellular components and physiologic pathways operative in LA, as well as drugs potentially able to target this common manifestation of SLE.

immunology↗

bioRxiv2020

Comprehensive Transcriptomic Analysis of COVID-19 Blood, Lung, and Airway

AbstractSARS-CoV2 is a previously uncharacterized coronavirus and causative agent of the COVID-19 pandemic. The host response to SARS-CoV2 has not yet been fully delineated, hampering a precise approach to therapy. To address this, we carried out a comprehensive analysis of gene expression data from the blood, lung, and airway of COVID-19 patients. Our results indicate that COVID-19 pathogenesis is driven by populations of myeloid-lineage cells with highly inflammatory but distinct transcriptional signatures in each compartment. The relative absence of cytotoxic cells in the lung suggests a model in which delayed clearance of the virus may permit exaggerated myeloid cell activation that contributes to disease pathogenesis by the production of inflammatory mediators. The gene expression profiles also identify potential therapeutic targets that could be modified with available drugs. The data suggest that transcriptomic profiling can provide an understanding of the pathogenesis of COVID-19 in individual patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/121889v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@7dccedorg.highwire.dtl.DTLVardef@1190e1forg.highwire.dtl.DTLVardef@1ee2e67org.highwire.dtl.DTLVardef@289f72_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗