Biology subjects

Lowe, M. M.

Publications and source records attributed to Lowe, M. M..

6 recordsLinked to original sources

bioRxiv2026

Computational discovery of precision therapeutics for hidradenitis suppurativa

Hidradenitis suppurativa (HS) is an underdiagnosed chronic, immune-mediated inflammatory skin disease that causes severe pain, drainage, and scarring, leading to significant physical and psychosocial burdens. HS is characterized by heterogenous molecular changes that are poorly understood, posing a significant challenge for drug development. Therapeutic options remain limited, and many patients experience disease relapse despite treatment. Therefore, precision medicine approaches are urgently needed to identify new therapies for HS. Here, we combine integrative transcriptomics, large-scale drug perturbational datasets, and translational immunology to identify sirolimus, pioglitazone, and fulvestrant as novel therapies for HS that can directly target and reverse the HS disease gene signature in immune cell types relevant to HS pathogenesis. Using a novel ex vivo HS skin model, sirolimus, pioglitazone, and fulvestrant inhibited T cell proliferation and activation, and suppressed the production of pro-inflammatory cytokines from HS skin. These results show that unbiased data-driven precision medicine approaches can identify novel therapies for HS and can serve more generally as a model approach for therapeutic discovery in other chronic inflammatory diseases. One Sentence SummaryData-driven precision medicine approach identifies sirolimus, pioglitazone, and fulvestrant as novel therapies for hidradenitis suppurativa

immunology↗

bioRxiv2024

Layilin Regulates Treg Motility and Suppressive Capacity in Skin

Regulatory T cells (Tregs) are essential for maintaining immune tolerance in both lymphoid and non-lymphoid tissues. We discovered that layilin, a C-type lectin receptor, is predominantly expressed on Tregs in skin. Layilin was highly expressed on a subset of clonally expanded effector Tregs in both healthy and psoriatic skin. Layilin expressing Tregs exhibited a transcriptional profile indicative of enhanced adhesion. Deletion of layilin in Tregs in vivo resulted in significantly attenuated skin inflammation. Mechanistically, layilin enhanced Treg adhesion via modulation of LFA-1, resulting in distinct cytoskeletal alterations consistent with enhanced focal adhesion and lamellipodia formation. Taken together, we define layilin as a critical regulator of Treg suppressive capacity through modulating motility and adhesion in a non-lymphoid tissue.

immunology↗

bioRxiv2024

A Novel Whole Tissue Explant Model of Hidradenitis Suppurativa

Hidradenitis Suppurativa (HS) is a relatively common and highly morbid inflammatory skin disease. Due to our relatively limited understanding of HSs pathogenesis, there are currently insufficient treatment options available, and many patients medical needs are not being met. This is partly due to a scarcity of ex vivo human assays and animal models that accurately recapitulate the disease. To address this deficit, we have developed a whole-tissue explant model of HS to examine its pathogenic mechanisms and the efficacy of potential treatments within intact human tissue. We measured cytokine protein and RNA within whole tissue maintained in an agar-media solution, finding that IL-6 and IL-8 concentrations trended upwards in both HS explants and healthy controls, while IL-17A, IL-1{beta}, and TNF- exhibited increases in HS tissue alone. We also show that the explants were responsive to treatment with both dexamethasone and IL-2. Not only do our results show that this model effectively delivers treatments throughout the explants, but they also elucidate which cytokines are related to the explant process regardless of tissue state and which are related to HS tissue specifically, laying the groundwork for future implementations of this model.

immunology↗

bioRxiv2023

Tertiary Lymphoid Structures Sustain Cutaneous B cell Activity in Hidradenitis Suppurativa

Structured AbstractO_ST_ABSBackgroundC_ST_ABSHidradenitis suppurativa (HS) skin lesions are highly inflammatory and characterized by a large immune infiltrate. While B cells and plasma cells comprise a major component of this immune milieu the biology and contribution of these cells in HS pathogenesis is unclear. ObjectiveWe aimed to investigate the dynamics and microenvironmental interactions of B cells within cutaneous HS lesions. MethodsWe combined histological analysis, single-cell RNA-sequencing (scRNAseq), and spatial transcriptomic profiling of HS lesions to define the tissue microenvironment relative to B cell activity within this disease. ResultsOur findings identify tertiary lymphoid structures (TLS) within HS lesions and describe organized interactions between T cells, B cells, antigen presenting cells and skin stroma. We find evidence that B cells within HS TLS actively undergo maturation, including participation in germinal center reactions and class switch recombination. Moreover, skin stroma and accumulating T cells are primed to support the formation of TLS and facilitate B cell recruitment during HS. ConclusionOur data definitively demonstrate the presence of TLS in lesional HS skin and point to ongoing cutaneous B cell maturation through class switch recombination and affinity maturation during disease progression in this inflamed non-lymphoid tissue.

immunology↗

bioRxiv2020

Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA sequencing and T cell receptor (TCR) sequencing to detect and characterize "tumor matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors and melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared to non-matching T cells in blood, and appeared less exhausted than matching counterparts in tumor. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome we identified candidate cell surface marker panels for TM cells in mice and melanoma patients, and validated NKG2D, CD39, and CX3CR1 in mice. These data demonstrate that the TCR can be used to identify tumor-relevant populations for comprehensive characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells. SummaryUsing single-cell RNA-sequencing coupled with TCR sequencing, we detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in blood.

immunology↗

bioRxiv2020

Developing human fetal skin demonstrates a unique lymphocyte signature

Lymphocytes in barrier tissues play critical roles in host defense and homeostasis. These cells take up residence in tissues during defined developmental windows, when they may demonstrate distinct phenotypes and functions. Here, we utilized mass and flow cytometry to elucidate early features of human skin immunity, demonstrating a unique fetal skin lymphocyte signature. While most conventional {beta} T (Tconv) cells in fetal skin have a naive, proliferative phenotype, a subset of CD4+ Tconv and CD8+ cells demonstrate memory-like features and a propensity for IFN{gamma} production. Skin regulatory T cells dynamically accumulate over the second trimester in temporal and regional association with hair follicle development. These fetal skin Tregs demonstrate an effector memory phenotype while differing from their adult counterparts in expression of key effector molecules. Thus, we identify features of prenatal skin lymphocytes that may have key implications for understanding antigen and allergen encounters in utero and in infancy.

immunology↗