Mucosal immunology of the ocular surface

Mucosal Immunology, Год журнала: 2022, Номер 15(6), С. 1143 - 1157

Опубликована: Авг. 24, 2022

Язык: Английский

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Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 24, 2023

Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8+ T cells in various preclinical HCC models. Treatment relies upon mobilizing exhausted-like (CD8+ Tex) effector function cytolytic capacity. Mechanistically, LDRT sensitizes tumors DPVB recruiting stem-like Tpex, progenitor exhausted cells, draining lymph nodes (dLNs) into tumor via CXCL10/CXCR3 axis. Together, these results further support rationale combining atezolizumab bevacizumab, its clinical translation.

Язык: Английский

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Human conjunctiva organoids to study ocular surface homeostasis and disease

Cell stem cell, Год журнала: 2024, Номер 31(2), С. 227 - 243.e12

Опубликована: Янв. 11, 2024

The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their apical surface. Here, we describe long-term expanding organoids air-liquid interface representing mouse human conjunctiva. A single-cell RNA expression atlas of primary cultured conjunctiva reveals that keratinocytes express multiple antimicrobial peptides identifies tuft cells. IL-4/-13 exposure increases differentiation drastically modifies secretome. Human NGFR+ basal are identified as bipotent stem Conjunctival cultures can be infected by herpes simplex virus 1 (HSV1), adenovirus 8 (hAdV8), SARS-CoV-2. HSV1 infection was reversed acyclovir addition, whereas hAdV8 infection, lacks an approved drug therapy, inhibited cidofovir. We document transcriptional programs induced hAdV8. Finally, transplanted. Together, organoid enable study (patho)-physiology.

Язык: Английский

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Dendritic cell maturation in cancer

Nature reviews. Cancer, Год журнала: 2025, Номер unknown

Опубликована: Фев. 7, 2025

Язык: Английский

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Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Frontiers in Medicine, Год журнала: 2024, Номер 11

Опубликована: Март 15, 2024

Background Dry eye causes corneal inflammation, epitheliopathy and sensorineural changes. This study evaluates the hypothesis that dry alters percentages transcriptional profiles of immune cell populations in cornea. Methods Desiccating stress (DS) induced was created by pharmacologic suppression tear secretion exposure to drafty low humidity environment. Expression profiling cells performed single-cell RNA sequencing (scRNA-seq). Cell differentiation trajectories fate were modeled through velocity analysis. Confocal microscopy used immunodetect cells. Irritation response topical neurostimulants assessed. Results Twelve based on their identified at baseline consist monocytes, resident (rMP) MMP12/13 high macrophages, dendritic (cDC2), neutrophils, mast cells, pre T/B innate (γDT, ILC2, NK) conventional T B lymphocytes. macrophages largest normal cornea comprising 18.6 18.2 percent, respectively. rMP increased 55.2% after 5 days DS. Significant changes expression 1,365 genes (adj p < 0.0001) noted with increases cytokines chemokines ( Tnf, Cxcl1, Ccl12, Il1rn ), inflammatory markers Vcam, Adam17, Junb TAM receptor Mertk decreases complement MHCII genes. A trajectory from monocytes terminal state found. Phagocytosis, C-type lectin signaling, NF-kappa signaling Toll-like among pathways enhanced activity these The percentage MRC1 + rMPs they observed basal epithelium adjacent epithelial nerve plexus. Concentration chemokine CXCL1 it heightened irritation/pain responses topically applied hypertonic saline. Conclusion These findings indicate DS recruits differentiate inflammation associated proximity nerves neurosensitizers suggests contribute eye.

Язык: Английский

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Exploring Immune Cell Diversity in the Lacrimal Glands of Healthy Mice: A Single-Cell RNA-Sequencing Atlas

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(2), С. 1208 - 1208

Опубликована: Янв. 19, 2024

The lacrimal gland is responsible for maintaining the health of ocular surface through production tears. However, our understanding immune system within currently limited. Therefore, in this study, we utilized single-cell RNA sequencing and bioinformatic analysis to identify analyze cells molecules present glands normal mice. A total 34,891 were obtained from mice classified into 18 distinct cell clusters using Seurat clustering. Within these populations, 26 different subpopulations identified, including T cells, innate lymphocytes, macrophages, mast dendritic B cells. Network revealed complex cell-cell interactions between with particularly significant observed among plasma Interestingly, found be main source ligands Thy1 signaling pathway, while M2 macrophages identified as primary target pathway. Moreover, some validated immunohistological techniques. Collectively, findings highlight abundance provide valuable insights complexity its relevance associated diseases.

Язык: Английский

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Redefining our vision: an updated guide to the ocular immune system

Nature reviews. Immunology, Год журнала: 2024, Номер unknown

Опубликована: Авг. 30, 2024

Язык: Английский

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Single-Cell RNA Sequencing Revealed Functional Conjunctival Keratinocytes Loss via TGF-β-Wnt/β-Catenin Signaling in Sjögren’s Syndrome Related Dry Eye

Investigative Ophthalmology & Visual Science, Год журнала: 2025, Номер 66(4), С. 43 - 43

Опубликована: Апрель 16, 2025

The role of the conjunctiva in pathophysiology Sjögren's syndrome (SS) related dry eye disease (DED) remains obscure especially view functional conjunctival epithelia. In order to illustrate effects SS, we investigated interactions between parenchymal cells and immune with single-cell RNA sequencing technique. Freshly collected from a canonical SS model was prepared for 10 × Genomics T cell receptor (TCR) sequencing. Conjunctiva Western blot, immunofluorescence, multiplex immunohistochemical (mIHC), flow cytometry. Phenol red thread test, lissamine staining, qRT-PCR were applied evaluate signs DED. DED phenotype validated model. Loss water-secreting keratinocyte projected scRNA-seq data proved by mIHC test mice. proportion Lgr4+ basal epithelial poor ability differentiate into mature increased, Wnt/β-catenin signaling upregulated it under regulation TGF-β derived macrophages. Such macrophages promoted angiogenesis through secretion VEGFA activate endothelial cells. Immuno-fibroblasts had an increased population, which implicated specifically activated chemotaxis. conjunctiva, TGF-β-Wnt/β-catenin axis downregulated formation keratinocytes accompanied infiltration pro-angiogenetic pro-fibrotic macrophage pro-inflammatory cell.

Язык: Английский

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Mapping Resident Immune Cells in the Murine Ocular Surface and Lacrimal Gland by Flow Cytometry

Ocular Immunology and Inflammation, Год журнала: 2023, Номер 31(4), С. 748 - 759

Опубликована: Март 3, 2023

Background The ocular surface and lacrimal gland have a frontline position in mucosal immunology. However, there been few updates to the immune cell atlas of these tissues recent years.Purpose To map cells murine gland.Methods Central peripheral corneas, conjunctiva, were dissociated into single suspensions, followed by flow cytometry. Discrepancy between central corneas was compared. In conjunctiva gland, myeloid clustered tSNE FlowSOM based on expression F4/80, Ly6C, Ly6G, MHC II. ILCs, type 1 cells, 3 analyzed.Results number about 16 folds that corneas. B accounted for 8.74% most tended out be monocytes, macrophages, classical dendritic (cDCs). ILC3 6.28% 3.63% ILCs respectively. Th1, Tc1, NK predominant cells. γδ T17 outnumbered Th17 among T cells.Conclusion resident reported first time. Additionally, we proposed strategy clustering better understand their heterogeneity FlowSOM. Furthermore, identified Compositions summarized. Our study provides fundamental reference novel insights homeostasis diseases.

Язык: Английский

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Immunologic basis for development of keratoconjunctivitis sicca in systemic autoimmune diseases: Role of innate immune sensors

The Ocular Surface, Год журнала: 2024, Номер 32, С. 130 - 138

Опубликована: Фев. 22, 2024

The literature is filled with citations reporting an increased incidence of chronic dry eye disease, also known as keratoconjunctivitis sicca, in patients systemic autoimmune diseases such rheumatoid arthritis, Sjögren's Syndrome, sclerosis and lupus. As the most environmentally exposed mucosal surface body, conjunctiva constantly responds to environmental challenges which are typically self limited, but when persistent unresolved may provoke pathogenic innate adaptive immune reactions. Our understanding pathophysiological mechanisms by cause inducing ocular inflammation continues evolve. Conjunctival tone or foreign danger signals (including desiccating stress) on initial non-specific inflammatory response. If unchecked, this can lead activation dendritic cells that present antigen prime T B resulting reaction. These reactions generally resolve, dysfunctional, hyper-responsive found recruited amplify stress responses glandular tissues result disrupt tear stability disease. We here propose unique features system impact dysregulation diseases, predispose development exacerbate severity existing eye.

Язык: Английский

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