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Surico PL, Barone V, Singh RB, Coassin M, Blanco T, Dohlman TH, Basu S, Chauhan SK, Dana R, Di Zazzo A. Potential applications of mesenchymal stem cells in ocular surface immune-mediated disorders. Surv Ophthalmol 2025; 70:467-479. [PMID: 39097173 DOI: 10.1016/j.survophthal.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/29/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
We explore the interaction between corneal immunity and mesenchymal stem/stromal cells (MSCs) and their potential in treating corneal and ocular surface disorders. We outline the cornea's immune privilege mechanisms and the immunomodulatory substances involved. In this realm, MSCs are characterized by their immunomodulatory properties and regenerative potential, making them promising for therapeutic application. Therefore, we focus on the role of MSCs in immune-mediated corneal diseases such as dry eye disease, corneal transplantation rejection, limbal stem cell deficiency, and ocular graft-versus-host disease. Preclinical and clinical studies demonstrate MSCs' efficacy in promoting corneal healing and reducing inflammation in these conditions. Overall, we emphasize the potential of MSCs as innovative therapies in ophthalmology, offering promising solutions for managing various ocular surface pathologies.
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Affiliation(s)
- Pier Luigi Surico
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA; Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Vincenzo Barone
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Rohan Bir Singh
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Marco Coassin
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy
| | - Tomas Blanco
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Thomas H Dohlman
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Sayan Basu
- Brien Holden Eye Research Centre (BHERC), L. V. Prasad Eye Institute, Hyderabad, Telangana, India
| | - Sunil K Chauhan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Reza Dana
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Antonio Di Zazzo
- Department of Ophthalmology, Campus Bio-Medico University Hospital, Rome 00128, Italy; Cornea Rare Diseases Center, Fondazione Policlinico Campus Bio-Medico, Rome 00128, Italy.
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Tsai MC, Kureshi A, Daniels JT. Tissue engineered corneal endothelium transplantation in an ex vivo human cornea organ culture model. Sci Rep 2025; 15:12571. [PMID: 40221533 PMCID: PMC11993598 DOI: 10.1038/s41598-025-96494-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
Transplantation of corneal tissue is the standard treatment for irreversible corneal endothelium decompensation by replacing the malfunctioning corneal endothelial cells and Descemet's membrane. However, this surgery depends on limited donor tissue supply. Thus, developing suitable alternatives for donor grafting material through a tissue engineering approach is needed to enable the transplantation of cultured endothelial cells to restore normal endothelial function. Here, we proposed using a plastic compressed collagen 3D matrix called Real Architecture For 3D Tissues (RAFT) as a scaffold for cell culture. The porcine cornea endothelial cells (PCECs) were seeded on RAFT to construct a tissue-engineered corneal endothelium. Then, the porcine cell-seeded-RAFT graft was transplanted onto a human cornea and maintained in an ex vivo organ culture model. The results showed that PCECs formed a high-density monolayer on RAFT expressing endothelial cell markers, ZO-1, Na/K ATPase and N-cadherin. More importantly, the cell-seeded RAFT transplantation successfully restored corneal endothelium function, drawing the thickness of endothelium-wounded cornea back to normal in two weeks of the ex vivo human cornea organ culture.
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Affiliation(s)
- Meng-Chen Tsai
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
| | - Alvena Kureshi
- Centre for 3D Models of Health and Disease, Division of Surgery and Interventional Science, University College London, London, UK
| | - Julie T Daniels
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
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Luo S, Li J, Yang Y, Jiang Y, Jie Y, Ge W. Spatial transcriptomics and single-cell RNA-sequencing revealed dendritic cell-mediated inflammation in keratoconus. Ocul Surf 2025; 36:134-150. [PMID: 39837422 DOI: 10.1016/j.jtos.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/07/2025] [Accepted: 01/17/2025] [Indexed: 01/23/2025]
Abstract
Keratoconus (KC) is a corneal disorder characterized by central corneal protrusion and thinning. In this study, spatial transcriptomics was employed to investigate molecular and cellular variations in KC, revealing a distinct pattern of inflammatory responses across the cornea. Upregulation of inflammatory processes was observed in the central cornea, while downregulation was noted in the periphery, indicating complex regional inflammatory changes in the KC cornea. Integration with single-cell RNA sequencing (scRNA-seq) further identified enhanced interactions between dendritic cells (DCs) and stromal cells, particularly mediated via the IL-1β pathway, alongside increased matrix metalloproteinase (MMP) production by corneal stromal cells, underscoring the role of inflammation in KC pathogenesis. In vitro and in vivo experiments confirmed that activated DCs promoted the matrix degradation activity of stromal cells, thereby exacerbating KC pathology. Notably, inhibition of the IL-1β pathway effectively mitigated the progression of KC. These findings provide a comprehensive spatial, cellular, and molecular characterization of KC, demonstrating its inflammatory nature. The results also highlight the importance of inflammation in the peripheral cornea for early diagnosis and suggest that anti-inflammatory treatments could serve as potential adjuvant therapy for KC.
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Affiliation(s)
- Shiqi Luo
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100730, China
| | - Jingying Li
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100730, China
| | - Yan Yang
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100730, China
| | - Yang Jiang
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Ying Jie
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
| | - Wei Ge
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100730, China.
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D’Souza S, Shetty R, Sethu S. Understanding the immunology of the ocular surface and its relevance to clinical practice. Indian J Ophthalmol 2025; 73:516-520. [PMID: 40146139 PMCID: PMC12097414 DOI: 10.4103/ijo.ijo_1721_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/05/2024] [Accepted: 11/12/2024] [Indexed: 03/28/2025] Open
Abstract
The immunology of the ocular surface has an important role in maintaining homeostasis and in the etiopathogenesis of a number of diseases when dysregulated. This can result in damage to the cornea and ocular surface and loss of clarity and vision. As the entire ocular surface is linked via its epithelium, vascular supply, and innervation, changes across one aspect have tangible effects on the other. Immune cells residing on the ocular surface and those that traffic across the ocular surface interact with the structural tissues to release molecular factors and result in tissue response and disease. Studies in animal models and in vitro experiments along with in vivo studies on the human ocular surface have given newer insights with closer representation of actual health and disease. Some of the diseases which have been found to have a strong immunological basis include dry eye disease (DED) and Sjogren's syndrome, keratoconus, corneal graft rejection, autoimmune conditions such as peripheral ulcerative keratitis, and Stevens-Johnson syndrome. The ocular surface immunology has unique patterns and signatures across different diseases. These give us an opportunity to understand the diseases better find newer targets for therapy and an opportunity to reduce visual morbidity. Clinically, we envisage a shift from steroids and broad action immunomodulators toward target specific drugs making personalized medicine and customized therapy the way forward.
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Affiliation(s)
- Sharon D’Souza
- Department of Cornea, Ocular Surface and Refractive Surgery, Narayana Nethralaya Eye Hospital, Bengaluru, Karnataka, India
| | - Rohit Shetty
- Department of Cornea, Ocular Surface and Refractive Surgery, Narayana Nethralaya Eye Hospital, Bengaluru, Karnataka, India
| | - Swaminathan Sethu
- GROW Laboratory, Narayana Nethralaya Foundation, Bengaluru, Karnataka, India
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Tahvildari M, Me R, Setia M, Gao N, Suvas P, McClellan SA, Suvas S. Foxp3 + regulatory T cells reside within the corneal epithelium and co-localize with limbal stem cells. Exp Eye Res 2024; 249:110123. [PMID: 39396695 PMCID: PMC11622170 DOI: 10.1016/j.exer.2024.110123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 09/08/2024] [Accepted: 10/10/2024] [Indexed: 10/15/2024]
Abstract
In this study we investigated the presence of resident Foxp3+ regulatory T cells (Tregs) within the cornea and assessed the role of resident Tregs in corneal epithelial wound healing. Using a mouse model, we showed that in the steady state Foxp3+Tregs are either in close proximity or co-localize with ABCG2+ limbal stem cells. We also showed that these Tregs reside within the epithelial layer and not the corneal stroma. In addition, using a mouse model of mechanical injury, we demonstrated that depletion of Tregs from the cornea prior to corneal mechanical injury, using subconjunctival injection of anti-CD25, was associated with delayed epithelial healing. These results suggest a role for cornea resident Tregs in corneal epithelial cell function and wound healing and opens doors for further exploration of the role of Tregs in limbal stem cell function and survival.
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Affiliation(s)
- Maryam Tahvildari
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA; Department of Ophthalmology and Visual Science, Yale University, New Haven, CT, USA.
| | - Rao Me
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Mizumi Setia
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Nan Gao
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Pratima Suvas
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Sharon A McClellan
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Susmit Suvas
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA.
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Schmitz F, Klimas R, Spenner M, Schumacher A, Hieke A, Greiner T, Enax-Krumova E, Sgodzai M, Fels M, Brünger J, Huckemann S, Stude P, Tegenthoff M, Gold R, Philipps J, Fisse AL, Grüter T, Pitarokoili K, Motte J, Sturm D. Morphological Differentiation of Corneal Inflammatory Cells. Cornea 2024; 43:1481-1488. [PMID: 38588437 DOI: 10.1097/ico.0000000000003543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 02/18/2024] [Indexed: 04/10/2024]
Abstract
PURPOSE Corneal confocal microscopy is a noninvasive imaging technique to analyze corneal nerve fibers and corneal inflammatory cells (CICs). The amount of CICs is a potential biomarker of disease activity in chronic autoinflammatory diseases. To date, there are no standardized criteria for the morphological characterization of CICs. The aim was to establish a protocol for a standardized morphological classification of CICs based on a literature search and to test this protocol for applicability and reliability. METHODS A systematic review of the literature about definitions of CICs was conducted. Existing morphological descriptions were translated into a structured algorithm and applied by raters. Subsequently, the protocol was optimized by reducing and defining the criteria of the cell types. The optimized algorithm was applied by 4 raters. The interrater reliability was calculated using Fleiss kappa (K). RESULTS A systematic review of the literature revealed no uniform morphological criteria for the differentiation of the individual cell types in CICs. Our first protocol achieved only a low level of agreement between 3 raters (K = 0.09; 1062 rated cells). Our revised protocol was able to achieve a higher interrater reliability with 3 (K = 0.64; 471 rated cells) and 4 (K = 0.61; 628 rated cells) raters. CONCLUSIONS The indirect use of criteria from the literature leads to a high error rate. By clearly defining the individual cell types and standardizing the protocol, reproducible results were obtained, allowing the introduction of this protocol for the future evaluation of CICs in the corneal confocal microscopy.
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Affiliation(s)
- Fynn Schmitz
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Rafael Klimas
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Marie Spenner
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Aurelian Schumacher
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Alina Hieke
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Tineke Greiner
- Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
| | - Elena Enax-Krumova
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
- Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
| | - Melissa Sgodzai
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Miriam Fels
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Jil Brünger
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Sophie Huckemann
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Philipp Stude
- Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
| | - Martin Tegenthoff
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
- Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
| | - Ralf Gold
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Jörg Philipps
- Department of Neurology and Neurogeriatrics, Johannes Wesling Klinikum Minden, Minden, Germany
| | - Anna Lena Fisse
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Thomas Grüter
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Kalliopi Pitarokoili
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Jeremias Motte
- Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
| | - Dietrich Sturm
- Immune-mediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum, Bochum, Germany
- Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
- Department of Neurology, Agaplesion Bethesda Krankenhaus, Wuppertal, Germany ; and
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Antony F, Kinha D, Nowińska A, Rouse BT, Suryawanshi A. The immunobiology of corneal HSV-1 infection and herpetic stromal keratitis. Clin Microbiol Rev 2024; 37:e0000624. [PMID: 39078136 PMCID: PMC11391706 DOI: 10.1128/cmr.00006-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/31/2024] Open
Abstract
SUMMARYHuman alphaherpesvirus 1 (HSV-1) is a highly successful neurotropic pathogen that primarily infects the epithelial cells lining the orofacial mucosa. After primary lytic replication in the oral, ocular, and nasal mucosal epithelial cells, HSV-1 establishes life-long latency in neurons within the trigeminal ganglion. Patients with compromised immune systems experience frequent reactivation of HSV-1 from latency, leading to virus entry in the sensory neurons, followed by anterograde transport and lytic replication at the innervated mucosal epithelial surface. Although recurrent infection of the corneal mucosal surface is rare, it can result in a chronic immuno-inflammatory condition called herpetic stromal keratitis (HSK). HSK leads to gradual vision loss and can cause permanent blindness in severe untreated cases. Currently, there is no cure or successful vaccine to prevent latent or recurrent HSV-1 infections, posing a significant clinical challenge to managing HSK and preventing vision loss. The conventional clinical management of HSK primarily relies on anti-virals to suppress HSV-1 replication, anti-inflammatory drugs (such as corticosteroids) to provide symptomatic relief from pain and inflammation, and surgical interventions in more severe cases to replace damaged cornea. However, each clinical treatment strategy has limitations, such as local and systemic drug toxicities and the emergence of anti-viral-resistant HSV-1 strains. In this review, we summarize the factors and immune cells involved in HSK pathogenesis and highlight alternate therapeutic strategies for successful clinical management of HSK. We also discuss the therapeutic potential of immunoregulatory cytokines and immunometabolism modulators as promising HSK therapies against emerging anti-viral-resistant HSV-1 strains.
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Affiliation(s)
- Ferrin Antony
- Department of Molecular and Cell Biology, University of California, Berkeley, California, USA
| | - Divya Kinha
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - Anna Nowińska
- Clinical Department of Ophthalmology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Katowice, Poland
- Ophthalmology Department, Railway Hospital in Katowice, Katowice, Poland
| | - Barry T. Rouse
- College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, USA
| | - Amol Suryawanshi
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
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Surico PL, Lee S, Singh RB, Naderi A, Bhullar S, Blanco T, Chen Y, Dana R. Local administration of myeloid-derived suppressor cells prevents progression of immune-mediated dry eye disease. Exp Eye Res 2024; 242:109871. [PMID: 38527580 PMCID: PMC11055659 DOI: 10.1016/j.exer.2024.109871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/12/2024] [Accepted: 03/18/2024] [Indexed: 03/27/2024]
Abstract
Myeloid derived suppressor cells (MDSCs) are a heterogenous population of immature hematopoietic precursors with known immunoregulatory functions. The immunosuppressive role of MDSCs has been highlighted in several inflammatory ophthalmic disorders; however, their therapeutic application in suppressing the immune-mediated changes in dry eye disease (DED) has not been studied. We observed significant reduction in antigen presenting cell (APC) frequencies and their maturation in the presence of MDSCs. Moreover, co-culturing MDSCs with T helper 17 cells (Th17) resulted in reduced Th17 frequencies and their IL-17 expression. On the contrary, MDSCs maintained regulatory T cell frequencies and enhanced their function in-vitro. Furthermore, we delineated the role of interleukin-10 (IL-10) secreted by MDSCs in their immunoregulatory functions. We confirmed these results by flow cytometry analysis and observed that treatment with MDSCs in DED mice effectively suppressed the maturation of APCs, pathogenic Th17 response, and maintained Treg function and significantly ameliorated the disease. The results in this study highlight the potential therapeutic application of MDSCs in treating refractory DED.
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Affiliation(s)
- Pier Luigi Surico
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Seokjoo Lee
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Rohan Bir Singh
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Amirreza Naderi
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Shilpy Bhullar
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Tomas Blanco
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Yihe Chen
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Reza Dana
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
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9
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Surico PL, Narimatsu A, Forouzanfar K, Singh RB, Shoushtari S, Dana R, Blanco T. Effects of Diabetes Mellitus on Corneal Immune Cell Activation and the Development of Keratopathy. Cells 2024; 13:532. [PMID: 38534376 PMCID: PMC10969384 DOI: 10.3390/cells13060532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/12/2024] [Accepted: 03/16/2024] [Indexed: 03/28/2024] Open
Abstract
Diabetes mellitus (DM) is one of the most prevalent diseases globally, and its prevalence is rapidly increasing. Most patients with a long-term history of DM present with some degree of keratopathy (DK). Despite its high incidence, the underlying inflammatory mechanism of DK has not been elucidated yet. For further insights into the underlying immunopathologic processes, we utilized streptozotocin-induced mice to model type 1 DM (T1D) and B6.Cg-Lepob/J mice to model type 2 DM (T2D). We evaluated the animals for the development of clinical manifestations of DK. Four weeks post-induction, the total frequencies of corneal CD45+CD11b+Ly-6G- myeloid cells, with enhanced gene and protein expression levels for the proinflammatory cytokines TNF-α and IL-1β, were higher in both T1D and T2D animals. Additionally, the frequencies of myeloid cells/mm2 in the sub-basal neural plexus (SBNP) were significantly higher in T1D and T2D compared to non-diabetic mice. DK clinical manifestations were observed four weeks post-induction, including significantly lower tear production, corneal sensitivity, and epitheliopathy. Nerve density in the SBNP and intraepithelial terminal endings per 40x field were lower in both models compared to the normal controls. The findings of this study indicate that DM alters the immune quiescent state of the cornea during disease onset, which may be associated with the progressive development of the clinical manifestations of DK.
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Affiliation(s)
| | | | | | | | | | | | - Tomas Blanco
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; (P.L.S.); (A.N.); (K.F.); (R.B.S.); (S.S.); (R.D.)
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10
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Alam J, Yaman E, Silva GCV, Chen R, de Paiva CS, Stepp MA, Pflugfelder SC. Single cell analysis of short-term dry eye induced changes in cornea immune cell populations. Front Med (Lausanne) 2024; 11:1362336. [PMID: 38560382 PMCID: PMC10978656 DOI: 10.3389/fmed.2024.1362336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/28/2024] [Indexed: 04/04/2024] Open
Abstract
Background Dry eye causes corneal inflammation, epitheliopathy and sensorineural changes. This study evaluates the hypothesis that dry eye alters the percentages and transcriptional profiles of immune cell populations in the cornea. Methods Desiccating stress (DS) induced dry eye was created by pharmacologic suppression of tear secretion and exposure to drafty low humidity environment. Expression profiling of corneal immune cells was performed by single-cell RNA sequencing (scRNA-seq). Cell differentiation trajectories and cell fate were modeled through RNA velocity analysis. Confocal microscopy was used to immunodetect corneal immune cells. Irritation response to topical neurostimulants was assessed. Results Twelve corneal immune cell populations based on their transcriptional profiles were identified at baseline and consist of monocytes, resident (rMP) and MMP12/13 high macrophages, dendritic cells (cDC2), neutrophils, mast cells, pre T/B cells, and innate (γDT, ILC2, NK) and conventional T and B lymphocytes. T cells and resident macrophages (rMP) were the largest populations in the normal cornea comprising 18.6 and 18.2 percent, respectively. rMP increased to 55.2% of cells after 5 days of DS. Significant changes in expression of 1,365 genes (adj p < 0.0001) were noted in rMP with increases in cytokines and chemokines (Tnf, Cxcl1, Ccl12, Il1rn), inflammatory markers (Vcam, Adam17, Junb), the TAM receptor (Mertk), and decreases in complement and MHCII genes. A differentiation trajectory from monocytes to terminal state rMP was found. Phagocytosis, C-type lectin receptor signaling, NF-kappa B signaling and Toll-like receptor signaling were among the pathways with enhanced activity in these cells. The percentage of MRC1+ rMPs increased in the cornea and they were observed in the basal epithelium adjacent to epithelial nerve plexus. Concentration of the chemokine CXCL1 increased in the cornea and it heightened irritation/pain responses to topically applied hypertonic saline. Conclusion These findings indicate that DS recruits monocytes that differentiate to macrophages with increased expression of inflammation associated genes. The proximity of these macrophages to cornea nerves and their expression of neurosensitizers suggests they contribute to the corneal sensorineural changes in dry eye.
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Affiliation(s)
- Jehan Alam
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States
| | - Ebru Yaman
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States
| | - Gerda Cristal Villalba Silva
- Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Rui Chen
- Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Cintia S. de Paiva
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States
| | - Mary Ann Stepp
- Departments of Anatomy, Regenerative Biology and Ophthalmology, The George Washington University Medical School and Health Sciences, Washington, DC, United States
| | - Stephen C. Pflugfelder
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, United States
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11
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Lee SJ, Lee SH, Koh A, Kim KW. EGF-conditioned M1 macrophages Convey reduced inflammation into corneal endothelial cells through exosomes. Heliyon 2024; 10:e26800. [PMID: 38434401 PMCID: PMC10906407 DOI: 10.1016/j.heliyon.2024.e26800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/20/2024] [Accepted: 02/20/2024] [Indexed: 03/05/2024] Open
Abstract
Epidermal Growth Factor (EGF), a protein pivotal in cell proliferation and survival, has recently shown promise in alleviating inflammation. This study investigates EGF's impact on M1 macrophages, exploring its potential for anti-inflammatory and anti-vasculogenic interactions with corneal endothelial cells (CECs). Polarized M1 macrophages treated with EGF exhibited a suppression of gene expressions related to inflammatory and vasculogenic signals. The anti-inflammatory effects of EGF were observed in co-culture systems with human CECs (HCECs), showcasing its ability to alter macrophage phenotypes. Exosomes derived from EGF-treated M1 macrophages demonstrated enriched proteomic profiles related to immune system regulation and inflammation inhibition. When applied as eye drops in murine corneas, EGF-conditioned M1 macrophage-derived exosomes effectively reduced inflammation and increased M2-related ARG1 expression. This study highlights EGF's potential in mitigating inflammation in M1 macrophages and its delivery through exosomes to cultured HCECs and murine corneas, suggesting a novel therapeutic avenue for ocular surface anti-inflammatory treatments.
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Affiliation(s)
- Soo Jin Lee
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
| | - Seung Hyeun Lee
- Department of Ophthalmology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - Ahra Koh
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
- Chung-Ang University Graduate School, Republic of Korea
| | - Kyoung Woo Kim
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
- Department of Ophthalmology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea
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12
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Lai J, Rigas Y, Kantor N, Cohen N, Tomlinson A, St. Leger AJ, Galor A. Living with your biome: how the bacterial microbiome impacts ocular surface health and disease. EXPERT REVIEW OF OPHTHALMOLOGY 2024; 19:89-103. [PMID: 38764699 PMCID: PMC11101146 DOI: 10.1080/17469899.2024.2306582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 01/14/2024] [Indexed: 05/21/2024]
Abstract
Introduction Microbiome research has grown exponentially but the ocular surface microbiome (OSM) remains an area in need of further study. This review aims to explore its complexity, disease-related microbial changes, and immune interactions, and highlights the potential for its manipulation as a therapeutic for ocular surface diseases. Areas Covered We introduce the OSM by location and describe what constitutes a normal OSM. Second, we highlight aspects of the ocular immune system and discuss potential immune microbiome interactions in health and disease. Finally, we highlight how microbiome manipulation may have therapeutic potential for ocular surface diseases. Expert Opinion The ocular surface microbiome varies across its different regions, with a core phyla identified, but with genus variability. A few studies have linked microbiome composition to diseases like dry eye but more research is needed, including examining microbiome interactions with the host. Studies have noted that manipulating the microbiome may impact disease presentation. As such, microbiome manipulation via diet, oral and topical pre and probiotics, and hygienic measures may provide new therapeutic algorithms in ocular surface diseases.
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Affiliation(s)
- James Lai
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Yannis Rigas
- University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Nicole Kantor
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Noah Cohen
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Ana Tomlinson
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Anthony J. St. Leger
- University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
- Miami Veterans Affairs Hospital, Miami, Florida, USA
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13
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Hadrian K, Cursiefen C. The role of lymphatic vessels in corneal fluid homeostasis and wound healing. J Ophthalmic Inflamm Infect 2024; 14:4. [PMID: 38252213 PMCID: PMC10803698 DOI: 10.1186/s12348-023-00381-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 12/16/2023] [Indexed: 01/23/2024] Open
Abstract
The cornea, essential for vision, is normally avascular, transparent, and immune-privileged. However, injuries or infections can break this privilege, allowing blood and lymphatic vessels to invade, potentially impairing vision and causing immune responses. This review explores the complex role of corneal lymphangiogenesis in health and diseases. Traditionally, the cornea was considered devoid of lymphatic vessels, a phenomenon known as "corneal (lymph)angiogenic privilege." Recent advances in molecular markers have enabled the discovery of lymphatic vessels in the cornea under certain conditions. Several molecules contribute to preserving both immune and lymphangiogenic privileges. Lymphangiogenesis, primarily driven by VEGF family members, can occur directly or indirectly through macrophage recruitment. Corneal injuries and diseases disrupt these privileges, reducing graft survival rates following transplantation. However, modulation of lymphangiogenesis offers potential interventions to promote graft survival and expedite corneal edema resolution.This review underscores the intricate interplay between lymphatic vessels, immune privilege, and corneal pathologies, highlighting innovative therapeutic possibilities. Future investigations should explore the modulation of lymphangiogenesis to enhance corneal health and transparency, as well as corneal graft survival, and this benefits patients with various corneal conditions.
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Affiliation(s)
- Karina Hadrian
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, University of Cologne, Cologne, Germany.
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
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14
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Li W, Gurdziel K, Pitchaikannu A, Gupta N, Hazlett LD, Xu S. The miR-183/96/182 cluster is a checkpoint for resident immune cells and shapes the cellular landscape of the cornea. Ocul Surf 2023; 30:17-41. [PMID: 37536656 PMCID: PMC10834862 DOI: 10.1016/j.jtos.2023.07.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023]
Abstract
PURPOSE The conserved miR-183/96/182 cluster (miR-183C) regulates both corneal sensory innervation and corneal resident immune cells (CRICs). This study is to uncover its role in CRICs and in shaping the corneal cellular landscape at a single-cell (sc) level. METHODS Corneas of naïve, young adult [2 and 6 months old (mo)], female miR-183C knockout (KO) mice and wild-type (WT) littermates were harvested and dissociated into single cells. Dead cells were removed using a Dead Cell Removal kit. CD45+ CRICs were enriched by Magnetic Activated Cell Sorting (MACS). scRNA libraries were constructed and sequenced followed by comprehensive bioinformatic analyses. RESULTS The composition of major cell types of the cornea stays relatively stable in WT mice from 2 to 6 mo, however the compositions of subtypes of corneal cells shift with age. Inactivation of miR-183C disrupts the stability of the major cell-type composition and age-related transcriptomic shifts of subtypes of corneal cells. The diversity of CRICs is enhanced with age. Naïve mouse cornea contains previously-unrecognized resident fibrocytes and neutrophils. Resident macrophages (ResMφ) adopt cornea-specific function by expressing abundant extracellular matrix (ECM) and ECM organization-related genes. Naïve cornea is endowed with partially-differentiated proliferative ResMφ and contains microglia-like Mφ. Resident lymphocytes, including innate lymphoid cells (ILCs), NKT and γδT cells, are the major source of innate IL-17a. miR-183C limits the diversity and polarity of ResMφ. CONCLUSION miR-183C serves as a checkpoint for CRICs and imposes a global regulation of the cellular landscape of the cornea.
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Affiliation(s)
- Weifeng Li
- Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Department of Genetic Medicine, USA; Wilmer Eye Institute, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA
| | | | - Ahalya Pitchaikannu
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Naman Gupta
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Linda D Hazlett
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Shunbin Xu
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI, USA.
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15
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Blanco T, Musayeva A, Singh RB, Nakagawa H, Lee S, Alemi H, Gonzalez-Nolasco B, Ortiz G, Wang S, Kahale F, Dohlman TH, Chen Y, Dana R. The impact of donor diabetes on corneal transplant immunity. Am J Transplant 2023; 23:1345-1358. [PMID: 37245642 PMCID: PMC10527508 DOI: 10.1016/j.ajt.2023.05.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/12/2023] [Accepted: 05/24/2023] [Indexed: 05/30/2023]
Abstract
Corneal transplantation is the most common form of solid tissue grafting, with an approximately 80% to 90% success rate. However, success rates may decline when donor tissues are derived from patients with a history of diabetes mellitus (DM). To evaluate the underlying immunopathologic processes that cause graft rejection, we used streptozotocin-induced type 1 DM (DM1) and transgenic Lepob/ob type 2 DM (DM2) diabetic murine models as donors and nondiabetic BALB/c as recipients. DM resulted in an increased frequency of corneal antigen-presenting cells (APCs) with an acquired immunostimulatory phenotype. Following transplantation, recipients that received either type of diabetic graft showed increased APC migration and T helper type 1 alloreactive cells, impaired functional regulatory T cells, and graft survival. Insulin treatment in streptozotocin-induced diabetic mice led to an increased tolerogenic profile of graft APC, lower T helper type 1 sensitization, and a higher frequency of functional regulatory T cells with high suppressive capacity, reflected in increased graft survival. We conclude that both DM1 and DM2 in donors can impact corneal APC functional phenotype, rendering the tissue more immunogenic and thereby increasing the risk of graft failure.
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Affiliation(s)
- Tomás Blanco
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Aytan Musayeva
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Rohan Bir Singh
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Hayate Nakagawa
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Seokjoo Lee
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Hamid Alemi
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Bruno Gonzalez-Nolasco
- Transplant Research Center, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Gustavo Ortiz
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Shudan Wang
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Francesca Kahale
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas H Dohlman
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Yihe Chen
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Reza Dana
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
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16
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Wilson SE. The corneal fibroblast: The Dr. Jekyll underappreciated overseer of the responses to stromal injury. Ocul Surf 2023; 29:53-62. [PMID: 37080483 DOI: 10.1016/j.jtos.2023.04.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 04/22/2023]
Abstract
PURPOSE To review the functions of corneal fibroblasts in wound healing. METHODS Literature review. RESULTS Corneal fibroblasts arise in the corneal stroma after anterior, posterior or limbal injuries and are derived from keratocytes. Transforming growth factor (TGF) β1 and TGFβ2, along with platelet-derived growth factor (PDGF), are the major modulators of the keratocyte to corneal fibroblast transition, while fibroblast growth factor (FGF)-2, TGFβ3, and retinoic acid are thought to regulate the transition of corneal fibroblasts back to keratocytes. Adequate and sustained levels of TGFβ1 and/or TGFβ2, primarily from epithelium, tears, aqueous humor, and corneal endothelium, drive the development of corneal fibroblasts into myofibroblasts. Myofibroblasts have been shown in vitro to transition back to corneal fibroblasts, although apoptosis of myofibroblasts has been documented as a major contributor to the resolution of fibrosis in several in situ corneal injury models. Corneal fibroblasts, aside from their role as a major progenitor to myofibroblasts, also perform many critical functions in the injured cornea, including the production of critical basement membrane (BM) components during regeneration of the epithelial BM and Descemet's membrane, production of non-basement membrane-associated stromal collagen type IV to control and downregulate TGFβ effects on stromal cells, release of chemotactic chemokines that attract bone marrow-derived cells to the injured stroma, production of growth factors that modulate regeneration and maturation of the overlying epithelium, and production of collagens and other ECM components that contribute to stromal integrity after injury. CONCLUSIONS Corneal fibroblasts are major contributors to and overseers of the corneal response to injuries.
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Affiliation(s)
- Steven E Wilson
- The Cole Eye Institute, The Cleveland Clinic, Cleveland, OH, USA.
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17
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Levine H, Tovar A, Cohen AK, Cabrera K, Locatelli E, Galor A, Feuer W, O'Brien R, Goldhagen BE. Automated identification and quantification of activated dendritic cells in central cornea using artificial intelligence. Ocul Surf 2023; 29:480-485. [PMID: 37385344 DOI: 10.1016/j.jtos.2023.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 05/17/2023] [Accepted: 06/02/2023] [Indexed: 07/01/2023]
Abstract
PURPOSE To validate an algorithm quantifying activated dendritic cells (aDCs) using in-vivo confocal microscopy (IVCM) images. METHODS IVCM images obtained at the Miami Veterans Affairs Hospital were retrospectively analyzed. ADCs were quantified both with an automated algorithm and manually. Intra-class-correlation (ICC) and a Bland-Altman plot were used to compare automated and manual counts. As a secondary analysis, individuals were grouped by Dry Eye (DE) subtype: 1) aqueous-tear deficiency (ATD; Schirmer's test ≤5 mm); 2) evaporative DE (EDE; TBUT≤5s); or 3) control (Schirmer's test>5 mm; TBUT>5s) and ICCs were re-examined. RESULTS 173 non-overlapping images from 86 individuals were included in this study. The mean age was 55.2 ± 16.7 years; 77.9% were male; 20 had ATD; 18 EDE and 37 were controls. The mean number of aDCs in the central cornea quantified automatically was 0.83 ± 1.33 cells/image and manually was 1.03 ± 1.65 cells/image. A total of 143 aDCs were identified by the automated algorithm and 178 aDCs were identified manually. While a Bland-Altman plot indicated a small difference between the two methods (0.19, p < 0.01), the ICC of 0.80 (p = 0.01) demonstrated excellent agreement. Secondarily, similar results were found by DE type with an ICC of 0.75 (p = 0.01) for the ATD group, 0.80 (p = 0.01) for EDE, and 0.82 (p = 0.01) for controls. CONCLUSIONS Quantification of aDCs within the central cornea may be successfully estimated using an automated machine learning based algorithm. While this study suggests that analysis using artificial intelligence has comparable results with manual quantification, further longitudinal research to validate our findings in more diverse populations may be warranted.
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Affiliation(s)
- Harry Levine
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Arianna Tovar
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Adam K Cohen
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Kimberly Cabrera
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Elyana Locatelli
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA
| | - William Feuer
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Robert O'Brien
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Brian E Goldhagen
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Miami Veterans Administration Medical Center, 1201 NW 16th St, Miami, FL, 33125, USA.
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18
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Sonkodi B, Marsovszky L, Csorba A, Balog A, Kopper B, Nagy ZZ, Resch MD. Neural Regeneration in Dry Eye Secondary to Systemic Lupus Erythematosus Is Also Disrupted like in Rheumatoid Arthritis, but in a Progressive Fashion. Int J Mol Sci 2023; 24:10680. [PMID: 37445856 DOI: 10.3390/ijms241310680] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/16/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Our objective in this study was to analyze the aberrant neural regeneration activity in the cornea by means of in vivo confocal microscopy in systemic lupus erythematosus patients with concurrent dry eye disease. We examined 29 systemic lupus erythematosus patients and 29 age-matched healthy control subjects. Corneal nerve fiber density (CNFD, the number of fibers/mm2) and peripheral Langerhans cell morphology were lower (p < 0.05) in systemic lupus erythematosus patients compared to the control group. Interestingly, corneal nerve branch density, corneal nerve fiber length, corneal nerve fiber total branch density, and corneal nerve fiber area showed a negative correlation with disease duration. A negative correlation was also demonstrated between average corneal nerve fiber density and central Langerhans cell density. This is in line with our hypothesis that corneal somatosensory terminal Piezo2 channelopathy-induced impaired Piezo2-Piezo1 crosstalk not only disrupts regeneration and keeps transcription activated, but could lead to Piezo1 downregulation and cell activation on Langerhans cells when we consider a chronic path. Hence, Piezo2 containing mechanosensory corneal nerves and dendritic Langerhans cells could also be regarded as central players in shaping the ocular surface neuroimmune homeostasis through the Piezo system. Moreover, lost autoimmune neuroinflammation compensation, lost phagocytic self-eating capacity, and lost transcription regulation, not to mention autoantibodies against vascular heparin sulfate proteoglycans and phospholipids, could all contribute to the progressive fashion of dry eye disease in systemic lupus erythematosus.
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Affiliation(s)
- Balázs Sonkodi
- Department of Health Sciences and Sport Medicine, Hungarian University of Sports Science, 1123 Budapest, Hungary
| | - László Marsovszky
- Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary
| | - Anita Csorba
- Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary
| | - Attila Balog
- Department of Rheumatology and Immunology, Faculty of Medicine, Albert Szent-Györgyi Health Center, University of Szeged, 6725 Szeged, Hungary
| | - Bence Kopper
- Faculty of Kinesiology, Hungarian University of Sports Science, 1123 Budapest, Hungary
| | - Zoltán Zsolt Nagy
- Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary
| | - Miklós D Resch
- Department of Ophthalmology, Semmelweis University, 1085 Budapest, Hungary
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19
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Amorim M, Martins B, Fernandes R. Immune Fingerprint in Diabetes: Ocular Surface and Retinal Inflammation. Int J Mol Sci 2023; 24:9821. [PMID: 37372968 DOI: 10.3390/ijms24129821] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 05/29/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetes is a prevalent global health issue associated with significant morbidity and mortality. Diabetic retinopathy (DR) is a well-known inflammatory, neurovascular complication of diabetes and a leading cause of preventable blindness in developed countries among working-age adults. However, the ocular surface components of diabetic eyes are also at risk of damage due to uncontrolled diabetes, which is often overlooked. Inflammatory changes in the corneas of diabetic patients indicate that inflammation plays a significant role in diabetic complications, much like in DR. The eye's immune privilege restricts immune and inflammatory responses, and the cornea and retina have a complex network of innate immune cells that maintain immune homeostasis. Nevertheless, low-grade inflammation in diabetes contributes to immune dysregulation. This article aims to provide an overview and discussion of how diabetes affects the ocular immune system's main components, immune-competent cells, and inflammatory mediators. By understanding these effects, potential interventions and treatments may be developed to improve the ocular health of diabetic patients.
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Affiliation(s)
- Madania Amorim
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Beatriz Martins
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Rosa Fernandes
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-561 Coimbra, Portugal
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Carnel N, Lancia HH, Guinier C, Benichou G. Pathways of Antigen Recognition by T Cells in Allograft Rejection. Transplantation 2023; 107:827-837. [PMID: 36398330 PMCID: PMC10600686 DOI: 10.1097/tp.0000000000004420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The adaptive immune response leading to the rejection of allogeneic transplants is initiated and orchestrated by recipient T cells recognizing donor antigens. T-cell allorecognition is mediated via 3 distinct mechanisms: the direct pathway in which T cells recognize allogeneic major histocompatibility complex (MHC) molecules on donor cells, the indirect pathway through which T cells interact with donor peptides bound with self-MHC molecules on recipient antigen-presenting cells, and the recently described semidirect pathway whereby T cells recognize donor MHC proteins on recipient antigen-presenting cells. In this article, we present a description of each of these allorecognition pathways and discuss their role in acute and chronic rejection of allogeneic transplants.
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Affiliation(s)
- Natacha Carnel
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Hyshem H. Lancia
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Claire Guinier
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Gilles Benichou
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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21
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Guo R, Jiang J, Zhang Y, Liang Q, Chen T, Hu K. Evaluation of corneal dendritic cell density and subbasal nerve density in contact lens wearers using IVCM: A systematic review and meta-analysis. Front Med (Lausanne) 2023; 10:1149803. [PMID: 36993811 PMCID: PMC10040792 DOI: 10.3389/fmed.2023.1149803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 02/27/2023] [Indexed: 03/14/2023] Open
Abstract
PurposeTo evaluate the subclinical changes in corneal dendritic cell density (CDCD) and corneal subbasal nerve density (CSND) in asymptomatic contact lens (CL) wearers.MethodsDatabases including PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched for trials and studies reporting the changes of corneal CDCD and CSND in contact lens wearers published until 25 June 2022. PRISMA guidelines as well as recommended meta-analysis practices were followed. Meta-analysis was conducted using RevMan V.5.3 software.ResultsAfter the screening, 10 studies with 587 eyes of 459 participants were included. Seven studies reported the data of CDCD. Compared with the control group, CDCD in the CL wearers was higher (18.19, 95% CI 18.8–27.57, p = 0.0001). Type of in vivo confocal microscopy (IVCM), wear duration, and frequency of lens change were sources of heterogeneity. The difference in CSND between CL wearers and the control group was insignificant, and subgroup analysis did not reveal a source of heterogeneity.ConclusionOverall, CDCD increased in CL wears, while CSND did not show significant differences. IVCM is a feasible tool to assess subclinical changes in CL wearers.
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22
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Ma B, Zhou Y, Hu Y, Duan H, Sun Z, Wang P, Li W, Han W, Qi H. Mapping Resident Immune Cells in the Murine Ocular Surface and Lacrimal Gland by Flow Cytometry. Ocul Immunol Inflamm 2023; 31:748-759. [PMID: 36867079 DOI: 10.1080/09273948.2023.2182327] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
BACKGROUND The ocular surface and lacrimal gland have a frontline position in mucosal immunology. However, there have been few updates to the immune cell atlas of these tissues in recent years. PURPOSE To map the immune cells in murine ocular surface tissues and lacrimal gland. METHODS Central and peripheral corneas, conjunctiva, and lacrimal gland were dissociated into single cell suspensions, followed by flow cytometry. Discrepancy of immune cells between the central and peripheral corneas was compared. In the conjunctiva and lacrimal gland, myeloid cells were clustered by tSNE and FlowSOM based on the expression of F4/80, Ly6C, Ly6G, and MHC II. ILCs, type 1 immune cells, and type 3 immune cells were analyzed. RESULTS The number of immune cells in peripheral corneas was about 16 folds of that in central corneas. B cells accounted for 8.74% of immune cells in murine peripheral corneas. In the conjunctiva and lacrimal gland, most myeloid cells tended out to be monocytes, macrophages, and classical dendritic cells (cDCs). ILC3 were 6.28% and 3.63% of ILCs in the conjunctiva and lacrimal gland, respectively. Th1, Tc1, and NK cells were predominant type 1 immune cells. γδ T17 cells and ILC3 outnumbered Th17 cells among type 3 T cells. CONCLUSION B cells resident in murine corneas were reported for the first time. Additionally, we proposed a strategy of clustering myeloid cells to better understand their heterogeneity in the conjunctiva and lacrimal gland based on tSNE and FlowSOM. Furthermore, we identified the ILC3 in the conjunctiva and lacrimal gland for the first time. Compositions of type 1 and type 3 immune cells were summarized. Our study provides a fundamental reference and novel insights for ocular surface immune homeostasis and diseases.
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Affiliation(s)
- Baikai Ma
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing, China
| | - Yifan Zhou
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing, China
| | - Yuzhe Hu
- Department of Immunology, Peking University Health Science Center, Beijing, China.,NHC Key Laboratory of Medical Immunology, Beijing, China.,Peking University Center for Human Disease Genomics, Beijing, China
| | - Hongyu Duan
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing, China
| | - Zhengze Sun
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing, China
| | - Pingzhang Wang
- Department of Immunology, Peking University Health Science Center, Beijing, China.,NHC Key Laboratory of Medical Immunology, Beijing, China.,Peking University Center for Human Disease Genomics, Beijing, China
| | - Wei Li
- Eye Institute of Xiamen University, Xiamen, China.,Xiang'an Hospital of Xiamen University, Xiamen, China.,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, China
| | - Wenling Han
- Department of Immunology, Peking University Health Science Center, Beijing, China.,NHC Key Laboratory of Medical Immunology, Beijing, China.,Peking University Center for Human Disease Genomics, Beijing, China
| | - Hong Qi
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Beijing, China
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23
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Gulka SMD, Gowen B, Litke AM, Delaney KR, Chow RL. Laser-induced microinjury of the corneal basal epithelium and imaging of resident macrophage responses in a live, whole-eye preparation. Front Immunol 2023; 14:1050594. [PMID: 36814930 PMCID: PMC9939765 DOI: 10.3389/fimmu.2023.1050594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 01/23/2023] [Indexed: 02/09/2023] Open
Abstract
The corneal epithelium is continuously subjected to external stimuli that results in varying degrees of cellular damage. The use of live-cell imaging approaches has facilitated understanding of the cellular and molecular mechanisms underlying the corneal epithelial wound healing process. Here, we describe a live, ex vivo, whole-eye approach using laser scanning confocal microscopy to simultaneously induce and visualize short-term cellular responses following microdamage to the corneal epithelium. Live-cell imaging of corneal cell layers was enabled using the lipophilic fluorescent dyes, SGC5 or FM4-64, which, when injected into the anterior chamber of enucleated eyes, readily penetrated and labelled cell membranes. Necrotic microdamage to a defined region (30 μm x 30 μm) through the central plane of the corneal basal epithelium was induced by continuously scanning for at least one minute using high laser power and was dependent on the presence of lipophilic fluorescent dye. This whole-mount live-cell imaging and microdamage approach was used to examine the behavior of Cx3cr1:GFP-expressing resident corneal stromal macrophages (RCSMs). In undamaged corneas, RCSMs remained stationary, but exhibited a constant extension and retraction of short (~5 μm) semicircular, pseudopodia-like processes reminiscent of what has previously been reported in corneal dendritic cells. Within minutes of microdamage, nearby anterior RCSMs became highly polarized and extended projections towards the damaged region. The extension of the processes plateaued after about 30 minutes and remained stable over the course of 2-3 hours of imaging. Retrospective immunolabeling showed that these responding RCSMs were MHC class II+. This study adds to existing knowledge of immune cell behavior in response to corneal damage and introduces a simple corneal epithelial microdamage and wound healing paradigm.
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Affiliation(s)
- Sebastian M. D. Gulka
- Department of Biology, University of Victoria, Victoria, BC, Canada
- University of Illinois College of Medicine, Chicago, IL, United States
| | - Brent Gowen
- Department of Biology, University of Victoria, Victoria, BC, Canada
| | | | - Kerry R. Delaney
- Department of Biology, University of Victoria, Victoria, BC, Canada
| | - Robert L. Chow
- Department of Biology, University of Victoria, Victoria, BC, Canada
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24
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Filiberti A, Gmyrek GB, Berube AN, Carr DJJ. Osteopontin contributes to virus resistance associated with type I IFN expression, activation of downstream ifn-inducible effector genes, and CCR2 +CD115 +CD206 + macrophage infiltration following ocular HSV-1 infection of mice. Front Immunol 2023; 13:1028341. [PMID: 36685562 PMCID: PMC9846535 DOI: 10.3389/fimmu.2022.1028341] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 12/05/2022] [Indexed: 01/06/2023] Open
Abstract
Ocular pathology is often associated with acute herpes simplex virus (HSV)-1 infection of the cornea in mice. The present study was undertaken to determine the role of early T lymphocyte activation 1 protein or osteopontin (OPN) in corneal inflammation and host resistance to ocular HSV-1 infection. C57BL/6 wild type (WT) and osteopontin deficient (OPN KO) mice infected in the cornea with HSV-1 were evaluated for susceptibility to infection and cornea pathology. OPN KO mice were found to possess significantly more infectious virus in the cornea at day 3 and day 7 post infection compared to infected WT mice. Coupled with these findings, HSV-1-infected OPN KO mouse corneas were found to express less interferon (IFN)-α1, double-stranded RNA-dependent protein kinase, and RNase L compared to infected WT animals early post infection that likely contributed to decreased resistance. Notably, OPN KO mice displayed significantly less corneal opacity and neovascularization compared to WT mice that paralleled a decrease in expression of vascular endothelial growth factor (VEGF) A within 12 hr post infection. The change in corneal pathology of the OPN KO mice aligned with a decrease in total leukocyte infiltration into the cornea and specifically, in neutrophils at day 3 post infection and in macrophage subpopulations including CCR2+CD115+CD206+ and CD115+CD183+CD206+ -expressing cells. The infiltration of CD4+ and CD8+ T cells into the cornea was unaltered comparing infected WT to OPN KO mice. Likewise, there was no difference in the total number of HSV-1-specific CD4+ or CD8+ T cells found in the draining lymph node with both sets functionally competent in response to virus antigen comparing WT to OPN KO mice. Collectively, these results demonstrate OPN deficiency directly influences the host innate immune response to ocular HSV-1 infection reducing some aspects of inflammation but at a cost with an increase in local HSV-1 replication.
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Affiliation(s)
- Adrian Filiberti
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Grzegorz B. Gmyrek
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Amanda N. Berube
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Daniel J. J. Carr
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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25
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Xia D, Toy R, Pradhan P, Hejri A, Chae J, Grossniklaus HE, Cursiefen C, Roy K, Prausnitz MR. Enhanced immune responses to vaccine antigens in the corneal stroma. J Control Release 2023; 353:434-446. [PMID: 36462639 PMCID: PMC9892265 DOI: 10.1016/j.jconrel.2022.11.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/24/2022] [Accepted: 11/26/2022] [Indexed: 12/12/2022]
Abstract
To examine the widely accepted dogma that the eye is an immune-privileged organ that can suppress antigen immunogenicity, we explored systemic immune responses to a model vaccine antigen (tetanus toxoid) delivered to six compartments of the rodent eye (ocular surface, corneal stroma, anterior chamber, subconjunctival space, suprachoroidal space, vitreous body). We discovered that antigens delivered to corneal stroma induced enhanced, rather than suppressed, antigen-specific immune responses, which were 18- to 30-fold greater than conventional intramuscular injection and comparable to intramuscular vaccination with alum adjuvant. Systemic immune responses to antigen delivered to the other ocular compartments were much weaker. The enhanced systemic immune responses after intrastromal injection were related to a sequence of events involving the formation of an antigen "depot" in the avascular stroma, infiltration of antigen-presenting cells, up-regulation of MHC class II and costimulatory molecules CD80/CD86, and induction of lymphangiogenesis in the corneal stroma facilitating sustained presentation of antigen to the lymphatic system. These enhanced immune responses in corneal stroma suggest new approaches to medical interventions for ocular immune diseases and vaccination methods.
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Affiliation(s)
- Dengning Xia
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, China
| | - Randall Toy
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Pallab Pradhan
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Amir Hejri
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Jeremy Chae
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Hans E Grossniklaus
- Departments of Ophthalmology and Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Cologne 50937, Germany
| | - Krishnendu Roy
- Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, GA 30332, USA.
| | - Mark R Prausnitz
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, GA 30332, USA.
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26
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Liu F, Liu C, Lee IXY, Lin MTY, Liu YC. Corneal dendritic cells in diabetes mellitus: A narrative review. Front Endocrinol (Lausanne) 2023; 14:1078660. [PMID: 36777336 PMCID: PMC9911453 DOI: 10.3389/fendo.2023.1078660] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023] Open
Abstract
Diabetes mellitus is a global public health problem with both macrovascular and microvascular complications, such as diabetic corneal neuropathy (DCN). Using in-vivo confocal microscopy, corneal nerve changes in DCN patients can be examined. Additionally, changes in the morphology and quantity of corneal dendritic cells (DCs) in diabetic corneas have also been observed. DCs are bone marrow-derived antigen-presenting cells that serve both immunological and non-immunological roles in human corneas. However, the role and pathogenesis of corneal DC in diabetic corneas have not been well understood. In this article, we provide a comprehensive review of both animal and clinical studies that report changes in DCs, including the DC density, maturation stages, as well as relationships between the corneal DCs, corneal nerves, and corneal epithelium, in diabetic corneas. We have also discussed the associations between the changes in corneal DCs and various clinical or imaging parameters, including age, corneal nerve status, and blood metabolic parameters. Such information would provide valuable insight into the development of diagnostic, preventive, and therapeutic strategies for DM-associated ocular surface complications.
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Affiliation(s)
- Fengyi Liu
- University of Cambridge, Girton College, Cambridgeshire, United Kingdom
| | - Chang Liu
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore, Singapore
| | - Isabelle Xin Yu Lee
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore, Singapore
| | - Molly Tzu Yu Lin
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore, Singapore
| | - Yu-Chi Liu
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore, Singapore
- Cornea and Refractive Surgery Group, Singapore Eye Research Institute, Singapore, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
- Department of Ophthalmology, National Taiwan University, Taipei, Taiwan
- *Correspondence: Yu-Chi Liu,
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27
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Zhang W, Schönberg A, Bassett F, Hadrian K, Hos D, Becker M, Bock F, Cursiefen C. Different Murine High-Risk Corneal Transplant Settings Vary Significantly in Their (Lymph)angiogenic and Inflammatory Cell Signatures. Invest Ophthalmol Vis Sci 2022; 63:18. [PMID: 36534386 PMCID: PMC9769342 DOI: 10.1167/iovs.63.13.18] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Purpose Pathologic conditions in the cornea, such as transplant rejection or trauma, can lead to corneal neovascularization, creating a high-risk environment that may compromise subsequent transplantation. This study aimed to evaluate the impact of different types of corneal injury on hemangiogenesis (HA), lymphangiogenesis (LA) and immune cell pattern in the cornea. Methods We used five different corneal injury models, namely, incision injury, alkali burn, suture placement, and low-risk keratoplasty, as well as high-risk keratoplasty and naïve corneas as control. One week after incision and 2 weeks after all other different injuries, corneal HA and LA were quantified by morphometric analysis. In addition, immune cell patterns of the whole cornea and the recipient rim were analyzed by immunohistochemistry. Immune cells in the draining lymph nodes (dLNs) were quantified by flow cytometry. Results Different types of corneal injury caused significantly different HA and LA responses (both P < 0.0001). The infiltration of corneal macrophages, dendritic cells, neutrophils, major histocompatibility complex (MHC) II+ cells, CD4+ T cells, and CD8+ T cells varied significantly in different high-risk settings (all P < 0.0001). Both the expression of MHC II on macrophages (P = 0.0005) and the frequency of MHC II+ dendritic cells (P = 0.0014) in the draining lymph nodes were significantly different across the various high-risk scenarios. Conclusions Murine high-risk settings caused by different underlying pathologies vary significantly in their (lymph)angiogenic and inflammatory cell patterns. Therefore, anti(lymph)angiogenic or immunomodulatory strategies to prevent and/or treat immune responses after subsequent corneal transplantation may need to be customized according to their immune-vascular "signatures."
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Affiliation(s)
- Wei Zhang
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Alfrun Schönberg
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Fiona Bassett
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Karina Hadrian
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Deniz Hos
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Martina Becker
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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Asiedu K. Role of ocular surface neurobiology in neuronal-mediated inflammation in dry eye disease. Neuropeptides 2022; 95:102266. [PMID: 35728484 DOI: 10.1016/j.npep.2022.102266] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 01/18/2023]
Abstract
Inflammation is the consequence of dry eye disease regardless of its etiology. Several injurious or harmless processes to the ocular surface neurons promote ocular surface neurogenic inflammation, leading to the vicious cycle of dry eye disease. These processes include the regular release of neuromediators during the conduction of ocular surface sensations, hyperosmolarity-induced ocular surface neuronal damage, neuro-regenerative activities, and neuronal-mediated dendritic cell activities. Neurogenic inflammation appears to be the main culprit, instigating the self-perpetuating inflammation observed in patients with dry eye disease.
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Affiliation(s)
- Kofi Asiedu
- School of Optometry & Vision Science, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia.
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Identification of Treatment Protocols for Effective Cross-Linking of the Peripheral Cornea: An Experimental Study. Ophthalmol Ther 2022; 11:2057-2066. [PMID: 36066843 DOI: 10.1007/s40123-022-00564-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/24/2022] [Indexed: 10/14/2022] Open
Abstract
INTRODUCTION This study aimed to test and evaluate modified corneal cross-linking (CXL) protocols regarding improved treatment effects on the peripheral cornea in terms of tissue stability and cellular response. METHODS Peripheral CXL (pCXL) was performed within a ring of 9-11 mm of 36 human donor corneas with variations in applied energy (5.4, 7.2, and 10 J/cm2) at 9 mW/cm2 irradiance. Each energy level was additionally modulated regarding the oxygen level surrounding the cornea during treatment (21%; 100%). Stress-strain tests with endpoints at 12% strain and collagenase A-assisted digestions to complete digestion were performed to evaluate the rigidity and resistance of treated and control tissue. Further, corneas were processed histologically via TUNEL assay and H&E staining to demonstrate the effects on stromal cells during treatment under varying CXL conditions. RESULTS Increases in energy dosage achieved significant increases in resistance to stress in all variations except when comparing protocols A and B under normoxic conditions. Supplemental oxygen significantly increased rigidity in protocols B (p < 0.01) and C (p = 0.018). Hyperoxic conditions significantly increased resistance to digestion in all protocols. The number of DNA strand breaks in TUNEL assay staining showed significant increases in all increases in energy as well as with oxygen supplementation. CONCLUSIONS Increases in energy and supplemental oxygen improved the effect of CXL, though endothelial safety could not be verified with confidence in high-fluence CXL with supplemental oxygen. Results suggest that CXL protocols using 7.2 J/cm2 with 100% O2 or 10 J/cm2 without supplemental oxygen prove most effective without anticipated risk of endothelial damage.
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Density and distribution of dendritiform cells in the peripheral cornea of healthy subjects using in vivo confocal microscopy. Ocul Surf 2022; 26:157-165. [PMID: 35998820 DOI: 10.1016/j.jtos.2022.07.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 07/21/2022] [Accepted: 07/25/2022] [Indexed: 11/20/2022]
Abstract
PURPOSE To establish dendritiform cell (DC) density and morphological parameters in the central and peripheral cornea in a large healthy cohort, using in vivo confocal microscopy (IVCM). METHODS A prospective, cross-sectional, observational study was conducted in 85 healthy volunteers (n = 85 eyes). IVCM images of corneal center and four peripheral zones were analyzed for DC density and morphology to compare means and assess correlations (p < 0.05 being statistically significant). RESULTS Central cornea had lower DC density (40.83 ± 5.14 cells/mm2; mean ± SEM) as compared to peripheral cornea (75.42 ± 2.67 cells/mm2, p < 0.0001). Inferior and superior zones demonstrated higher DC density (105.01 ± 7.12 and 90.62 ± 4.62 cells/mm2) compared to the nasal and temporal zones (59.93 ± 3.42 and 51.77 ± 2.98 cells/mm2, p < 0.0001). Similarly, lower DC size, field and number of dendrites were observed in the central as compared to the average peripheral cornea (p < 0.0001), with highest values in the inferior zone (p < 0.001 for all, except p < 0.05 for number of dendrites in superior zone). DC parameters did not correlate with age or gender. Inter-observer reliability was 0.987 for DC density and 0.771-0.922 for morphology. CONCLUSION In healthy individuals, the peripheral cornea demonstrates higher DC density and larger morphology compared to the center, with highest values in the inferior zone. We provide the largest normative cohort for sub-stratified DC density and morphology, which can be used in future clinical trials to compare differential changes in diseased states. Furthermore, as DC parameters in the peripheral zones are dissimilar, random sampling of peripheral cornea may be inaccurate.
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Puri S, Kenyon BM, Hamrah P. Immunomodulatory Role of Neuropeptides in the Cornea. Biomedicines 2022; 10:1985. [PMID: 36009532 PMCID: PMC9406019 DOI: 10.3390/biomedicines10081985] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/21/2022] Open
Abstract
The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems.
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Affiliation(s)
- Sudan Puri
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Brendan M. Kenyon
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
- Departments of Immunology and Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA
- Cornea Service, Tufts New England Eye Center, Boston, MA 02111, USA
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Neuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation. Prog Retin Eye Res 2022; 91:101105. [PMID: 35868985 DOI: 10.1016/j.preteyeres.2022.101105] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/29/2022]
Abstract
In the cornea, resident immune cells are in close proximity to sensory nerves, consistent with their important roles in the maintenance of nerves in both homeostasis and inflammation. Using in vivo confocal microscopy in humans, and ex vivo immunostaining and fluorescent reporter mice to visualize corneal sensory nerves and immune cells, remarkable progress has been made to advance our understanding of the physical and functional interactions between corneal nerves and immune cells. In this review, we summarize and discuss recent studies relating to corneal immune cells and sensory nerves, and their interactions in health and disease. In particular, we consider how disrupted corneal nerve axons can induce immune cell activity, including in dendritic cells, macrophages and other infiltrating cells, directly and/or indirectly by releasing neuropeptides such as substance P and calcitonin gene-related peptide. We summarize growing evidence that the role of corneal intraepithelial immune cells is likely different in corneal wound healing versus other inflammatory-dominated conditions. The role of different types of macrophages is also discussed, including how stromal macrophages with anti-inflammatory phenotypes communicate with corneal nerves to provide neuroprotection, while macrophages with pro-inflammatory phenotypes, along with other infiltrating cells including neutrophils and CD4+ T cells, can be inhibitory to corneal re-innervation. Finally, this review considers the bidirectional interactions between corneal immune cells and corneal nerves, and how leveraging this interaction could represent a potential therapeutic approach for corneal neuropathy.
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Yu FSX, Lee PSY, Yang L, Gao N, Zhang Y, Ljubimov AV, Yang E, Zhou Q, Xie L. The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas. Prog Retin Eye Res 2022; 89:101039. [PMID: 34991965 PMCID: PMC9250553 DOI: 10.1016/j.preteyeres.2021.101039] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 12/10/2021] [Accepted: 12/20/2021] [Indexed: 02/08/2023]
Abstract
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, with several underlying pathophysiological mechanisms, some of which are still uncertain. The cornea is an avascular tissue and sensitive to hyperglycemia, resulting in several diabetic corneal complications including delayed epithelial wound healing, recurrent erosions, neuropathy, loss of sensitivity, and tear film changes. The manifestation of DPN in the cornea is referred to as diabetic neurotrophic keratopathy (DNK). Recent studies have revealed that disturbed epithelial-neural-immune cell interactions are a major cause of DNK. The epithelium is supplied by a dense network of sensory nerve endings and dendritic cell processes, and it secretes growth/neurotrophic factors and cytokines to nourish these neighboring cells. In turn, sensory nerve endings release neuropeptides to suppress inflammation and promote epithelial wound healing, while resident immune cells provide neurotrophic and growth factors to support neuronal and epithelial cells, respectively. Diabetes greatly perturbs these interdependencies, resulting in suppressed epithelial proliferation, sensory neuropathy, and a decreased density of dendritic cells. Clinically, this results in a markedly delayed wound healing and impaired sensory nerve regeneration in response to insult and injury. Current treatments for DPN and DNK largely focus on managing the severe complications of the disease. Cell-based therapies hold promise for providing more effective treatment for diabetic keratopathy and corneal ulcers.
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Affiliation(s)
- Fu-Shin X Yu
- Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
| | - Patrick S Y Lee
- Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Lingling Yang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Nan Gao
- Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Yangyang Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Alexander V Ljubimov
- Departments of Biomedical Sciences and Neurosurgery, Cedars-Sinai Medical Center, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ellen Yang
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Qingjun Zhou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Lixin Xie
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.
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Datta A, Lee J, Truong T, Evans DJ, Fleiszig SMJ. Topical antibiotics reduce CD11c+ cell numbers in the healthy murine cornea and modulate their response to contact lens wear. Sci Rep 2022; 12:10655. [PMID: 35739166 PMCID: PMC9226138 DOI: 10.1038/s41598-022-14847-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 06/13/2022] [Indexed: 11/21/2022] Open
Abstract
Previously we reported contact lens-induced CD11c+ cell responses in healthy mouse corneas, a phenomenon that also occurs in humans. To test involvement of ocular-associated bacteria, the impact of topical antibiotics on corneal CD11c+ cell populations during 24 h of lens wear was examined. Corneas were treated with gentamicin and ofloxacin (0.3%) or gentamicin alone, some also treated prior to lens wear (24 h). Contralateral PBS-treated eyes served as controls. CD11c-YFP (Yellow Fluorescent Protein) mice allowed CD11c+ cell visualization. Viable bacteria, on the ocular surface or contact lens, were labeled using FISH (16S rRNA-targeted probe) or click-chemistry (alkDala). Antibiotic treatment reduced baseline CD11c+ cell numbers without lens wear and suppressed CD11c+ cell responses to lens wear if corneas were both pretreated and treated during wear. Few bacteria colonized corneas or lenses under any circumstances. Conjunctival commensals were significantly reduced by antibiotics with or without lens wear, but minimally impacted by lens wear alone. Deliberate inoculation with conjunctival commensals triggered CD11c+ cell responses irrespective of antibiotic pretreatment. These results suggest that while lens wear does not necessarily increase quantifiable numbers of conjunctival commensals, those neutralized by antibiotics play a role in lens-associated CD11c+ cell responses and maintaining baseline CD11c+ cell populations.
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Affiliation(s)
- Ananya Datta
- Herbert Wertheim School of Optometry & Vision Science, University of California, Berkeley, CA, 94720, USA
| | - Justin Lee
- Herbert Wertheim School of Optometry & Vision Science, University of California, Berkeley, CA, 94720, USA
| | - Tiffany Truong
- Herbert Wertheim School of Optometry & Vision Science, University of California, Berkeley, CA, 94720, USA
| | - David J Evans
- Herbert Wertheim School of Optometry & Vision Science, University of California, Berkeley, CA, 94720, USA
- College of Pharmacy, Touro University California, Vallejo, CA, USA
| | - Suzanne M J Fleiszig
- Herbert Wertheim School of Optometry & Vision Science, University of California, Berkeley, CA, 94720, USA.
- Graduate Groups in Vision Science, Microbiology, and Infectious Diseases and Immunity, University of California, Berkeley, CA, USA.
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Loi JK, Alexandre YO, Senthil K, Schienstock D, Sandford S, Devi S, Christo SN, Mackay LK, Chinnery HR, Osborne PB, Downie LE, Sloan EK, Mueller SN. Corneal tissue-resident memory T cells form a unique immune compartment at the ocular surface. Cell Rep 2022; 39:110852. [PMID: 35613584 DOI: 10.1016/j.celrep.2022.110852] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 03/27/2022] [Accepted: 04/29/2022] [Indexed: 11/03/2022] Open
Abstract
The eye is considered immune privileged such that immune responses are dampened to protect vision. As the most anterior compartment of the eye, the cornea is exposed to pathogens and can mount immune responses that recruit effector T cells. However, presence of immune memory in the cornea is not defined. Here, we use intravital 2-photon microscopy to examine T cell responses in the cornea in mice. We show that recruitment of CD8+ T cells in response to ocular virus infection results in the formation of tissue-resident memory T (TRM) cells. Motile corneal TRM cells patrol the cornea and rapidly respond in situ to antigen rechallenge. CD103+ TRM cell generation requires antigen and transforming growth factor β. In vivo imaging in humans also reveals highly motile cells that patrol the healthy cornea. Our study finds that TRM cells form in the cornea where they can provide local protective immunity.
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Affiliation(s)
- Joon Keit Loi
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Yannick O Alexandre
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Kirthana Senthil
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Dominik Schienstock
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Sarah Sandford
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Sapna Devi
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Susan N Christo
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Laura K Mackay
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Holly R Chinnery
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC, Australia
| | - Peregrine B Osborne
- Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, VIC, Australia
| | - Laura E Downie
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC, Australia
| | - Erica K Sloan
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; Division of Surgery, Peter MacCallum Cancer Center, Melbourne, VIC, Australia
| | - Scott N Mueller
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
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Hao R, Liu Z, Chou Y, Huang C, Jing D, Wang H, Gao S, Li X. Analysis of Globular Cells in Corneal Nerve Vortex. Front Med (Lausanne) 2022; 9:806689. [PMID: 35273973 PMCID: PMC8901892 DOI: 10.3389/fmed.2022.806689] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/27/2022] [Indexed: 12/21/2022] Open
Abstract
Purpose Less was known about globular cells which were a type of dendritic cells (DCs) in cornea. We aimed to investigate the morphological and distribution characteristics of globular cells in corneal vortex and their clinical correlations with ocular surface. Methods Case records of patients who underwent in vivo confocal microscopy (IVCM) were evaluated retrospectively. The morphology and distribution features of globular cells in cornea nerve vortex and their co-existence status with Langerhans cells (LCs) were analyzed. Data of ocular surface symptoms and signs were collected and their correlations with globular cells distribution patterns and dendritic forms were performed. Dry eye patients without LCs were treated with preservative-free artificial tears, while patients with LCs were treated with artificial tears and fluoromethalone until the activated LCs disappeared. Results A total of 836 eyes from 451 individuals were included. Three distribution patterns of globular cells in vortex were investigated, type 1 scattered globular cells (57.66%), type 2 large amounts of globular cells (≥50 cells) gathering in vortex and along some fixed vortex direction horizontally (13.52%) and type 3 no globular cells (28.83%). Their location and cell count altered slightly in the follow-ups but would not disappear. LCs could co-exist with globular cells and could fade after treatment. The type 2 distribution pattern was associated with older age (p = 0.000) and higher upper eyelid Meiboscore (p = 0.006). Dendritic globular cells had higher Meiboscore than Non-dendritic forms. Conclusions Globular cells had characteristic distribution patterns and biological features different from LCs. They were associated with long-term irritation of the meibomian gland dysfunction.
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Affiliation(s)
- Ran Hao
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Ziyuan Liu
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Yilin Chou
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Chen Huang
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Dalan Jing
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Haikun Wang
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Shuang Gao
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Xuemin Li
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Department of Ophthalmology, Peking University Third Hospital, Beijing, China
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Frutos-Rincón L, Gómez-Sánchez JA, Íñigo-Portugués A, Acosta MC, Gallar J. An Experimental Model of Neuro-Immune Interactions in the Eye: Corneal Sensory Nerves and Resident Dendritic Cells. Int J Mol Sci 2022; 23:ijms23062997. [PMID: 35328417 PMCID: PMC8951464 DOI: 10.3390/ijms23062997] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 12/04/2022] Open
Abstract
The cornea is an avascular connective tissue that is crucial, not only as the primary barrier of the eye but also as a proper transparent refractive structure. Corneal transparency is necessary for vision and is the result of several factors, including its highly organized structure, the physiology of its few cellular components, the lack of myelinated nerves (although it is extremely innervated), the tightly controlled hydration state, and the absence of blood and lymphatic vessels in healthy conditions, among others. The avascular, immune-privileged tissue of the cornea is an ideal model to study the interactions between its well-characterized and dense sensory nerves (easily accessible for both focal electrophysiological recording and morphological studies) and the low number of resident immune cell types, distinguished from those cells migrating from blood vessels. This paper presents an overview of the corneal structure and innervation, the resident dendritic cell (DC) subpopulations present in the cornea, their distribution in relation to corneal nerves, and their role in ocular inflammatory diseases. A mouse model in which sensory axons are constitutively labeled with tdTomato and DCs with green fluorescent protein (GFP) allows further analysis of the neuro-immune crosstalk under inflammatory and steady-state conditions of the eye.
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Affiliation(s)
- Laura Frutos-Rincón
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
| | - José Antonio Gómez-Sánchez
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- Correspondence: ; Tel.: +34-965-91-9594
| | - Almudena Íñigo-Portugués
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
| | - M. Carmen Acosta
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
| | - Juana Gallar
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
- Instituto de Investigación Biomédica y Sanitaria de Alicante, 03010 Alicante, Spain
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Herb VM, Url A, Tichy A, Nell B. Immunohistochemical staining of immunoglobulin G in healthy equine, canine, and feline corneas. Vet Ophthalmol 2022; 25:232-239. [PMID: 35239261 PMCID: PMC9314887 DOI: 10.1111/vop.12976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 01/03/2022] [Accepted: 02/14/2022] [Indexed: 11/29/2022]
Abstract
Objective Establishing an immunohistochemical approach for semi‐quantitative assessment of the presence of immunoglobulin G (IgG) in equine, canine, and feline corneas. Procedures Healthy corneas of horses, dogs, and cats, euthanized because of a fatal disease or an unrecoverable trauma unrelated to and without a history of ophthalmic disease were formalin‐fixed, paraffin‐embedded, and determined to be pathomorphologically healthy by light microscopy. Automated immunohistochemistry was performed using primary antibodies against IgG, biotin‐conjugated secondary antibodies, and streptavidin‐peroxidase, as well as diaminobenzidine for visualization. After counterstaining with hematoxylin, epithelium, stroma, Descemet´s membrane (DM), and endothelium were semi‐quantitatively scored for the presence of IgG on a 4‐grade scale (0 = no, 1 = faint, 2 = medium, 3 = strong staining) by light microscopy. Results Corneal specimens of 20 horses (40 eyes) with a median age of 15.5 years (range 2–31 years), 12 dogs (21 eyes) with a median age of 10.0 years (range 4–16), and 13 cats (24 eyes) with a median age of 10.0 years (range 2–18) were included in the study. Different sexes and breeds were represented. In all corneas (100%), significant medium signal intensity in the stroma was observed. Variable immunosignal was obtained in epithelium, DM, and endothelium. Conclusion This method reproducibly allows for the detection of IgG in healthy equine, canine, and feline corneas, particularly stroma. Semi‐quantitative results evidence medium presence of IgG in the corneal stroma. Further research is needed to evaluate IgG presence in diseased corneas.
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Affiliation(s)
- Verena Maria Herb
- Department of Companion Animals and Horses, University of Veterinary Medicine, Vienna, Austria
| | - Angelika Url
- Department of Pathobiology, University of Veterinary Medicine, Vienna, Austria
| | - Alexander Tichy
- Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
| | - Barbara Nell
- Department of Companion Animals and Horses, University of Veterinary Medicine, Vienna, Austria
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Chen Y, Wang S, Alemi H, Dohlman T, Dana R. Immune regulation of the ocular surface. Exp Eye Res 2022; 218:109007. [PMID: 35257715 PMCID: PMC9050918 DOI: 10.1016/j.exer.2022.109007] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/10/2022] [Accepted: 02/20/2022] [Indexed: 01/01/2023]
Abstract
Despite constant exposure to various environmental stimuli, the ocular surface remains intact and uninflamed while maintaining the transparency of the cornea and its visual function. This 'immune privilege' of the ocular surface is not simply a result of the physical barrier function of the mucosal lining but, more importantly, is actively maintained through a variety of immunoregulatory mechanisms that prevent the disruption of immune homeostasis. In this review, we focus on essential molecular and cellular players that promote immune quiescence in steady-state conditions and suppress inflammation in disease-states. Specifically, we examine the interactions between the ocular surface and its local draining lymphoid compartment, by encompassing the corneal epithelium, corneal nerves and cornea-resident myeloid cells, conjunctival goblet cells, and regulatory T cells (Treg) in the context of ocular surface autoimmune inflammation (dry eye disease) and alloimmunity (corneal transplantation). A better understanding of the immunoregulatory mechanisms will facilitate the development of novel, targeted immunomodulatory strategies for a broad range of ocular surface inflammatory disorders.
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Affiliation(s)
- Yihe Chen
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA.
| | - Shudan Wang
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Hamid Alemi
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Thomas Dohlman
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
| | - Reza Dana
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, 02114, USA
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40
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Lamy R, Wolf M, Bispo C, Clay SM, Zheng S, Wolfreys F, Pan P, Chan MF. Characterization of Recruited Mononuclear Phagocytes following Corneal Chemical Injury. Int J Mol Sci 2022; 23:ijms23052574. [PMID: 35269717 PMCID: PMC8910730 DOI: 10.3390/ijms23052574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/18/2022] [Accepted: 02/23/2022] [Indexed: 02/07/2023] Open
Abstract
Mononuclear phagocytes (MP) have central importance in innate immunity, inflammation, and fibrosis. Recruited MPs, such as macrophages, are plastic cells and can switch from an inflammatory to a restorative phenotype during the healing process. However, the role of the MPs in corneal wound healing is not completely understood. The purpose of this study is to characterize the kinetics of recruited MPs and evaluate the role of macrophage metalloelastase (MMP12) in the healing process, using an in vivo corneal chemical injury model. Unwounded and wounded corneas of wild-type (WT) and Mmp12-/- mice were collected at 1, 3, and 6 days after chemical injury and processed for flow cytometry analysis. Corneal MP phenotype significantly changed over time with recruited Ly6Chigh (proinflammatory) cells being most abundant at 1 day post-injury. Ly6Cint cells were highly expressed at 3 days post-injury and Ly6Cneg (patrolling) cells became the predominant cell type at 6 days post-injury. CD11c+ dendritic cells were abundant in corneas from Mmp12-/- mice at 6 days post-injury. These findings show the temporal phenotypic plasticity of recruited MPs and provide valuable insight into the role of the MPs in the corneal repair response, which may help guide the future development of MP-targeted therapies.
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Affiliation(s)
- Ricardo Lamy
- Department of Ophthalmology, University of California, San Francisco, CA 94158, USA; (R.L.); (M.W.); (S.M.C.); (S.Z.); (F.W.); (P.P.)
| | - Marie Wolf
- Department of Ophthalmology, University of California, San Francisco, CA 94158, USA; (R.L.); (M.W.); (S.M.C.); (S.Z.); (F.W.); (P.P.)
| | - Claudia Bispo
- UCSF Parnassus Flow Cytometry Core Facility, University of California, San Francisco, CA 94143, USA;
| | - Selene M. Clay
- Department of Ophthalmology, University of California, San Francisco, CA 94158, USA; (R.L.); (M.W.); (S.M.C.); (S.Z.); (F.W.); (P.P.)
| | - Siyu Zheng
- Department of Ophthalmology, University of California, San Francisco, CA 94158, USA; (R.L.); (M.W.); (S.M.C.); (S.Z.); (F.W.); (P.P.)
| | - Finn Wolfreys
- Department of Ophthalmology, University of California, San Francisco, CA 94158, USA; (R.L.); (M.W.); (S.M.C.); (S.Z.); (F.W.); (P.P.)
| | - Peipei Pan
- Department of Ophthalmology, University of California, San Francisco, CA 94158, USA; (R.L.); (M.W.); (S.M.C.); (S.Z.); (F.W.); (P.P.)
| | - Matilda F. Chan
- Department of Ophthalmology, University of California, San Francisco, CA 94158, USA; (R.L.); (M.W.); (S.M.C.); (S.Z.); (F.W.); (P.P.)
- Francis I. Proctor Foundation, University of California, San Francisco, CA 94158, USA
- Correspondence:
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41
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Zhou Q, Yang L, Wang Q, Li Y, Wei C, Xie L. Mechanistic investigations of diabetic ocular surface diseases. Front Endocrinol (Lausanne) 2022; 13:1079541. [PMID: 36589805 PMCID: PMC9800783 DOI: 10.3389/fendo.2022.1079541] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/02/2022] [Indexed: 12/23/2022] Open
Abstract
With the global prevalence of diabetes mellitus over recent decades, more patients suffered from various diabetic complications, including diabetic ocular surface diseases that may seriously affect the quality of life and even vision sight. The major diabetic ocular surface diseases include diabetic keratopathy and dry eye. Diabetic keratopathy is characterized with the delayed corneal epithelial wound healing, reduced corneal nerve density, decreased corneal sensation and feeling of burning or dryness. Diabetic dry eye is manifested as the reduction of tear secretion accompanied with the ocular discomfort. The early clinical symptoms include dry eye and corneal nerve degeneration, suggesting the early diagnosis should be focused on the examination of confocal microscopy and dry eye symptoms. The pathogenesis of diabetic keratopathy involves the accumulation of advanced glycation end-products, impaired neurotrophic innervations and limbal stem cell function, and dysregulated growth factor signaling, and inflammation alterations. Diabetic dry eye may be associated with the abnormal mitochondrial metabolism of lacrimal gland caused by the overactivation of sympathetic nervous system. Considering the important roles of the dense innervations in the homeostatic maintenance of cornea and lacrimal gland, further studies on the neuroepithelial and neuroimmune interactions will reveal the predominant pathogenic mechanisms and develop the targeting intervention strategies of diabetic ocular surface complications.
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Affiliation(s)
- Qingjun Zhou
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Lingling Yang
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Qun Wang
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Ya Li
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Chao Wei
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Lixin Xie
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
- *Correspondence: Lixin Xie,
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McClellan S, Pitchaikannu A, Wright R, Bessert D, Iulianelli M, Hazlett LD, Xu S. Prophylactic Knockdown of the miR-183/96/182 Cluster Ameliorates Pseudomonas aeruginosa-Induced Keratitis. Invest Ophthalmol Vis Sci 2021; 62:14. [PMID: 34919120 PMCID: PMC8684302 DOI: 10.1167/iovs.62.15.14] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Previously, we demonstrated that miR-183/96/182 cluster (miR-183C) knockout mice exhibit decreased severity of Pseudomonas aeruginosa (PA)-induced keratitis. This study tests the hypothesis that prophylactic knockdown of miR-183C ameliorates PA keratitis indicative of a therapeutic potential. Methods Eight-week-old miR-183C wild-type and C57BL/6J inbred mice were used. Locked nucleic acid-modified anti-miR-183C or negative control oligoribonucleotides with scrambled sequences (NC ORNs) were injected subconjunctivally 1 day before and then topically applied once daily for 5 days post-infection (dpi) (strain 19660). Corneal disease was graded at 1, 3, and 5 dpi. Corneas were harvested for RT-PCR, ELISA, immunofluorescence (IF), myeloperoxidase and plate count assays, and flow cytometry. Corneal nerve density was evaluated in flatmounted corneas by IF staining with anti-β-III tubulin antibody. Results Anti-miR-183C downregulated miR-183C in the cornea. It resulted in an increase in IL-1β at 1 dpi, which was decreased at 5 dpi; fewer polymorphonuclear leukocytes (PMNs) at 5 dpi; lower viable bacterial plate count at both 1 and 5 dpi; increased percentages of MHCII+ macrophages (Mϕ) and dendritic cells (DCs), consistent with enhanced activation/maturation; and decreased severity of PA keratitis. Anti-miR-183C treatment in the cornea of naïve mice resulted in a transient reduction of corneal nerve density, which was fully recovered one week after the last anti-miR application. miR-183C targets repulsive axon-guidance receptor molecule Neuropilin 1, which may mediate the effect of anti-miR-183C on corneal nerve regression. Conclusions Prophylactic miR-183C knockdown is protective against PA keratitis through its regulation of innate immunity, corneal innervation, and neuroimmune interactions.
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Affiliation(s)
- Sharon McClellan
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Ahalya Pitchaikannu
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Robert Wright
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Denise Bessert
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Mason Iulianelli
- Departments of Biological Sciences and Public Health, College of Liberal Arts and Sciences, Wayne State University, Detroit, Michigan, United States
| | - Linda D Hazlett
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Shunbin Xu
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
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Immune responses to injury and their links to eye disease. Transl Res 2021; 236:52-71. [PMID: 34051364 PMCID: PMC8380715 DOI: 10.1016/j.trsl.2021.05.005] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/12/2021] [Accepted: 05/24/2021] [Indexed: 12/31/2022]
Abstract
The eye is regarded as an immune privileged site. Since the presence of a vasculature would impair vision, the vasculature of the eye is located outside of the central light path. As a result, many regions of the eye evolved mechanisms to deliver immune cells to sites of dysgenesis, injury, or in response to the many age-related pathologies. While the purpose of these immune responses is reparative or protective, cytokines released by immune cells compromise visual acuity by inducing inflammation and fibrosis. The response to traumatic or pathological injury is distinct in different regions of the eye. Age-related diseases impact both the anterior and posterior segment and lead to reduced quality of life and blindness. Here we focus attention on the role that inflammation and fibrosis play in the progression of age-related pathologies of the cornea and the lens as well as in glaucoma, the formation of epiretinal membranes, and in proliferative vitreoretinopathy.
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Key Words
- 2ryERM
- A T-helper cell that expresses high levels of IL-17 which can suppress T-regulatory cell function
- A cytokine expressed early during inflammation that attracts neutrophils
- A cytokine expressed early during inflammation that attracts neutrophils, sometimes referred to as monocyte chemoattractant protein-1 (MCP-1))
- A mouse model that lacks functional T and B cells and used to study the immune response
- A pigmented mouse strain used for research and known to mount a primarily Th1 response to infection
- A protein encoded by the ADGRE1 gene that, in mice, is expressed primarily on macrophages
- A strain of pigmented mice used in glaucoma research
- ACAID
- APCs
- ASC
- An albino mouse strain used for research and known to mount a primarily Th2 response to infection
- Antigen Presenting Cells, this class includes dendritic cells and monocytes
- BALB/c
- BM
- C57BL6
- CCL2
- CD45
- CNS
- CXCL1
- Central Nervous System
- Cluster of differentiation 45 antigen
- DAMPs
- DBA/2J
- EBM
- ECM
- EMT
- ERM
- Epithelial Basement Membrane
- F4/80
- FGF2
- HA =hyaluronic acid
- HSK
- HSP
- HSPGs
- HSV
- ICN
- IL-20
- IL6
- ILM
- IOP
- Inner (or internal) limiting membrane
- Interleukin 6
- Interleukin-20
- MAGP1
- MHC-II
- Major histocompatibility complex type II, a class of MHC proteins typically found only on APCs
- Microfibril-associated glycoprotein 1
- N-cad
- N-cadherin
- NEI
- NK
- National Eye Institute
- Natural killer T cells
- PCO
- PDGF
- PDR
- PVD
- PVR
- Platelet derived growth factor
- Posterior capsular opacification
- RGC
- RPE
- RRD
- Rag1-/-
- Retinal ganglion cells
- Retinal pigment epithelial cells
- SMAD
- Sons of Mothers Against Decapentaplegic, SMADs are a class of molecules that mediate TGF and bone morphogenetic protein signaling
- T-helper cell 1 response, proinflammatory adaptive response involving interferon gamma and associated with autoimmunity
- T-helper cell 2 response involving IgE and interleukins 4,5, and 13, also induces the anti-inflammatory interleukin 10 family cytokines
- T-regulatory cell
- TG
- TGF1
- TM
- TNF
- Th1
- Th17
- Th2
- Transforming growth factor 1
- Treg
- Tumor necrosis factor a cytokine produced during inflammation
- VEGF
- Vascular endothelial growth factor
- WHO
- World Health Organization
- anterior chamber immune deviation
- anterior subcapsular cataracts
- basement membrane
- damage-associated molecular patterns
- epiretinal membrane
- epiretinal membrane secondary to disease pathology
- epithelial-mesenchymal transition
- extracellular matrix
- fibroblast growth factor 2, also referred to as basic FGF
- heat shock protein
- heparan sulfate proteoglycans
- herpes simplex virus
- herpes stromal keratitis
- iERM
- idiopathic epiretinal membrane
- intraepithelial corneal nerves
- intraocular pressure
- mTOR
- mechanistic target of rapamycin, a protein kinase encoded by the MTOR genes that regulates a variety of signal transduction events including cell growth, autophagy and actin cytoskeleton
- posterior vitreous detachment
- proliferative diabetic retinopathy
- proliferative vitreoretinopathy
- rhegmatogenous (rupture, tear) retinal detachment
- trabecular meshwork
- trigeminal ganglion
- αSMA
- α−Smooth muscle actin, a class of actin expressed in mesenchymal cells
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Chen Y, Dana R. Autoimmunity in dry eye disease - An updated review of evidence on effector and memory Th17 cells in disease pathogenicity. Autoimmun Rev 2021; 20:102933. [PMID: 34509656 DOI: 10.1016/j.autrev.2021.102933] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 06/16/2021] [Indexed: 12/27/2022]
Abstract
The classic Th1/Th2 dogma has been significantly reshaped since the subsequent introduction of several new T helper cell subsets, among which the most intensively investigated during the last decade is the Th17 lineage that demonstrates critical pathogenic roles in autoimmunity and chronic inflammation - including the highly prevalent dry eye disease. In this review, we summarize current concepts of Th17-mediated disruption of ocular surface immune homeostasis that leads to autoimmune inflammatory dry eye disease, by discussing the induction, activation, differentiation, migration, and function of effector Th17 cells in disease development, highlighting the phenotypic and functional plasticity of Th17 lineage throughout the disease initiation, perpetuation and sustention. Furthermore, we emphasize the most recent advance in Th17 memory formation and function in the chronic course of dry eye disease, a major area to be better understood for facilitating the development of effective treatments in a broader field of autoimmune diseases that usually present a chronic course with recurrent episodes of flare in the target tissues or organs.
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Affiliation(s)
- Yihe Chen
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
| | - Reza Dana
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
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Time-Dependent Serial Changes of Antigen-Presenting Cell Subsets in the Ocular Surface Are Distinct between Corneal Sterile Inflammation and Allosensitization in a Murine Model. Cells 2021; 10:cells10092210. [PMID: 34571859 PMCID: PMC8467177 DOI: 10.3390/cells10092210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/22/2021] [Accepted: 08/23/2021] [Indexed: 11/30/2022] Open
Abstract
The kinetics of antigen-presenting cells (APCs) vary depending on their resident tissues and the manner of immunization. We investigated the long-term changes in mature APC and T-cell subsets over 4 weeks in the ocular surface in murine models of corneal quiescent or potent sterile inflammation, and allosensitization using partial (PT), syngeneic (Syn), and allogeneic (Allo) corneal transplantation. In PT, CD11bintCD11chiMHCIIhiCD86hi cells increased until 4 weeks with an increase in IFNγhi T cells. In Syn, both CD11bintCD11chiMHCIIhiCD86hi and CD11bhiCD11chiMHCIIhiCD86hi APC subsets increased until 4 weeks with a brief increase in CD69hi T cells at 2 weeks. In Allo, CD11bintCD11chiMHCIIhiCD86hi and CD11bhiCD11chiMHCIIhiCD86hi APC subsets increased until 4 weeks, and an early increase in CD69hi T cells was observed at 2 weeks followed by a late increase in IFNγhi T cells at 4 weeks. The frequency of the IFNγhi T cell subset was positively correlated with the frequency of the CD11bintCD11chiMHCIIhiCD86hi subset, indicating the existence of APC–T cell interaction in the ocular surface. Together, the results indicate that allosensitization in mature APCs leads to T-cell activation in the ocular surface, whereas sterile inflammation merely induces a brief and non-specific T-cell activation in the ocular surface.
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Ung L, Chodosh J. Foundational concepts in the biology of bacterial keratitis. Exp Eye Res 2021; 209:108647. [PMID: 34097906 PMCID: PMC8595513 DOI: 10.1016/j.exer.2021.108647] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/28/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022]
Abstract
Bacterial infections of the cornea, or bacterial keratitis (BK), are notorious for causing rapidly fulminant disease and permanent vision loss, even among treated patients. In the last sixty years, dramatic upward trajectories in the frequency of BK have been observed internationally, driven in large part by the commercialization of hydrogel contact lenses in the late 1960s. Despite this worsening burden of disease, current evidence-based therapies for BK - including broad-spectrum topical antibiotics and, if indicated, topical corticosteroids - fail to salvage vision in a substantial proportion of affected patients. Amid growing concerns of rapidly diminishing antibiotic utility, there has been renewed interest in urgently needed novel treatments that may improve clinical outcomes on an individual and public health level. Bridging the translational gap in the care of BK requires the identification of new therapeutic targets and rational treatment design, but neither of these aims can be achieved without understanding the complex biological processes that determine how bacterial corneal infections arise, progress, and resolve. In this chapter, we synthesize the current wealth of human and animal experimental data that now inform our understanding of basic BK pathophysiology, in context with modern concepts in ocular immunology and microbiology. By identifying the key molecular determinants of clinical disease, we explore how novel treatments can be developed and translated into routine patient care.
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Affiliation(s)
- Lawson Ung
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA; Infectious Disease Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - James Chodosh
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA; Infectious Disease Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
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Jung YH, Ryu JS, Yoon CH, Kim MK. Age-Dependent Distinct Distributions of Dendritic Cells in Autoimmune Dry Eye Murine Model. Cells 2021; 10:1857. [PMID: 34440626 PMCID: PMC8392312 DOI: 10.3390/cells10081857] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/14/2021] [Accepted: 07/20/2021] [Indexed: 02/03/2023] Open
Abstract
We investigated whether aging-dependent changes in dendritic cell (DC) distributions are distinct in autoimmune dry eye compared with an aging-related murine model. Corneal staining and tear secretion were evaluated in young and aged C57BL/6 (B6) and NOD.B10.H2b mice (NOD). In the corneolimbus, lacrimal gland (LG), and mesenteric lymph node (MLN), CD11b- and CD11b+ DCs, CD103+ DCs and MHC-IIhi B cells were compared between young and aged B6 and NOD mice. With increased corneal staining, tear secretion decreased in both aged B6 and NOD mice (p < 0.001). In both aged B6 and NOD mice, the percentages of corneolimbal CD11b+ DCs were higher (p < 0.05) than those in young mice. While, the percentages of lymph nodal CD103+ DCs were higher in aged B6 and NOD mice (p < 0.05), the percentages of corneolimbal CD103+ DCs were only higher in aged NOD mice (p < 0.05). In aged NOD mice, the proportions of lacrimal glandial and lymph nodal MHC-IIhi B cells were also higher than those in young mice (p < 0.05). It indicates that corneolimbal or lacrimal glandial distribution of CD103+ DCs or MHC-IIhi B cells may be distinct in aged autoimmune dry eye models compared to those in aged immune competent murine models.
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Affiliation(s)
- Young-Ho Jung
- Department of Ophthalmology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea; (Y.-H.J.); (C.-H.Y.)
- Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea;
| | - Jin-Suk Ryu
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea;
| | - Chang-Ho Yoon
- Department of Ophthalmology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea; (Y.-H.J.); (C.-H.Y.)
- Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea;
| | - Mee-Kum Kim
- Department of Ophthalmology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea; (Y.-H.J.); (C.-H.Y.)
- Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea;
- Transplantation Research Institute, Seoul National University Medical Research Center, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea
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Levine H, Hwang J, Dermer H, Mehra D, Feuer W, Galor A. Relationships between activated dendritic cells and dry eye symptoms and signs. Ocul Surf 2021; 21:186-192. [PMID: 34102312 PMCID: PMC8328957 DOI: 10.1016/j.jtos.2021.06.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 06/01/2021] [Accepted: 06/01/2021] [Indexed: 12/22/2022]
Abstract
PURPOSE To examine whether "activated" dendritic cells (aDCs) could serve as a biomarker of systemic immune disorders in individuals with dry eye (DE) symptoms. Secondarily, to examine the impact of a topical anti-inflammatory agent on aDC number. METHODS Retrospective analysis was conducted to identify individuals with DE symptoms who had in-vivo confocal microscopy (IVCM) imaging between October 2018 and July 2020 at the Miami Veterans Hospital. aDCs were manually quantified based on morphology. Receiver operating curve (ROC) analysis examined relationships between aDC number and systemic immune disease status. Individuals were then grouped by aDC number (≥2 versus <2) and demographics and DE parameters were examined. Paired t-test was performed to evaluated aDC number pre-vs post-initiation of an anti-inflammatory agent. RESULTS 128 individuals were included. Their mean age was 57.1 ± 15.0 years; 71.1% were male, 53.1% self-identified as White and 24.2% as Hispanic. The mean number of aDCs in the central cornea was 1.28 ± 2.16 cells/image. The presence of ≥2 aDCs had a sensitivity of 60% and specificity of 77% for the diagnosis of a systemic immune disorder. Individuals with ≥2 aDCs were more likely to self-identify as Black, have Secondary Sjögren's, and have higher nerve fiber area and fractal dimension. In 12 individuals, aDC number decreased from 2.69 ± 2.36 to 0.58 ± 0.73 cells/image after initiation of an anti-inflammatory agent, p = 0.01. CONCLUSIONS The presence of ≥2 aDCs in the central cornea suggests a systemic immune disorder in individuals with DE symptoms. Topical anti-inflammatory therapy can reduce the number of aDCs in the central cornea.
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Affiliation(s)
- Harry Levine
- Miami Veterans Administration Medical Center, Miami, FL, USA; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jodi Hwang
- Miami Veterans Administration Medical Center, Miami, FL, USA; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Harrison Dermer
- Miami Veterans Administration Medical Center, Miami, FL, USA; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Divy Mehra
- Miami Veterans Administration Medical Center, Miami, FL, USA; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - William Feuer
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anat Galor
- Miami Veterans Administration Medical Center, Miami, FL, USA; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
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Jamali A, Hu K, Sendra VG, Blanco T, Lopez MJ, Ortiz G, Qazi Y, Zheng L, Turhan A, Harris DL, Hamrah P. Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis. Cell Rep 2021; 32:108099. [PMID: 32877681 PMCID: PMC7511260 DOI: 10.1016/j.celrep.2020.108099] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 04/14/2020] [Accepted: 08/11/2020] [Indexed: 12/20/2022] Open
Abstract
The presence and potential functions of resident plasmacytoid dendritic cells (pDCs) in peripheral tissues is unclear. We report that pDCs constitutively populate naïve corneas and are increased during sterile injuries or acute herpes simplex virus 1 (HSV-1) keratitis. Their local depletion leads to severe clinical disease, nerve loss, viral dissemination to the trigeminal ganglion and draining lymph nodes, and mortality, while their local adoptive transfer limits disease. pDCs are the main source of HSV-1-induced IFN-α in the corneal stroma through TLR9, and they prevent re-programming of regulatory T cells (Tregs) to effector ex-Tregs. Clinical signs of infection are observed in pDC-depleted corneas, but not in pDC-sufficient corneas, following low-dose HSV-1 inoculation, suggesting their critical role in corneal antiviral immunity. Our findings demonstrate a vital role for corneal pDCs in the control of local viral infections. Jamali et al. show that the cornea, as an immune-privileged tissue, hosts resident pDCs, which mediate immunity against HSV-1 by secreting IFN-a via TLR9 and preserving Tregs. pDCs minimize the clinical severity of HSV-1 keratitis, infiltration of immune cells, nerve damage, and viral dissemination to TG and dLNs.
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Affiliation(s)
- Arsia Jamali
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Kai Hu
- Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - Victor G Sendra
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Tomas Blanco
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Maria J Lopez
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Gustavo Ortiz
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Yureeda Qazi
- Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Lixin Zheng
- Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - Aslihan Turhan
- Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - Deshea L Harris
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA; Program in Immunology, School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA; Cornea Service, Tufts New England Eye Center, Boston, MA, USA.
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Changes in Corneal Dendritic Cell and Sub-basal Nerve in Long-Term Contact Lens Wearers With Dry Eye. Eye Contact Lens 2021; 46:238-244. [PMID: 32097180 DOI: 10.1097/icl.0000000000000691] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To evaluate the changes of corneal sub-basal nerve (SBN) and dendritic cell (DC) in contact lens (CL) wearers with mild dry eye and their potential relationship. METHODS Twenty mild dry eye volunteers who had never worn CLs were recruited for long-term CL wearing. Each subject underwent ocular surface evaluations at baseline and at 1, 4, 12, and 24 weeks, including Ocular Surface Disease Index (OSDI) questionnaire, tear film break-up time (TBUT), and Schirmer I test. In vivo confocal microscopy was used to examine the density, area, number of dendrites, total dendritic length of DC, and SBN densities in central and peripheral corneas. Only right eyes were included. RESULTS The DCs were activated and peaked at week 4 after wearing CLs. The peripheral DC density increased beginning the first week, whereas the central ones increased by week 4. After 4 weeks, both began to decrease, but still higher than baseline at week 24. The central and peripheral SBN densities decreased. However, the peripheral SBN tended to increase beginning at week 12. In early period, SBN was negatively correlated with DC parameters. After 4 weeks, the correlation changed to be positive. The OSDI increased, whereas the Schirmer I test and TBUT showed no significant change. CONCLUSIONS After wearing CLs, corneal DC were activated and increased, indicating ocular surface inflammation and decreased after week 4. In the early period, increases in DC may lead to decreases in SBN. Upon decrease of DC, the SBN may regenerate.
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