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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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Potenza M, Moramarco A, Astolfi A, Ciavarella C, Fontana L, Versura P. Ocular Surface Microbiota and Corneal Transplant Outcome: Is There a Link? Biomedicines 2025; 13:972. [PMID: 40299643 PMCID: PMC12025228 DOI: 10.3390/biomedicines13040972] [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: 02/19/2025] [Revised: 04/04/2025] [Accepted: 04/10/2025] [Indexed: 05/01/2025] Open
Abstract
Recent research has highlighted the critical role of microbiota in organ transplant outcomes, particularly in the gut. However, the impact of ocular surface microbiota (OSM) on corneal transplantation remains largely unexplored. This piece examines the potential connection between OSM imbalances and corneal graftoutcomes, suggesting that microbial shifts could influence immune responses and transplant success. The OSM, though characterized by low microbial density, plays a critical role in local immune modulation and ocular surface homeostasis. Dysbiosis in this microbiota may compromise the immune privilege of the cornea, potentially increasing the risk of graft rejection. Looking at gut microbiota studies, where dysbiosis has been linked to graft failure, it is reasonable to hypothesize that similar mechanisms might be at play on the ocular surface. Disruptions in cornea's immune tolerance pathways, such as anterior chamber-associated immune deviation (ACAID), may lead to pro-inflammatory responses that threaten graft survival. In addition, ocular surface diseases such as dry eye disease, microbial keratitis, and allergic conjunctivitis, already associated with OSM dysbiosis, may further exacerbate post-transplant complications. Despite the lack of direct studies linking OSM to corneal transplant outcomes, this opinion piece highlights the necessity for future research. Standardizing microbiota analysis methodologies and exploring therapeutic interventions, such as ocular probiotics, could open new roads for improving corneal transplant success and patient prognosis.
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Affiliation(s)
- Michele Potenza
- Ophthalmology Unit, DIMEC, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (M.P.); (L.F.)
| | - Antonio Moramarco
- IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.A.)
| | - Annalisa Astolfi
- IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.A.)
- DIMEC, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy;
| | - Carmen Ciavarella
- DIMEC, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy;
| | - Luigi Fontana
- Ophthalmology Unit, DIMEC, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (M.P.); (L.F.)
- IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.A.)
| | - Piera Versura
- Ophthalmology Unit, DIMEC, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (M.P.); (L.F.)
- IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.A.)
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Liu Y, Ma B, Zhao L, Li H, Li W, Sun Z, Duan H, Zhao Y, Qi H. Influence of dendritic cells on corneal nerve morphological analysis and clinical relevance in chronic dry eye disease after femtosecond laser-assisted laser in situ keratomileusis. Front Med (Lausanne) 2025; 12:1568787. [PMID: 40231078 PMCID: PMC11994687 DOI: 10.3389/fmed.2025.1568787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 03/03/2025] [Indexed: 04/16/2025] Open
Abstract
Purpose This study aims to investigate the influence of dendritic cells (DCs) on corneal nerve morphology and the clinical significance in chronic Femtosecond Laser-Assisted Laser in Situ Keratomileusis (FS-LASIK) related dry eye disease (DED). Methods The cross-sectional study was conducted involving healthy control, DED without FS-LASIK group, and DED after FS-LASIK group. Clinical parameters such as ocular surface disease index (OSDI), fluorescein tear breakup time (FBUT), corneal fluorescein staining (CFS) scores, Schirmer I test (SIt), Cochet-Bonnet esthesiometer (C-BE) were recorded. DCs of in vivo confocal microscopy images were included or excluded during corneal nerve segmentation. Key morphological parameters, including corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), tortuosity, and box-count fractal dimension (Boxdim), were measured. The impact of DCs on nerve metrics and clinical parameters and the correlations between each other were assessed. Results The significant reduce in key morphological parameters was observed after eliminating DCs. Significant differences of morphological parameters were observed in DED after FS-LASIK group compared with other two groups. With the increased presence of DCs density in DED especially in DED after FS-LASIK group, the presence of DCs introduced false positives in the correlation analysis of DCs density with corneal morphology in DED after FS-LASIK and in the correlation analysis of corneal morphology with clinical characteristics in DED without FS-LASIK. Conclusion The presence of DCs introduces significant biases in the assessments of corneal nerve morphology, primarily false-positive results in DED especially chronic FS-LASIK related DED. Their exclusion improves the precision of nerve measurements, which may enhance the clinical evaluation of corneal nerve morphology. These findings highlight the importance of precise segmentation techniques to minimize DCs related interference in clinical practice.
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Affiliation(s)
- Yilin Liu
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China
| | - Baikai Ma
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China
| | - Lu Zhao
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmic and Visual Science Key Laboratory, Beijing, China
| | - Hongshuo Li
- Cixi Institute of BioMedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China
| | - Wenlong Li
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China
| | - Zhengze Sun
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China
| | - Hongyu Duan
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China
| | - Yitian Zhao
- Cixi Institute of BioMedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China
| | - Hong Qi
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
- Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China
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Fang G, Zhao R, Zhu L, Wang Q, Peng S, Kang L, Lu H, Zhang G, Tang B. Nanoemulsion-based pseudopolyrotaxane hydrogel for enhanced corneal bioavailability and treatment of corneal inflammation. J Control Release 2025; 379:14-29. [PMID: 39756683 DOI: 10.1016/j.jconrel.2024.12.075] [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: 10/27/2024] [Revised: 12/10/2024] [Accepted: 12/29/2024] [Indexed: 01/07/2025]
Abstract
Corneal inflammation, a condition that can potentially lead to blindness, is often treated with topical eye drops. However, the limited ocular drug bioavailability of the eye drops necessitates frequent dosing. Herein, a nanoemulsion-based pseudopolyrotaxane hydrogel was fabricated to improve corneal bioavailability and thereby suppress inflammation. In this approach, dexamethasone was encapsulated into a nanoemulsion emulsified by Tween 80. The nanoemulsion was then mixed with γ-Cyclodextrin (γ-CD) aqueous solution to produce dexamethasone-loaded nanoemulsion-based pseudopolyrotaxane hydrogel (DEX-NPH) via host-guest interaction between Tween 80 and γ-CD. The hydrogel exhibited a shear-thinning and thixotropy character. In vitro drug release and hydrogel dissolution studies showed that drugs released from hydrogel predominantly in the form of nanoemulsion. The ocular surface fluorescence imaging and tear pharmacokinetics indicated that the hydrogel could significantly prolong precorneal residence time. The corneal pharmacokinetics suggested that DEX-NPH with 35 % γ-CD improved corneal bioavailability by 1.29-fold compared with nanoemulsion and by 4.09-fold compared with free drug solution. In particular, the precorneal retention capacity and corneal bioavailability could be adjusted by changing the γ-CD content in the hydrogel. Moreover, ocular irritation evaluation confirmed the excellent safety of such hydrogel. In an alkali burn-induced corneal inflammation model, the hydrogel exhibited a superior anti-inflammatory effect compared to nanoemulsion or free drug solution alone. In summary, the nanoemulsion-based pseudopolyrotaxane hydrogel is promising for enhancing corneal bioavailability and treating corneal inflammation.
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Affiliation(s)
- Guihua Fang
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Rongrong Zhao
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Lu Zhu
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Qiuxiang Wang
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Sifan Peng
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China
| | - Lihua Kang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Hong Lu
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Guowei Zhang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
| | - Bo Tang
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226001, China.
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Stinnett GS, Kuo CH, Ono SJ. Impact of inflammasomes on the ocular surface. Curr Opin Allergy Clin Immunol 2024; 24:368-374. [PMID: 38900843 PMCID: PMC11356675 DOI: 10.1097/aci.0000000000001004] [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] [Indexed: 06/22/2024]
Abstract
PURPOSE OF REVIEW The ocular surface is prone to inflammation due to exposure to environmental irritants and pathogens. Inflammasomes are intracellular, multiprotein complexes that communicate potentially dangerous signals to the immune system. The identification of inflammasomes in various inflammatory ocular surface conditions can aid in the development of therapeutics to treat these chronic inflammatory conditions. RECENT FINDINGS Several inflammasomes have been associated with ocular surface disorders including dry eye disease, keratitis, and allergies. Mechanisms for activation of these inflammasomes with regards to specific disorders have been explored in models to aid in the development of targeted treatments. SUMMARY Research efforts continue to characterize the types of inflammasomes and activators of these in inflammatory ocular surface conditions. Various therapies targeting specific inflammasome types or pyroptosis are being tested preclinically to assess effects on decreasing the associated chronic inflammation.
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Affiliation(s)
- Gwen S. Stinnett
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Chuan-Hui Kuo
- Department of Ophthalmology and Visual Sciences, Faculty of Medicine, Eye Care Centre, The University of British Columbia, Vancouver, BC, Canada
| | - Santa J. Ono
- Departments of Ophthalmology & Visual Science, Microbiology & Immunology and Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
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Ganugula R, Babalola KT, Heyns IM, Arora M, Agarwal SK, Mohan C, Kumar MNVR. Lymph node targeting of cyclosporine ameliorates ocular manifestations in a mouse model of systemic lupus erythematosus (SLE) via PD-L1. NANO TODAY 2024; 57:102359. [PMID: 38911970 PMCID: PMC11192230 DOI: 10.1016/j.nantod.2024.102359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/25/2024]
Abstract
One-third of systemic lupus erythematosus (SLE) patients experience various degrees of ocular manifestations, with immunosuppressants recommended as a treatment option. Targeted immune suppression via oral administration is challenging due to the harsh gastrointestinal tract environment combined with complex physiological barriers. Here, we report the efficacy of orally administered cyclosporine (CsA)-laden polymer nanoparticles decorated with the ligand - Gambogic Acid (P2Ns-GA-CsA) in sustained lymph node delivery. This is the first report demonstrating the CD71 specificity of P2Ns-GA-CsA in the CD71 knockout mouse model and the influence of spacer length in achieving target tissue bioavailability in a lupus mouse model. P2Ns-GA-CsA effectively regulates T-cell chemotaxis by PD-L1 at a 50 % lower dose compared to conventional CsA in a mouse model exhibiting lupus-associated corneal inflammation. Collectively, these results suggest the possibility for further development of P2Ns-GA to target a diverse range of lymphatic disorders.
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Affiliation(s)
- Raghu Ganugula
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL, USA
- Department of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL, USA
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL, USA
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA
| | - Kabirat T. Babalola
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL, USA
- Department of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL, USA
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL, USA
| | - Ingrid M. Heyns
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL, USA
- Department of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL, USA
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL, USA
| | - Meenakshi Arora
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL, USA
- Department of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL, USA
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL, USA
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA
| | - Sandeep. K. Agarwal
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
| | - Chandra Mohan
- Department of Biomedical Engineering, University of Houston, Houston, TX, USA
| | - M. N. V. Ravi Kumar
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL, USA
- Department of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL, USA
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL, USA
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA
- Chemical and Biological Engineering, University of Alabama, Tuscaloosa, AL, USA
- Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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Watson SL, Le DTM. Corneal neuropathic pain: a review to inform clinical practice. Eye (Lond) 2024; 38:2350-2358. [PMID: 38627548 PMCID: PMC11306374 DOI: 10.1038/s41433-024-03060-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/25/2024] [Accepted: 04/02/2024] [Indexed: 08/09/2024] Open
Abstract
Corneal neuropathic pain (CNP) is a poorly defined disease entity characterised by an aberrant pain response to normally non-painful stimuli and categorised into having peripheral and central mechanisms, with the former responding to instillation of topical anaesthetic. CNP is a challenging condition to diagnose due to numerous aetiologies, an absence of clinical signs and ancillary tests (in vivo confocal microscopy and esthesiometry), lacking the ability to confirm the diagnosis and having limited availability. Symptomatology maybe mirrored by severe and chronic forms of dry eye disease (DED), often leading to misdiagnosis and inadequate treatment. In practice, patients with suspected CNP can be assessed with questionnaires to elicit symptoms. A thorough ocular assessment is also performed to exclude any co-existent ocular conditions. A medical and mental health history should be sought due to associations with autoimmune disease, chronic pain syndromes, anxiety and depression. Management begins with communicating to the patient the nature of their condition. Ophthalmologists can prescribe topical therapies such as autologous serum eyedrops to optimise the ocular surface and promote neural regeneration. However, a multi-disciplinary treatment approach is often required, including mental health support, particularly when there are central mechanisms. General practitioners, pain specialists, neurologists and psychologists may be needed to assist with oral and behavioural therapies. Less data is available to support the safety and efficacy of adjuvant and surgical therapies and the long-term natural history remains to be determined. Hence clinical trials and registry studies are urgently needed to fill these data gaps with the aim to improve patient care.
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Affiliation(s)
- Stephanie L Watson
- The University of Sydney, Save Sight Institute, Faculty of Medicine and Health, Sydney, NSW, Australia.
- Sydney Eye Hospital, Sydney, NSW, Australia.
| | - Damien Tuan-Man Le
- The University of Sydney, Save Sight Institute, Faculty of Medicine and Health, Sydney, NSW, Australia
- Sydney Eye Hospital, Sydney, NSW, Australia
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Li S, Zhang P, Li A, Bao J, Pan Z, Jie Y. Rho-kinase inhibitor alleviates CD4 +T cell mediated corneal graft rejection by modulating its STAT3 and STAT5 activation. Exp Eye Res 2024; 242:109857. [PMID: 38479724 DOI: 10.1016/j.exer.2024.109857] [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: 07/30/2023] [Revised: 12/14/2023] [Accepted: 01/03/2024] [Indexed: 03/27/2024]
Abstract
Penetrating keratoplasty remains the most common treatment to restore vision for corneal diseases. Immune rejection after corneal transplantation is one of the major causes of graft failure. In recent years, Rho-associated protein kinase (ROCK) inhibitors have been found to be associated with the activation of the STATs pathway and are widely studied in autoimmune diseases. Therefore, it may be possible that the ROCK inhibitors also participate in the local and systemic immune regulation in corneal transplantation through activation of the STATs pathway and affect the CD4+ T cell differentiation. This study aimed to explore the role of ROCK-STATs pathway in the occurrence of immune rejection in corneal transplantation by applying Y27632, a ROCK inhibitor, to the recipient mice and peripheral CD4+ T cells. We found that Y27632 significantly up-regulated the phosphorylation level of STAT5 in both spleen and lymph nodes, down-regulated the phosphorylation level of STAT3 in the CD4+ T cells in the spleen. It also increased the proportion of CD4+CD25+Foxp3+Helios+ Tregs while decreased CD4+IL17A+ -Th17 cells. Moreover, Y27632 also reduced the proportion of dendritic cells in both spleen and lymph nodes, as well as the expression level of CD86 on their surfaces in the spleen, while the proportion of macrophages was not affected. The expression levels of ROCK1, ROCK2, CD11c and IL-17A mRNA were also found to be low in the graft tissue while the expression of Helios was upregulated. Rho-kinase inhibitor can modulate the balance of Tregs/Th17 by regulating the phosphorylation levels of both STAT3 and STAT5, thereby inhibiting the occurrence of immune rejection in allogeneic corneal transplantation.
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Affiliation(s)
- Shang Li
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Lab, Beijing, China
| | - Peng Zhang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Lab, Beijing, China
| | - Ao Li
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Lab, Beijing, China
| | - Jiayu Bao
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Lab, Beijing, China
| | - Zhiqiang Pan
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Lab, Beijing, China
| | - Ying Jie
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Lab, Beijing, China.
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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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Zheng N, Zhu SQ. Randomized controlled trial on the efficacy and safety of autologous serum eye drops in dry eye syndrome. World J Clin Cases 2023; 11:6774-6781. [PMID: 37901024 PMCID: PMC10600870 DOI: 10.12998/wjcc.v11.i28.6774] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/31/2023] [Accepted: 09/14/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND Autologous serum eye drops (ASEDs), a novel treatment derived from blood serum, have emerged as a groundbreaking solution for managing dry eye syndrome (DES). These drops have shown significant promise in relieving the distressing symptoms of DES. This study aimed to evaluate the safety and effectiveness of ASEDs compared to traditional treatments, which often prove inadequate or result in unwanted side effects, particularly in individuals with moderate-to-severe DES. AIM To evaluate whether ASEDs are safer and more effective than conventional artificial tears in the treatment of moderate-to-severe DES. METHODS This multi-centered randomized controlled trial included 240 patients with moderate-to-severe DES from three ophthalmology clinics in China. They were randomly assigned to receive either ASEDs or artificial tears for 12 wk. The primary outcome was the change in the ocular surface disease index (OSDI) score, with secondary outcomes including tear break-up time (TBUT), Schirmer I test, corneal fluorescein staining (CFS), and conjunctival impression cytology (CIC). Statistics analysis was performed using an analysis of covariance with adjustments made for baseline values. RESULTS Our findings revealed that both ASEDs and artificial tears significantly improved the OSDI score, TBUT, Schirmer I test, CFS, and CIC from baseline to week 12. The ASEDs group showed significantly greater improvement in all these measures than the artificial tears group (all P values < 0.05). The average difference in the OSDI score between the two cohorts was -10.3 (95% confidence interval: -13.6 to -7.0), indicating a substantial improvement in the ASEDs group. The occurrence of adverse events was comparable between cohorts, with no reports of severe adverse events. CONCLUSION ASEDs are more effective and safer than artificial tears for mitigating symptoms of moderate-to-severe DES. ASEDs could be an alternative/supplementary therapy for patients with DES less responsive to traditional treatments.
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Affiliation(s)
- Na Zheng
- Department of Ophthalmology, Chengdu University of Traditional Chinese Medicine, Chengdu 610032, Sichuan Province, China
| | - Si-Quan Zhu
- Department of Ophthalmology, Beijing Anzhen Hospital Affiliated to China Medical University, Beijing 100029, China
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Tajbakhsh Z, Golebiowski B, Stapleton F, Alghamdi A, Gray PE, Altavilla B, Briggs N, Jalbert I. Increased dendritic cell density and altered morphology in allergic conjunctivitis. Eye (Lond) 2023; 37:2896-2904. [PMID: 36747109 PMCID: PMC10516863 DOI: 10.1038/s41433-023-02426-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Corneal and conjunctival epithelial dendritic cells (DC) have an established role in vernal keratoconjunctivitis, however, their role in more prevalent forms of allergic eye disease remains unclear. This study evaluated corneal and conjunctival epithelial DC density, morphology, and distribution observed using in vivo confocal microscopy (IVCM) in allergic conjunctivitis. METHODS In this prospective, observational study, 66 participants (mean age 36.6 ± 12.0 years, 56% female): 33 with allergic conjunctivitis and 33 controls were recruited. IVCM was performed at the corneal centre, inferior whorl, corneal periphery, corneal limbus, and temporal bulbar conjunctiva. DC were counted and their morphology was assessed as follows: largest cell body size, presence of dendrites, and presence of long and thick dendrites. Mixed model analysis (DC density) and non-parametric tests (DC morphology) were used. RESULTS DC density was higher in allergic participants at all locations (p ≤ 0.01), (corneal centre median (IQR) 21.9 (8.7-50.9) cells/mm2 vs 13.1 (2.8-22.8) cells/mm2; periphery 37.5 (15.6-67.2) cells/mm2 vs 20 (9.4-32.5) cells/mm2; limbus 75 (60-120) cells/mm2 vs 58.1 (44.4-66.2) cells/mm2; conjunctiva 10 (0-54.4) cells/mm2 vs 0.6 (0-5.6) cells/mm2, but not at the inferior whorl 21.9 (6.2-34.4) cells/mm2 vs 12.5 (1.9-37.5) cells/mm2, p = 0.20. At the corneal centre, allergic participants had larger DC bodies (p = 0.02), a higher proportion of DC with dendrites (p = 0.02) and long dendrites (p = 0.003) compared to controls. CONCLUSIONS Corneal and conjunctival DC density was increased, and morphology altered in allergic conjunctivitis. These findings imply that the ocular surface immune response was upregulated and support an increased antigen-capture capacity of DC in allergic conjunctivitis.
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Affiliation(s)
- Zahra Tajbakhsh
- School of Optometry and Vision Science, UNSW, Sydney, NSW, Australia.
| | | | - Fiona Stapleton
- School of Optometry and Vision Science, UNSW, Sydney, NSW, Australia
| | - Ali Alghamdi
- School of Optometry and Vision Science, UNSW, Sydney, NSW, Australia
| | - Paul E Gray
- Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, NSW, Australia
| | - Betina Altavilla
- Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, NSW, Australia
| | - Nancy Briggs
- Stats Central, Mark Wainwright Analytical Centre, UNSW, Sydney, NSW, Australia
| | - Isabelle Jalbert
- School of Optometry and Vision Science, UNSW, Sydney, NSW, Australia
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12
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Blanco T, Singh RB, Nakagawa H, Taketani Y, Dohlman TH, Chen Y, Chauhan SK, Yin J, Dana R. Conventional type I migratory CD103 + dendritic cells are required for corneal allograft survival. Mucosal Immunol 2023; 16:711-726. [PMID: 36642378 PMCID: PMC10413378 DOI: 10.1016/j.mucimm.2022.12.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 12/14/2022] [Indexed: 01/15/2023]
Abstract
Corneal transplant rejection primarily occurs because of the T helper 1 (Th1) effector cell-mediated immune response of the host towards allogeneic tissue. The evidence suggests that type 1 migratory conventional CD103+ dendritic cells (CD103+DC1) acquire an immunosuppressive phenotype in the tumor environment; however, the involvement of CD103+DC1 in allograft survival continues to be an elusive question of great clinical significance in tissue transplantation. In this study, we assess the role of CD103+DC1 in suppressing Th1 alloreactivity against transplanted corneal allografts. The immunosuppressive function of CD103+DC1 has been extensively studied in non-transplantation settings. We found that host CD103+DC1 infiltrates the corneal graft and migrates to the draining lymph nodes to suppress alloreactive CD4+ Th1 cells via the programmed death-ligand 1 axis. The systemic depletion of CD103+ DC1 in allograft recipients leads to amplified Th1 activation, impaired Treg function, and increased rate of allograft rejection. Although allograft recipient Rag1 null mice reconstituted with naïve CD4+CD25- T cells efficiently generated peripheral Treg cells (pTreg), the CD103+DC1-depleted mice failed to generate pTreg. Furthermore, adoptive transfer of pTreg failed to rescue allografts in CD103+DC1-depleted recipients from rejection. These data demonstrate the critical role of CD103+DC1 in regulating host alloimmune responses.
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Affiliation(s)
- Tomas Blanco
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, 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, 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, USA
| | - Yukako Taketani
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, 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, 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, USA
| | - Sunil K Chauhan
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, USA
| | - Jia Yin
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, 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, USA.
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13
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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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14
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Perez VL, Mah FS, Willcox M, Pflugfelder S. Anti-Inflammatories in the Treatment of Dry Eye Disease: A Review. J Ocul Pharmacol Ther 2023; 39:89-101. [PMID: 36796014 DOI: 10.1089/jop.2022.0133] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023] Open
Abstract
Inflammation is an important driver of dry eye disease (DED) pathogenesis. An initial insult that results in the loss of tear film homeostasis can initiate a nonspecific innate immune response that leads to a chronic and self-sustaining inflammation of the ocular surface, which results in classic symptoms of dry eye. This initial response is followed by a more prolonged adaptive immune response, which can perpetuate and aggravate inflammation and result in a vicious cycle of chronic inflammatory DED. Effective anti-inflammatory therapies can help patients exit this cycle, and effective diagnosis of inflammatory DED and selection of the most appropriate treatment are therefore key to successful DED management and treatment. This review explores the cellular and molecular mechanisms of the immune and inflammatory components of DED, and examines the evidence base for the use of currently available topical treatment options. These agents include topical steroid therapy, calcineurin inhibitors, T cell integrin antagonists, antibiotics, autologous serum/plasma therapy, and omega-3 fatty acid dietary supplements.
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Affiliation(s)
- Victor L Perez
- Department of Ophthalmology, Foster Center for Ocular Immunology at Duke Eye Center, Duke University School of Medicine, Durham, North Carolina. USA
| | - Francis S Mah
- Scripps Clinic Torrey Pines, La Jolla, California, USA
| | - Mark Willcox
- School of Optometry and Vision Science, UNSW Sydney, Sydney, New South Wales, Australia
| | - Stephen Pflugfelder
- Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA
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15
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Tajbakhsh Z, Jalbert I, Stapleton F, Briggs N, Golebiowski B. Diurnal changes and topographical distribution of ocular surface epithelial dendritic cells in humans, and repeatability of density and morphology assessment. Ophthalmic Physiol Opt 2023; 43:273-283. [PMID: 36592129 PMCID: PMC10108257 DOI: 10.1111/opo.13087] [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: 05/22/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 01/03/2023]
Abstract
PURPOSE Dendritic cells (DC) play a crucial role in ocular surface defence. DC can be visualised in vivo by confocal microscopy but have not yet been fully characterised in humans. This study investigated the diurnal variation, topographical distribution and repeatability of DC density and morphology measurements. METHODS In vivo confocal microscopy (IVCM) was conducted on 20 healthy participants (mean age 32.7 ± 6.4 years, 50% female) at baseline and repeated after 30 minutes, 2, 6 and 24 h. Images were captured at the corneal centre, inferior whorl, corneal periphery, limbus and bulbar conjunctiva. DC were counted manually, and their morphology was assessed for cell body size, presence of dendrites, and presence of long and thick dendrites. Mixed-model analysis, non-parametric analyses, Bland and Altman plots, coefficient of repeatability (CoR) and kappa were used. RESULTS There were no significant changes in DC density (p ≥ 0.74) or morphology (p > 0.07) at any location over the 24-h period. The highest DC density was observed at the corneal limbus followed by the peripheral cornea (p < 0.001), with the lowest density at the corneal centre, inferior whorl and bulbar conjunctiva. Most DC at the corneal periphery, limbus and bulbar conjunctiva had larger cell bodies compared with the corneal centre (p ≤ 0.01), and the presence of long dendrites was observed mostly at non-central locations. Day-to-day CoR for DC density ranged from ±28.1 cells/mm2 at the corneal centre to ±56.4 cells/mm2 at the limbus. Day-to-day agreement of DC morphology determined by kappa ranged from 0.5 to 0.95 for cell body size, 0.60 to 0.95 for presence of dendrites, and 0.55 to 0.80 for the presence of long dendrites at various locations. CONCLUSIONS No diurnal changes are apparent in corneal or conjunctival DC. Substantial topographical differences exist in DC density and morphology. IVCM provides good repeatability of DC density and acceptable agreement of DC morphology.
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Affiliation(s)
- Zahra Tajbakhsh
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
| | - Isabelle Jalbert
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
| | - Fiona Stapleton
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
| | - Nancy Briggs
- Stats Central, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia
| | - Blanka Golebiowski
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
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16
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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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17
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Şimşek C, Kaya C, Karalezli A. Evaluation of Corneal Alterations After Short-Term Silicone Hydrogel Contact Lens Use by Confocal Microscopy. Turk J Ophthalmol 2022; 52:386-393. [PMID: 36578196 PMCID: PMC9811230 DOI: 10.4274/tjo.galenos.2021.27163] [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: 05/21/2021] [Accepted: 12/09/2021] [Indexed: 01/13/2023] Open
Abstract
Objectives To evaluate the corneal subbasal nerve morphology, corneal sensitivity, and anterior segment alterations in short-term silicone hydrogel contact lens (SiHCL) users by confocal microscopy. Materials and Methods The study included 25 right eyes of 25 male volunteers aged 25-30 years who had never used SiHCLs before. ocular surface disease index (OSDI), tear break-up time, Schirmer test, tear meniscus area, strip meniscometry tube, corneal sensitivity, and corneal subbasal nerve morphology were evaluated before and after 1 month of CL use. Results OSDI was 10.6±1.1 before CL use and 17.2±1.2 after 1 month of CL use (p<0.01). Schirmer test distance was 16.3±2.3 mm before and 14.3±1.9 mm after 1 month of CL use (p>0.05). Tear film break-up time was 7.1±0.4 s before and 6.2±0.3 s after CL use (p>0.05). The tear meniscus area was 0.026±0.002 mm2 before and 0.024±0.001 mm2 after 1 month of CL use (p>0.05). Strip meniscometry tube results were 5.4±0.9 mm before and 4.9±0.8 mm after 1 month of CL use (p>0.05). Corneal sensitivity values were 3.2±0.4 mm before and 2.95±0.3 mm after 1 month of CL use (p>0.05). Dendritic cell density evaluated by confocal microscopy was 14.84±3.1 cells/mm2 before and 32.57±4.2 cells/mm2 after 1 month of CL use (p<0.01). Subbasal nerve tortuosity was 0.92±0.2 before and 1.03±0.2 after 1 month of CL use (p>0.05). Subbasal nerve density was measured as 4726±310 pixels/frame before and 4570±272 pixels/frame after 1 month of CL use (p>0.05). Conclusion After a month of SiHCL use, no significant changes were observed in tear secretion, corneal sensitivity, tear meniscus volume, subbasal corneal nerve density, reflectivity, or tortuosity, while a significant increase was found in OSDI and dendritic cell density.
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Affiliation(s)
- Cem Şimşek
- Muğla Sıtkı Koçman University Faculty of Medicine, Department of Ophthalmology, Muğla, Turkey
| | - Cansu Kaya
- Muğla Sıtkı Koçman University Faculty of Medicine, Department of Ophthalmology, Muğla, Turkey
| | - Aylin Karalezli
- Muğla Sıtkı Koçman University Faculty of Medicine, Department of Ophthalmology, Muğla, Turkey
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Mesenchymal Stromal Cells-Derived Extracellular Vesicles Regulate Dendritic Cell Functions in Dry Eye Disease. Cells 2022; 12:cells12010033. [PMID: 36611828 PMCID: PMC9818747 DOI: 10.3390/cells12010033] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/11/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
We explored the therapeutic efficacy of Mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) and its inhibition of the functions of dendritic cells (DCs) in dry eye disease (DED). MSC-EVs were isolated from the culture supernatants of mesenchymal stromal cells (MSCs) and characterized. In vitro, human corneal epithelial cells (HCECs) were cultured in hyperosmotic medium to simulate the DED hyperosmotic environment and treated with MSC-EVs. Cell viability was assessed, and the expression of inflammatory cytokines was quantified. Next, we induced DED in female C57BL/6 mice and divided the mice into groups treated with either MSC-EVs or phosphate buffer solution (PBS) eye drops. Disease severity was assessed; mRNA expression of inflammatory cytokines was analyzed by RT-PCR; and Th17 cells were detected by flow cytometry. Lastly, we evaluated DCs by immunofluorescence and flow cytometric analysis to assess its amounts and maturation. MSC-EVs showed protective effects on HCECs under hyperosmotic stress in vitro, suppressing the expression of inflammatory cytokines. In vivo, mice topically treated with MSC-Evs presented reduced DED disease severity compared to PBS-treated mice. MSC-Evs downregulated the expression of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, as well as the frequency of Th17 cells. Further investigation showed that MSC-EVs suppressed the increase of amounts and the maturation of DCs in DED. Changes of morphological characters of DCs were also inhibited by MSC-EVs. Our study revealed that MSC-EVs suppressed ocular surface inflammation by inhibiting DCs activation-mediated Th17 immune responses, explicating the therapeutic potential of MSC-EVs in DED and other ocular surface diseases.
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Local and Systemic Injections of Human Cord Blood Myeloid-Derived Suppressor Cells to Prevent Graft Rejection in Corneal Transplantation. Biomedicines 2022; 10:biomedicines10123223. [PMID: 36551981 PMCID: PMC9776015 DOI: 10.3390/biomedicines10123223] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are therapeutic agents to prevent graft rejection in organ transplants by modulating inflammation. Herein, the immunosuppressive effect of human cord blood MDSCs on corneal allograft models was confirmed. CB-MDSCs were locally (subconjuctival, 5 × 105) or systemically (intravenous, 1 × 106) injected twice on days 0 and 7. A corneal transplantation model was established using C57BL/6 and BALB/c mice, and corneal graft opacity was measured to evaluate graft rejection up to 6 weeks. Results showed that graft survival in the MDSCs groups increased compared to vehicle groups after 42 days. Systemic and local MDSC administration inhibited the maturation (MHC-IIhi CD11c+) of dendritic cells (DCs) and the differentiation of interferon γ+ CD4+ Th1 in draining lymph nodes (LNs). However, vehicle groups increased the infiltration of CD3+ T cells and F4/80+ macrophages and produced prominent neovascular and lymphatic vessels into the graft site with increased mRNA expression of VEGF-A/C and VEGFR-1/R-3. Local MDSCs administration showed prominent anti-angiogenic/anti-lymphangiogenic effects even at lower MDSCs doses. Thus, CB-MDSCs could relatively suppress the infiltration of pathological T cells/macrophages into the corneas and the migration of mature DCs into draining LNs Therefore, ocular and systemic MDSCs administration showed therapeutic potential for preventing corneal allograft rejection.
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20
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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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21
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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: 43] [Impact Index Per Article: 14.3] [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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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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23
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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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24
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Immunology and Donor-Specific Antibodies in Corneal Transplantation. Arch Immunol Ther Exp (Warsz) 2021; 69:32. [PMID: 34741683 PMCID: PMC8572187 DOI: 10.1007/s00005-021-00636-3] [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: 07/09/2021] [Accepted: 09/01/2021] [Indexed: 11/08/2022]
Abstract
The first human corneal transplantation was performed in 1905 by Eduard Zirm in the Olomouc Eye Clinic, now Czech Republic. However, despite great advancements in microsurgical eye procedures, penetrating keratoplasty in high-risk patients (e.g., vascularized or inflamed corneal tissue, consecutive transplants) remains a challenge. The difficulty is mainly due to the risk of irreversible allograft rejection, as an ocular immune privilege in these patients is abolished and graft rejection is the main cause of corneal graft failure. Therefore, tailored immunosuppressive treatment based on immunological monitoring [e.g., donor-specific antibodies (DSA)] is considered one of the best strategies to prevent rejection in transplant recipients. Although there is indirect evidence on the mechanisms underlying antibody-mediated rejection, the impact of DSA on cornea transplantation remains unknown. Determining the role of pre-existing and/or de novo DSA could advance our understanding of corneal graft rejection mechanisms. This may help stratify the immunological risk of rejection, ultimately leading to personalized treatment for this group of transplant recipients.
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25
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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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26
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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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27
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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: 41] [Impact Index Per Article: 10.3] [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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28
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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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29
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Baiula M, Spampinato S. Experimental Pharmacotherapy for Dry Eye Disease: A Review. J Exp Pharmacol 2021; 13:345-358. [PMID: 33790661 PMCID: PMC8001578 DOI: 10.2147/jep.s237487] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/11/2021] [Indexed: 01/22/2023] Open
Abstract
Dry eye disease (DED) is a complex multifactorial disease showing heterogenous symptoms, including dryness, photophobia, ocular discomfort, irritation and burning but also pain. These symptoms can affect visual function leading to restrictions in daily life activities and reduction in work productivity with a consequently high impact on quality of life. Several pathological mechanisms contribute to the disease: evaporative water loss leads to impairment and loss of tear homeostasis inducing either directly or indirectly to inflammation, in a self-perpetuating vicious cycle. Dysregulated ocular immune responses result in ocular surface damage, which further contributes to DED pathogenesis. Currently, DED treatment is based on a flexible stepwise approach to identify the most beneficial intervention. Although most of the available treatments may control to a certain extent some signs and symptoms of DED, they show significant limitations and do not completely address the needs of patients suffering from DED. This review provides an overview of the emerging experimental therapies for DED. Several promising therapeutic strategies are under development with the aim of dampening inflammation and restoring the homeostasis of the ocular surface microenvironment. Results from early phase clinical trials, testing the effects of EnaC blockers, TRPM8 agonist or mesenchymal stem cells in DED patients, are especially awaited to demonstrate their therapeutic value for the treatment of DED. Moreover, the most advanced experimental strategies in the pipeline for DED, tivanisiran, IL-1R antagonist EBI-005 and SkQ1, are being tested in Phase III clinical trials, still ongoing. Nevertheless, although promising results, further studies are still needed to confirm efficacy and safety of the new emerging therapies for DED.
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Affiliation(s)
- Monica Baiula
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Santi Spampinato
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
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30
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Guérin LP, Le-Bel G, Desjardins P, Couture C, Gillard E, Boisselier É, Bazin R, Germain L, Guérin SL. The Human Tissue-Engineered Cornea (hTEC): Recent Progress. Int J Mol Sci 2021; 22:ijms22031291. [PMID: 33525484 PMCID: PMC7865732 DOI: 10.3390/ijms22031291] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Each day, about 2000 U.S. workers have a job-related eye injury requiring medical treatment. Corneal diseases are the fifth cause of blindness worldwide. Most of these diseases can be cured using one form or another of corneal transplantation, which is the most successful transplantation in humans. In 2012, it was estimated that 12.7 million people were waiting for a corneal transplantation worldwide. Unfortunately, only 1 in 70 patients received a corneal graft that same year. In order to provide alternatives to the shortage of graftable corneas, considerable progress has been achieved in the development of living corneal substitutes produced by tissue engineering and designed to mimic their in vivo counterpart in terms of cell phenotype and tissue architecture. Most of these substitutes use synthetic biomaterials combined with immortalized cells, which makes them dissimilar from the native cornea. However, studies have emerged that describe the production of tridimensional (3D) tissue-engineered corneas using untransformed human corneal epithelial cells grown on a totally natural stroma synthesized by living corneal fibroblasts, that also show appropriate histology and expression of both extracellular matrix (ECM) components and integrins. This review highlights contributions from laboratories working on the production of human tissue-engineered corneas (hTECs) as future substitutes for grafting purposes. It overviews alternative models to the grafting of cadaveric corneas where cell organization is provided by the substrate, and then focuses on their 3D counterparts that are closer to the native human corneal architecture because of their tissue development and cell arrangement properties. These completely biological hTECs are therefore very promising as models that may help understand many aspects of the molecular and cellular mechanistic response of the cornea toward different types of diseases or wounds, as well as assist in the development of novel drugs that might be promising for therapeutic purposes.
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Affiliation(s)
- Louis-Philippe Guérin
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Gaëtan Le-Bel
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Pascale Desjardins
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Camille Couture
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Elodie Gillard
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Élodie Boisselier
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Richard Bazin
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Lucie Germain
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Sylvain L. Guérin
- CUO-Recherche, Médecine Régénératrice—Centre de Recherche du CHU de Québec, Université Laval, Québec, QC G1S 4L8, Canada; (L.-P.G.); (G.L.-B.); (P.D.); (C.C.); (E.G.); (É.B.); (R.B.); (L.G.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Correspondence: ; Tel.: +1-418-682-7565
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Singh RB, Marmalidou A, Amouzegar A, Chen Y, Dana R. Animal models of high-risk corneal transplantation: A comprehensive review. Exp Eye Res 2020; 198:108152. [PMID: 32721424 PMCID: PMC7508940 DOI: 10.1016/j.exer.2020.108152] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 07/05/2020] [Accepted: 07/15/2020] [Indexed: 12/16/2022]
Abstract
Over the past century, corneal transplantation has become the most commonly performed allogeneic solid tissue transplantation. Although more than 80% of the corneal transplantations have favorable outcomes, immune-mediated rejection continues to be the major cause of failure in well over 50% of graft recipients that have inflamed and vascularized host beds. Over the past two decades, the progress in our understanding of the immunological pathways that mediate graft rejection has aided in the development of novel therapeutic strategies. In order to successfully test the efficacy of these interventions, it is essential to model the immunological processes occurring as a consequence of corneal transplantation. Herein, we have comprehensively reviewed the established animal models used for replicating the immunopathological processes causing graft rejection in high-risk corneal transplantation settings. We have also discussed the practical and technical differences, as well as biological and immunological variations in different animal models.
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Affiliation(s)
- Rohan Bir Singh
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Anna Marmalidou
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Afsaneh Amouzegar
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA; Department of Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yihe Chen
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
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32
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Jamali A, Kenyon B, Ortiz G, Abou-Slaybi A, Sendra VG, Harris DL, Hamrah P. Plasmacytoid dendritic cells in the eye. Prog Retin Eye Res 2020; 80:100877. [PMID: 32717378 DOI: 10.1016/j.preteyeres.2020.100877] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/28/2020] [Accepted: 06/05/2020] [Indexed: 02/07/2023]
Abstract
Plasmacytoid dendritic cells (pDCs) are a unique subpopulation of immune cells, distinct from classical dendritic cells. pDCs are generated in the bone marrow and following development, they typically home to secondary lymphoid tissues. While peripheral tissues are generally devoid of pDCs during steady state, few tissues, including the lung, kidney, vagina, and in particular ocular tissues harbor resident pDCs. pDCs were originally appreciated for their potential to produce large quantities of type I interferons in viral immunity. Subsequent studies have now unraveled their pivotal role in mediating immune responses, in particular in the induction of tolerance. In this review, we summarize our current knowledge on pDCs in ocular tissues in both mice and humans, in particular in the cornea, limbus, conjunctiva, choroid, retina, and lacrimal gland. Further, we will review our current understanding on the significance of pDCs in ameliorating inflammatory responses during herpes simplex virus keratitis, sterile inflammation, and corneal transplantation. Moreover, we describe their novel and pivotal neuroprotective role, their key function in preserving corneal angiogenic privilege, as well as their potential application as a cell-based therapy for ocular diseases.
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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
| | - Brendan Kenyon
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, 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
| | - Abdo Abou-Slaybi
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Program in Immunology, Graduate School of Biomedical Sciences, Tufts University, 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
| | - 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
| | - 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; Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA; Program in Immunology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, USA; Cornea Service, Tufts New England Eye Center, Boston, MA, USA.
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Correlation of corneal immune cell changes with clinical severity in dry eye disease: An in vivo confocal microscopy study. Ocul Surf 2020; 19:183-189. [PMID: 32504855 DOI: 10.1016/j.jtos.2020.05.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 04/17/2020] [Accepted: 05/26/2020] [Indexed: 11/20/2022]
Abstract
PURPOSE To evaluate corneal immune dendritiform cell (DC) changes in dry eye disease (DED) using in vivo confocal microscopy (IVCM) and to correlate IVCM parameters with clinical severity. METHODS This was a retrospective, cross-sectional study including 300 eyes of 150 DED patients and 49 eyes of 49 age-matched controls. Severity of DED was based on the Dry Eye Workshop (DEWS) classification. IVCM images of subbasal layer of the central cornea were analyzed for DC density and morphology (including number of dendrites per DC, DC size and DC field). RESULTS DC density was significantly higher in DED compared to controls (93.4 ± 6.3 vs. 25.9 ± 3.9 cells/mm2; P < 0.001). Morphologically, number of dendrites, DC size and field were significantly larger in DED (3.3 ± 0.1, 106.9 ± 4.7 μm2, 403.8 ± 20.1 μm2 than controls (2.3 ± 0.1, 62.5 ± 5.7 μm2, 241.4 ± 24.4 μm2, P < 0.001). Significantly higher DC density compared to controls was observed as early as Level 1 DED severity (87 ± 10 cells/mm2, p < 0.001. Significant morphological changes in DC were detected for Levels 2 to 4 (p=<0.001, and p =< 0.05) for dendrites and DC field, respectively. Similarly, DC size showed significant increase at DED level 3-4. (p < 0.05). Linear regression analysis showed that both conjunctival and corneal staining were independently associated with DC density, while corneal staining was independently associated with DC morphology. CONCLUSION DC density and morphology correlated with clinical severity of DED. While, DC density is increased in mild DED, morphological changes are seen only in severe cases. IVCM may be a powerful tool to detect early immune changes and may complement clinical examination in DED.
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Jamali A, Seyed-Razavi Y, Chao C, Ortiz G, Kenyon B, Blanco T, Harris DL, Hamrah P. Intravital Multiphoton Microscopy of the Ocular Surface: Alterations in Conventional Dendritic Cell Morphology and Kinetics in Dry Eye Disease. Front Immunol 2020; 11:742. [PMID: 32457740 PMCID: PMC7227427 DOI: 10.3389/fimmu.2020.00742] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 04/01/2020] [Indexed: 01/07/2023] Open
Abstract
Dry eye disease (DED) is a multifactorial disease of the ocular surface, characterized by loss of tear film homeostasis and ocular symptoms, in which neurosensory abnormalities have recently been shown to play an etiological role. Although the role of inflammation has been widely studied in DED, the kinetics of immune cells of the ocular surface in this complex disease are hereto unclear. Herein, we utilized intravital multiphoton imaging on transgenic mice to investigate the 3D morphology and kinetics of conventional dendritic cells (cDCs) and the role of ocular surface sensory nerves in regulating them in both the naïve state and experimental DED. Mice with DED had significantly lower tear secretion (p < 0.01), greater corneal fluorescein staining (p < 0.001), and higher cDC density in the ocular surface (p < 0.05), compared to naïve mice. cDCs in DED mice showed morphological alterations in the limbus, exhibiting smaller surface area (p < 0.001) and volume (p < 0.001) compared to naïve mice. Furthermore, corneal cDCs showed greater sphericity in DED mice compared to naïve mice (p < 0.01). In addition, limbal cDCs displayed significantly increased migratory kinetics in DED, including mean track speed, 3D instantaneous velocity, track length, and displacement, compared to naïve mice (all p < 0.05). In mice with DED, cDCs showed a higher meandering index in the limbus compared to central cornea (p < 0.05). In DED, cDCs were less frequently found in contact with nerves in the limbus, peripheral, and central cornea (p < 0.05). cDCs in contact with nerves demonstrated a larger surface area (p < 0.001) and volume (p < 0.001), however, they exhibited less sphericity (p < 0.05) as compared to cDCs not in contact with nerves in naïve mice. Importantly, cDCs in contact with nerves during DED had a decreased track length, displacement, mean track speed, and 3D instantaneous velocity compared to those not in contact with nerves (all p < 0.05). Taken together, we present in vivo evidence of altered cDC kinetics and 3D morphology in DED. Furthermore, apparent neuronal contact significantly alters cDC kinetics and morphological characteristics, suggesting that ocular surface nerves may play a direct role in mediating immune responses in DED.
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Affiliation(s)
- Arsia Jamali
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Yashar Seyed-Razavi
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Cecilia Chao
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Gustavo Ortiz
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Brendan Kenyon
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Program in Neuroscience, School of Graduate Biomedical Sciences, Tufts University, Boston, MA, United States
| | - Tomas Blanco
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Deshea L Harris
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Program in Neuroscience, School of Graduate Biomedical Sciences, Tufts University, Boston, MA, United States.,Program in Immunology, School of Graduate Biomedical Sciences, Tufts University, Boston, MA, United States
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35
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Jiao H, Downie LE, Huang X, Wu M, Oberrauch S, Keenan RJ, Jacobson LH, Chinnery HR. Novel alterations in corneal neuroimmune phenotypes in mice with central nervous system tauopathy. J Neuroinflammation 2020; 17:136. [PMID: 32345316 PMCID: PMC7189727 DOI: 10.1186/s12974-020-01803-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 04/03/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tauopathy in the central nervous system (CNS) is a histopathological hallmark of frontotemporal dementia (FTD) and Alzheimer's disease (AD). Although AD is accompanied by various ocular changes, the effects of tauopathy on the integrity of the cornea, which is densely innervated by the peripheral nervous system and is populated by resident dendritic cells, is still unknown. The aim of this study was to investigate if neuroimmune interactions in the cornea are affected by CNS tauopathy. METHODS Corneas from wild type (WT) and transgenic rTg4510 mice that express the P301L tau mutation were examined at 2, 6, 8, and 11 months. Clinical assessment of the anterior segment of the eye was performed using spectral domain optical coherence tomography. The density of the corneal epithelial sensory nerves and the number and field area of resident epithelial dendritic cells were assessed using immunofluorescence. The immunological activation state of corneal and splenic dendritic cells was examined using flow cytometry and compared between the two genotypes at 9 months of age. RESULTS Compared to age-matched WT mice, rTg4510 mice had a significantly lower density of corneal nerve axons at both 8 and 11 months of age. Corneal nerves in rTg4510 mice also displayed a higher percentage of beaded nerve axons and a lower density of epithelial dendritic cells compared to WT mice. From 6 months of age, the size of the corneal dendritic cells was significantly smaller in rTg4510 compared to WT mice. Phenotypic characterization by flow cytometry demonstrated an activated state of dendritic cells (CD86+ and CD45+ CD11b+CD11c+) in the corneas of rTg4510 compared to WT mice, with no distinct changes in the spleen monocytes/dendritic cells. At 2 months of age, there were no significant differences in the neural or immune structures between the two genotypes. CONCLUSIONS Corneal sensory nerves and epithelial dendritic cells were altered in the rTg4510 mouse model of tauopathy, with temporal changes observed with aging. The activation of corneal dendritic cells prior to the gradual loss of neighboring sensory nerves suggests an early involvement of corneal immune cells in tau-associated pathology originating in the CNS.
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Affiliation(s)
- Haihan Jiao
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Australia
| | - Laura E Downie
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Australia
| | - Xin Huang
- Innate Phagocytosis Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
| | - Mengliang Wu
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Australia
| | - Sara Oberrauch
- Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Australia.,Sleep and Cognition Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
| | - Ryan J Keenan
- Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Australia.,Sleep and Cognition Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, Australia
| | - Laura H Jacobson
- Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Australia. .,Sleep and Cognition Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, Australia.
| | - Holly R Chinnery
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Australia.
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36
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Periman LM, Perez VL, Saban DR, Lin MC, Neri P. The Immunological Basis of Dry Eye Disease and Current Topical Treatment Options. J Ocul Pharmacol Ther 2020; 36:137-146. [PMID: 32175799 PMCID: PMC7175622 DOI: 10.1089/jop.2019.0060] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 12/29/2019] [Indexed: 12/13/2022] Open
Abstract
Homeostasis of the lacrimal functional unit is needed to ensure a well-regulated ocular immune response comprising innate and adaptive phases. When the ocular immune system is excessively stimulated and/or immunoregulatory mechanisms are disrupted, the balance between innate and adaptive phases is dysregulated and chronic ocular surface inflammation can result, leading to chronic dry eye disease (DED). According to the Tear Film and Ocular Surface Society Dry Eye Workshop II definition, DED is a multifactorial disorder of the ocular surface characterized by impairment and loss of tear homeostasis (hyperosmolarity), ocular discomfort or pain, and neurosensory abnormalities. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology. Several therapeutics are available to break the vicious circle of DED and prevent chronic disease and progression, including immunosuppressive agents (steroids) and immunomodulators (cyclosporine and lifitegrast). Given the chronic inflammatory nature of DED, each of these agents is commonly used in clinical practice. In this study, we review the immunopathology of DED and the molecular and cellular actions of current topical DED therapeutics to inform clinical decision making.
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Affiliation(s)
| | - Victor L. Perez
- Duke Eye Center, Duke University School of Medicine, Durham, North Carolina
| | - Daniel R. Saban
- Duke Eye Center, Duke University School of Medicine, Durham, North Carolina
| | - Meng C. Lin
- School of Optometry, Clinical Research Center, University of California, Berkeley, California
| | - Piergiorgio Neri
- The Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
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Kalogeropoulos D, Papoudou-Bai A, Lane M, Goussia A, Charchanti A, Moschos MM, Kanavaros P, Kalogeropoulos C. Antigen-presenting cells in ocular surface diseases. Int Ophthalmol 2020; 40:1603-1618. [PMID: 32107692 DOI: 10.1007/s10792-020-01329-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 02/18/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE To review the role of antigen-presenting cells (APC) in the pathogenesis of ocular surface diseases (OSD). METHODS A thorough literature search was performed in PubMed database. An additional search was made in Google Scholar to complete the collected items. RESULTS APCs have the ability to initiate and direct immune responses and are found in most lymphoid and non-lymphoid tissues. APCs continuously sample their environment, present antigens to T cells and co-ordinate immune tolerance and responses. Many different types of APCs have been described and there is growing evidence that these cells are involved in the pathogenesis of OSD. OSD is a complex term for a myriad of disorders that are often characterized by ocular surface inflammation, tear film instability and impairment of vision. CONCLUSIONS This review summarizes the current knowledge concerning the immunotopographical distribution of APCs in the normal ocular surface. APCs appear to play a critical role in the pathology of a number of conditions associated with OSD including infectious keratitis, ocular allergy, dry eye disease and pterygium.
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Affiliation(s)
- Dimitrios Kalogeropoulos
- Department of Ophthalmology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.
| | - Alexandra Papoudou-Bai
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Mark Lane
- Birmingham and Midland Eye Centre, Birmingham, UK
| | - Anna Goussia
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Antonia Charchanti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Marilita M Moschos
- First Department of Ophthalmology, General Hospital of Athens G. Gennimatas, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Chris Kalogeropoulos
- Department of Ophthalmology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
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38
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Lopez MJ, Seyed-Razavi Y, Yamaguchi T, Ortiz G, Sendra VG, Harris DL, Jamali A, Hamrah P. Multiphoton Intravital Microscopy of Mandibular Draining Lymph Nodes: A Mouse Model to Study Corneal Immune Responses. Front Immunol 2020; 11:39. [PMID: 32153558 PMCID: PMC7050419 DOI: 10.3389/fimmu.2020.00039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 01/08/2020] [Indexed: 12/20/2022] Open
Abstract
Multiphoton intravital microscopy (MP-IVM) is a powerful tool to image cells in vivo. Its application in immunology research has opened new horizons, allowing intravital imaging of leukocytes at the single-cell level. A transparent cornea is vital to retain vision. As an immune privileged site, a rapid innate response to foreign antigens is crucial in clearing opportunistic bacterial and viral pathogens, and minimizing collateral structural damage to the cornea. Furthermore, dissecting the mechanisms and preventing the immunological rejection process after corneal transplantation is imperative to retain sight. Therefore, understanding the underlying mechanisms behind corneal immunity, specifically the process of antigen presentation and adaptive immunity in the mandibular draining lymph nodes (dLNs) in vivo, is crucial. Attempts of intravital imaging of mandibular dLNs have yielded little success to date, due to breathing artifacts and the location that is difficult to access. Herein, we present the first MP-IVM mouse model of the mandibular dLNs, utilizing transgenic mice in which CD11c+ cells are fluorescently labeled. Furthermore, we demonstrate that CD11c-YFP+ cells are localized mainly in the parafollicular cortex (T cell zone) and subcapsular area and are sparsely distributed in the follicular region (B cell zone) of mandibular dLNs during steady state. A significant increase in host CD11c-YFP+ cell density is noted at 14 and 21 days following allogeneic corneal transplantation, compared to steady state (p < 0.05). Moreover, allogeneic corneal transplantation results in increased host-derived CD11c-YFP+ cell mean speed and displacement in mandibular dLNs, compared to steady state (p < 0.001). The meandering index, an index for directionality, is significantly increased after allogeneic corneal transplantation at both 14 and 21 days, compared to steady state (p < 0.001). Taken together, our study demonstrates the necessary methodology required for intravital multiphoton imaging of the mandibular dLNs, allowing visualization of spatiotemporal kinetics of immune cells in vivo, and provides a window into the corneal immune reflex arc. This technique will be a powerful tool to investigate the pathogenesis of ocular immune and inflammatory diseases.
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Affiliation(s)
- Maria J Lopez
- Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Boston, MA, United States
| | - Yashar Seyed-Razavi
- Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Boston, MA, United States
| | - Takefumi Yamaguchi
- Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Gustavo Ortiz
- Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States
| | - Victor G Sendra
- Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Boston, MA, United States
| | - Deshea L Harris
- Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Boston, MA, United States
| | - Arsia Jamali
- Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Boston, MA, United States
| | - Pedram Hamrah
- Department of Ophthalmology, Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Boston, MA, United States.,Program in Immunology, School of Graduate Biomedical Sciences, Tufts University, Boston, MA, United States.,Cornea Service, Department of Ophthalmology, Tufts New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, United States.,Cornea Service, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, United States
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39
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Di Zazzo A, Lee SM, Sung J, Niutta M, Coassin M, Mashaghi A, Inomata T. Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology. J Clin Med 2020; 9:E586. [PMID: 32098130 PMCID: PMC7074162 DOI: 10.3390/jcm9020586] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 02/18/2020] [Indexed: 12/13/2022] Open
Abstract
Corneal grafts interact with their hosts via complex immunobiological processes that sometimes lead to graft failure. Prediction of graft failure is often a tedious task due to the genetic and nongenetic heterogeneity of patients. As in other areas of medicine, a reliable prediction method would impact therapeutic decision-making in corneal transplantation. Valuable insights into the clinically observed heterogeneity of host responses to corneal grafts have emerged from multidisciplinary approaches, including genomics analyses, mechanical studies, immunobiology, and theoretical modeling. Here, we review the emerging concepts, tools, and new biomarkers that may allow for the prediction of graft survival.
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Affiliation(s)
- Antonio Di Zazzo
- Ophthalmology Complex Operative Unit, Campus Bio Medico University, 00128 Rome, Italy; (A.D.Z.); (M.N.); (M.C.)
| | - Sang-Mok Lee
- Department of Ophthalmology, Catholic Kwandong University College of Medicine, Gangneung-si, Gangwon-do 25601, Korea;
- Department of Cornea, External Disease & Refractive Surgery, HanGil Eye Hospital, Incheon 21388, Korea
| | - Jaemyoung Sung
- University of South Florida, Morsani College of Medicine, Tampa, FL 33612, USA;
- Department of Ophthalmology, Juntendo University Faculty of Medicine, Tokyo 1130033, Japan
| | - Matteo Niutta
- Ophthalmology Complex Operative Unit, Campus Bio Medico University, 00128 Rome, Italy; (A.D.Z.); (M.N.); (M.C.)
| | - Marco Coassin
- Ophthalmology Complex Operative Unit, Campus Bio Medico University, 00128 Rome, Italy; (A.D.Z.); (M.N.); (M.C.)
| | - Alireza Mashaghi
- Systems Biomedicine and Pharmacology Division, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands
| | - Takenori Inomata
- Department of Ophthalmology, Juntendo University Faculty of Medicine, Tokyo 1130033, Japan
- Department of Strategic Operating Room Management and Improvement, Juntendo University Faculty of Medicine, Tokyo 1130033, Japan
- Department of Hospital Administration, Juntendo University Faculty of Medicine, Tokyo 1130033, Japan
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40
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Effect of age and contact lens wear on corneal epithelial dendritic cell distribution, density, and morphology. Cont Lens Anterior Eye 2020; 43:84-90. [DOI: 10.1016/j.clae.2019.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/17/2019] [Accepted: 05/22/2019] [Indexed: 01/03/2023]
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Coco G, Foulsham W, Nakao T, Yin J, Amouzegar A, Taketani Y, Chauhan SK, Dana R. Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10. Am J Transplant 2020; 20:389-398. [PMID: 31587452 PMCID: PMC6984989 DOI: 10.1111/ajt.15631] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 01/25/2023]
Abstract
The functional competence of corneal endothelial cells (CEnCs) is critical for survival of corneal allografts, but these cells are often targets of the immune response mediated by graft-attacking effector T cells. Although regulatory T cells (Tregs) have been studied for their role in regulating the host's alloimmune response towards the graft, the cytoprotective function of these cells on CEnCs has not been investigated. The aim of this study was to determine whether Tregs suppress effector T cell-mediated and inflammatory cytokine-induced CEnC death, and to elucidate the mechanism by which this cytoprotection occurs. Using 2 well-established models of corneal transplantation (low-risk and high-risk models), we show that Tregs derived from low-risk graft recipients have a superior capacity in protecting CEnCs against effector T cell-mediated and interferon-γ and tumor necrosis factor-α-induced cell death compared to Tregs derived from high-risk hosts. We further demonstrate that the cytoprotective function of Tregs derived from low-risk hosts occurs independently of direct cell-cell contact and is mediated by the immunoregulatory cytokine IL-10. Our study is the first to report that Tregs provide cytoprotection for CEnCs through secretion of IL-10, indicating potentially novel therapeutic targets for enhancing CEnC survival following corneal transplantation.
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Affiliation(s)
- Giulia Coco
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts,Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - William Foulsham
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts,Institute of Ophthalmology, University College London, London, UK
| | - Takeshi Nakao
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Jia Yin
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Afsaneh Amouzegar
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Yukako Taketani
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Sunil K Chauhan
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
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42
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Lagali N, Wowra B, Fries FN, Latta L, Moslemani K, Utheim TP, Wylegala E, Seitz B, Käsmann-Kellner B. Early phenotypic features of aniridia-associated keratopathy and association with PAX6 coding mutations. Ocul Surf 2020; 18:130-140. [DOI: 10.1016/j.jtos.2019.11.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 11/06/2019] [Accepted: 11/13/2019] [Indexed: 12/23/2022]
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Khamar P, Nair AP, Shetty R, Vaidya T, Subramani M, Ponnalagu M, Dhamodaran K, D'souza S, Ghosh A, Pahuja N, Deshmukh R, Ahuja P, Sainani K, Nuijts RMMA, Das D, Ghosh A, Sethu S. Dysregulated Tear Fluid Nociception-Associated Factors, Corneal Dendritic Cell Density, and Vitamin D Levels in Evaporative Dry Eye. Invest Ophthalmol Vis Sci 2019; 60:2532-2542. [PMID: 31195410 DOI: 10.1167/iovs.19-26914] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose The purpose of this study was to study the status and association among tear-soluble factors, corneal dendritic cell density, vitamin D, and signs and symptoms in dry eye disease (DED). Methods A total of 33 control subjects and 47 evaporative dry eye patients were included in the study. DED diagnosis and classification was based on the 2017 Report of the Tear Film & Ocular Surface Society International Dry Eye Workshop (TFOS DEWS II). DED workup, including tear film break-up time (TBUT), Schirmer's test I (STI), corneal and conjunctival staining, ocular surface disease index (OSDI) scoring, and in vivo confocal microscopy (to assess corneal dendritic cell density [cDCD] and subbasal nerve plexus [SBNP] features) was performed in the study subjects. Tear fluid using Schirmer's strip and serum were collected from the subjects. Multiplex ELISA or single analyte ELISA was performed to measure 34 tear-soluble factors levels including vitamin D. Results Significantly higher OSDI discomfort score, lower TBUT, and lower STI were observed in DED patients. cDCD was significantly higher in DED patients. No significant difference was observed in SBNP features. Tear fluid IL-1β, IL-17A, MMP9, MMP10, MMP9/TIMP ratio, and VEGF-B were significantly higher in DED patients. Significantly lower tear fluid IL-2, IP-10, NPY, VEGF-A, and vitamin D was observed in DED patients. These dysregulated tear factors showed significant associations with DED signs and symptoms. Conclusions Altered tear fluid soluble factors with potential to modulate nociception exhibited a distinct association with ocular surface discomfort status, TBUT, STI, and cDCD. This implies a functional relationship between the various tear-soluble factors and dry eye pathogenesis, indicating new molecular targets for designing targeted therapies.
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Affiliation(s)
- Pooja Khamar
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Archana Padmanabhan Nair
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.,Manipal Academy of Higher Education, Manipal, India
| | - Rohit Shetty
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Tanuja Vaidya
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.,Manipal Academy of Higher Education, Manipal, India
| | - Murali Subramani
- Stem Cell Lab, GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India
| | - Murugeswari Ponnalagu
- Stem Cell Lab, GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India
| | - Kamesh Dhamodaran
- Stem Cell Lab, GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India
| | - Sharon D'souza
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Anuprita Ghosh
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India
| | - Natasha Pahuja
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Rashmi Deshmukh
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Prerna Ahuja
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Kanchan Sainani
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Rudy M M A Nuijts
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Debashish Das
- Stem Cell Lab, GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India
| | - Arkasubhra Ghosh
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.,Singapore Eye Research Institute, Singapore
| | - Swaminathan Sethu
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India
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44
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Abstract
The cornea is a transparent outermost structure of the eye anterior segment comprising the highest density of innervated tissue. In the process of corneal innervation, trigeminal ganglion originated corneal nerves diligently traverse different corneal cell types in different corneal layers including the corneal stroma and epithelium. While crossing the stromal and epithelial cell layers during innervation, due to the existing physical contacts, close interactions occur between stromal keratocytes, epithelial cells, resident immune cells and corneal nerves. Furthermore, by producing various trophic and growth factors corneal cells assist in maintaining the growth and function of corneal nerves. Similarly, corneal nerve generated growth factors critically modify the corneal cell function in all the corneal layers. Due to their close association and contacts, on-going cross-communication between these cell types and corneal nerves play a vital role in the modulation of corneal nerve function, regeneration during wound healing. The present review highlights the influence of different corneal cell types and growth factors released from these cells on corneal nerve regeneration and function.
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Affiliation(s)
- Bhavani S Kowtharapu
- Department of Ophthalmology, Rostock University Medical Centre, Rostock, Germany
| | - Oliver Stachs
- Department of Ophthalmology, Rostock University Medical Centre, Rostock, Germany
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45
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Jin H, Liu L, Ding H, He M, Zhang C, Zhong X. Small Incision Femtosecond Laser-assisted X-ray-irradiated Corneal Intrastromal Xenotransplantation in Rhesus Monkeys: A Preliminary Study. Curr Mol Med 2019; 18:612-621. [PMID: 30698112 PMCID: PMC6463400 DOI: 10.2174/1566524019666190129123935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 12/18/2018] [Accepted: 01/27/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Gamma-ray irradiation could significantly induce widespread apoptosis in corneas and reduced the allogenicity of donor cornea. And the X-rays may have similar biological effects. The feasibility and effects of X-ray-irradiated corneal lamellae have not been assessed yet. METHODS Different doses (10 gray unit (Gy), 20 Gy, 50 Gy, 100 Gy) of X-ray irradiated corneal lamellae were collected from SMILE surgery. These corneal lamellae were assessed by physical characterization, hematoxylin and eosin (H-E) staining, Masson's staining, TdT-mediated dUTP nick end labeling (TUNEL), cell viability assay and transmission electron microscopy (TEM). We selected the optimum dose (100Gy) to treat the corneal lamellae to be the grafts. The human grafts and fresh allogeneic monkey corneal lamellae were implanted into rhesus monkeys via the small incision femtosecond laser-assisted surgery, respectively. Clinical examinations and the immunostaining were performed after surgery. RESULTS There were no significant changes in the transparency of the corneal lamellae, but the absorbency of the corneal lamellae was increased. According to the H-E and Masson's staining results, irradiation had little impact on the corneal collagen. The TUNEL assay and cell viability assay results showed that 100Gy X-ray irradiation resulted in complete apoptosis in the corneal lamellae, which was also confirmed by TEM observations. In the following animal model study, no immune reactions or severe inflammatory responses occurred, and the host corneas maintained transparency for 24 weeks of observation. And the expression of CD4 and CD8 were negative in the all host corneas. CONCLUSION X-ray irradiated corneal lamellae could serve as a potential material for xenogeneic inlay, and the small incision femtosecond laser-assisted implantation has the potential to become a new corneal transplantation surgical approach.
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Affiliation(s)
- He Jin
- Zhongshan Ophthalmic Center and State Key Laboratory of Ophthalmology, Sun Yat-sen University. Guangzhou 510060, China.,Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541001, China
| | - Liangping Liu
- Zhongshan Ophthalmic Center and State Key Laboratory of Ophthalmology, Sun Yat-sen University. Guangzhou 510060, China
| | - Hui Ding
- Hainan Eye Hospital, Hainan Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University. Haikou 570311, China
| | - Miao He
- Zhongshan Ophthalmic Center and State Key Laboratory of Ophthalmology, Sun Yat-sen University. Guangzhou 510060, China
| | - Chi Zhang
- Zhongshan Ophthalmic Center and State Key Laboratory of Ophthalmology, Sun Yat-sen University. Guangzhou 510060, China
| | - Xingwu Zhong
- Zhongshan Ophthalmic Center and State Key Laboratory of Ophthalmology, Sun Yat-sen University. Guangzhou 510060, China.,Hainan Eye Hospital, Hainan Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University. Haikou 570311, China
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46
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Kamel JT, Zhang AC, Downie LE. Corneal Epithelial Dendritic Cell Response as a Putative Marker of Neuro-inflammation in Small Fiber Neuropathy. Ocul Immunol Inflamm 2019; 28:898-907. [PMID: 31411914 DOI: 10.1080/09273948.2019.1643028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
We report a case of a 41-year old female with systemic lupus erythematosus and Sjögren's syndrome, who developed symptoms of painful small fiber neuropathy (SFN). Examination using in vivo confocal microscopy (IVCM) revealed dense accumulations of putative dendritic cells in the central cornea that was postulated to represent a peripheral neuro-inflammatory response. Interventions with higher dose prednisolone, and then intravenous immunoglobulin resulted in substantial, progressive improvements in her symptoms, which were paralleled by cumulative reductions in corneal dendritic cell density (DCD). This case identifies corneal DCD as a potential non-invasive marker of symptomatic SFN due to inflammatory causes.
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Affiliation(s)
- Jordan T Kamel
- Department of Neurology and Neurological Research, St. Vincent's Hospital Melbourne , Fitzroy, Australia
| | - Alexis Ceecee Zhang
- Department of Optometry and Vision Sciences, University of Melbourne , Parkville, Australia
| | - Laura E Downie
- Department of Optometry and Vision Sciences, University of Melbourne , Parkville, Australia
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47
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McKay TB, Seyed-Razavi Y, Ghezzi CE, Dieckmann G, Nieland TJF, Cairns DM, Pollard RE, Hamrah P, Kaplan DL. Corneal pain and experimental model development. Prog Retin Eye Res 2019; 71:88-113. [PMID: 30453079 PMCID: PMC6690397 DOI: 10.1016/j.preteyeres.2018.11.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 11/03/2018] [Accepted: 11/13/2018] [Indexed: 12/13/2022]
Abstract
The cornea is a valuable tissue for studying peripheral sensory nerve structure and regeneration due to its avascularity, transparency, and dense innervation. Somatosensory innervation of the cornea serves to identify changes in environmental stimuli at the ocular surface, thereby promoting barrier function to protect the eye against injury or infection. Due to regulatory demands to screen ocular safety of potential chemical exposure, a need remains to develop functional human tissue models to predict ocular damage and pain using in vitro-based systems to increase throughput and minimize animal use. In this review, we summarize the anatomical and functional roles of corneal innervation in propagation of sensory input, corneal neuropathies associated with pain, and the status of current in vivo and in vitro models. Emphasis is placed on tissue engineering approaches to study the human corneal pain response in vitro with integration of proper cell types, controlled microenvironment, and high-throughput readouts to predict pain induction. Further developments in this field will aid in defining molecular signatures to distinguish acute and chronic pain triggers based on the immune response and epithelial, stromal, and neuronal interactions that occur at the ocular surface that lead to functional outcomes in the brain depending on severity and persistence of the stimulus.
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Affiliation(s)
- Tina B McKay
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Yashar Seyed-Razavi
- Center for Translational Ocular Immunology and Cornea Service, Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Chiara E Ghezzi
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Gabriela Dieckmann
- Center for Translational Ocular Immunology and Cornea Service, Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Thomas J F Nieland
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Dana M Cairns
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Rachel E Pollard
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA
| | - Pedram Hamrah
- Center for Translational Ocular Immunology and Cornea Service, Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - David L Kaplan
- Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA, 02155, USA.
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48
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Foulsham W, Mittal SK, Nakao T, Coco G, Taketani Y, Chauhan SK, Dana R. The purinergic receptor antagonist oxidized adenosine triphosphate suppresses immune-mediated corneal allograft rejection. Sci Rep 2019; 9:8617. [PMID: 31197223 PMCID: PMC6565802 DOI: 10.1038/s41598-019-44973-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 05/20/2019] [Indexed: 01/09/2023] Open
Abstract
Adenosine triphosphate (ATP) is released into the extracellular environment during transplantation, and acts via purinergic receptors to amplify the alloimmune response. Here, using a well-established murine model of allogeneic corneal transplantation, we investigated the immunomodulatory mechanisms of the purinergic receptor antagonist oxidized ATP (oATP). Corneal transplantation was performed using C57BL/6 donors and BALB/c hosts. oATP or sterile saline was administered via intraperitoneal injection for 2 weeks postoperatively. Frequencies of CD45+ leukocytes, CD11b+MHCII+ antigen presenting cells (APCs), CD4+IFN-γ+ effector Th1 cells and CD4+Foxp3+ regulatory T cells (Tregs) were evaluated by flow cytometry. Slit-lamp microscopy was performed weekly for 8 weeks to evaluate graft opacity and determine transplant rejection. Treatment with oATP was shown to significantly reduce graft infiltration of CD45+ leukocytes, decrease APC maturation and suppress effector Th1 cell generation relative to saline-treated control. No difference in Treg frequencies or Foxp3 expression was observed between the oATP-treated and control groups. Finally, oATP treatment was shown to reduce graft opacity and increase graft survival. This report demonstrates that oATP limits the alloimmune response by regulating APC maturation and suppressing the generation of alloreactive Th1 immunity.
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Affiliation(s)
- William Foulsham
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Institute of Ophthalmology, University College London, London, UK
| | - Sharad K Mittal
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Takeshi Nakao
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Giulia Coco
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Yukako Taketani
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Sunil K Chauhan
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
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49
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Chidambaram JD, Prajna NV, Palepu S, Lanjewar S, Shah M, Elakkiya S, Lalitha P, Macleod D, Burton MJ. Cellular morphological changes detected by laser scanning in vivo confocal microscopy associated with clinical outcome in fungal keratitis. Sci Rep 2019; 9:8334. [PMID: 31171825 PMCID: PMC6554396 DOI: 10.1038/s41598-019-44833-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 05/24/2019] [Indexed: 11/10/2022] Open
Abstract
HRT3 in vivo confocal microscopy (IVCM) images may indicate clinical outcome, but few studies have analysed this in fungal keratitis (FK). Adults with FK (diameter ≥3 mm) presenting to Aravind Eye Hospital, India from 2012-3 were enrolled prospectively. IVCM was performed at baseline, days 7, 14 and 21 post-enrolment (+/- 3 days where possible). Specific morphologies were identified in IVCM images by a grader masked to microbiology and clinical outcome (defined as good: healed/improving, or poor: enlarged ulcer, perforation or transplant/glue). Associations with final visit outcome assessed using logistic regression. 143 FK participants were enrolled; 87 had good outcome, 56 had poor outcome. Poor outcomes were associated with stellate interconnected cellular processes with no visible nuclei (OR 2.28, 95% CI: 1.03-5.06, p = 0.043) in baseline IVCM images, and fungal filaments (OR 6.48, 95% CI:2.50-16.78, p < 0.001) or honeycomb distribution of inflammatory cells (OR 5.24, 95% CI: 1.44-19.06, p = 0.012) in final visit images. Fungal filaments (OR 3.61, 95% CI:1.64-7.95, p = 0.001), stromal dendritiform cells (OR 2.88, 95% CI:1.17-7.11, p = 0.022), or stellate cellular processes with no visible nuclei (OR 2.09, 95% CI:1.14-3.82, p = 0.017) were associated with poor outcome if not in baseline but present in final visit images. IVCM can reveal morphological changes associated with clinical outcome.
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Affiliation(s)
- Jaya D Chidambaram
- London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
| | - Namperumalsamy V Prajna
- Aravind Eye Hospital, 1 Anna Nagar, Madurai, 625 020, Tamil Nadu, India.,Aravind Medical Research Foundation, Kuruvikaran Salai, Anna Nagar, Shenoy Nagar, Madurai, 625020, Tamil Nadu, India
| | - Srikanthi Palepu
- Aravind Eye Hospital, 1 Anna Nagar, Madurai, 625 020, Tamil Nadu, India
| | - Shruti Lanjewar
- Aravind Eye Hospital, 1 Anna Nagar, Madurai, 625 020, Tamil Nadu, India
| | - Manisha Shah
- Aravind Eye Hospital, 1 Anna Nagar, Madurai, 625 020, Tamil Nadu, India.,Aravind Medical Research Foundation, Kuruvikaran Salai, Anna Nagar, Shenoy Nagar, Madurai, 625020, Tamil Nadu, India
| | - Shanmugam Elakkiya
- Aravind Medical Research Foundation, Kuruvikaran Salai, Anna Nagar, Shenoy Nagar, Madurai, 625020, Tamil Nadu, India
| | - Prajna Lalitha
- Aravind Eye Hospital, 1 Anna Nagar, Madurai, 625 020, Tamil Nadu, India.,Aravind Medical Research Foundation, Kuruvikaran Salai, Anna Nagar, Shenoy Nagar, Madurai, 625020, Tamil Nadu, India
| | - David Macleod
- London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Matthew J Burton
- London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.,Cornea Department, Moorfields Eye Hospital, 162 City Road, London, EC1V 2PD, UK
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50
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Abstract
BACKGROUND Regulatory T (Treg) cell-based immunotherapies have been studied as potential cell-based modalities for promoting transplant survival. However, the efficacy of local delivery of Treg cells in corneal transplantation has not been fully elucidated. Herein, we investigated the kinetics of migration of subconjunctivally injected Treg cells and their role in promoting corneal allograft survival. METHODS GFPCD4CD25Foxp3 Treg cells were isolated from draining lymph nodes (DLNs) of GFP transgenic mice and were subconjunctivally injected to corneal allograft recipients. Next, Treg cells, conventional T cells (Tconv) or a combination of both was locally injected to graft recipients, and graft survival was determined by evaluating opacity scores for 10 weeks. Transplanted mice without treatment served as controls. The frequencies of major histocompatibility complex-IICD11b antigen-presenting cells, IFNγCD4 Th1 cells, and CD45 cells in the DLNs and cornea were evaluated at week 2 posttransplantation using flow cytometry. Expressions of IFNγ, IL-10 and TGF-β in the grafts were assessed using reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS GFP Treg cells were detected in the ipsilateral cornea and DLNs of recipients 6 hours after injection. Subconjunctival injection of Treg cells significantly decreased the frequencies of mature antigen-presenting cells in the graft and DLNs, suppressed Th1 frequencies in DLNs, and inhibited CD45 cell infiltration to the graft. Finally, locally delivered Treg cells significantly reduced the expression of IFN-γ, enhanced the levels of IL-10 and TGF-β in the graft, and promoted long-term allograft survival. CONCLUSIONS Our study elucidates the kinetics of migration of locally delivered Treg cells and shows their role in suppressing host immune response against the allograft.
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