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Finger RP, Jungblut J, Just MD, Terheyden JH, Holz FG, Liegl R, Ach T, Wintergerst MWM. Quantitative autofluorescence is increased in clinically unaffected fellow eyes from patients with posterior uveitis. Sci Rep 2025; 15:6952. [PMID: 40011481 PMCID: PMC11865583 DOI: 10.1038/s41598-025-90071-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 02/10/2025] [Indexed: 02/28/2025] Open
Abstract
The purpose of this prospective case-control study is to investigate differences in quantitative autofluorescence (qAF) in clinically affected and unaffected eyes of patients with inactive posterior uveitis compared to healthy, age-matched controls. Patients with posterior uveitis and healthy controls were imaged using fundus autofluorescence (488 nm excitation; Spectralis HRA + OCT; Heidelberg Engineering) to measure qAF values using the proprietary HEYEX software. Mean background qAF (excluding vessels and retinal lesions) across all segments (as previously defined by Delori et al.) and in the segment with the highest mean qAF value were compared between affected and unaffected eyes from patients with posterior uveitis, and healthy age-matched control eyes using the Kruskal-Wallis-test. A total of 83 eyes from 83 patients were included: 33 affected eyes (33 patients with uni-/bilateral posterior uveitis), 21 clinically unaffected eyes (21 patients with unilateral posterior uveitis), and 29 healthy, age-matched control eyes (29 patients). Mean qAF values were significantly higher (p-value < 0.0001) in both clinically affected (177.0 ± 83.8 qAF arbitrary units [qAF a.u.]) and unaffected (173.8 ± 56.4 qAF a.u.) eyes compared to healthy, age-matched controls (135.7 ± 41.8 qAF a.u.). Likewise, mean qAF in the segment with the highest mean qAF value was significantly higher (p-value: <0.01) in affected (243.2 ± 103.1 qAF a.u.) and unaffected eyes (227.1 ± 63.4 qAF a.u.) in comparison to controls (168.9 ± 48.5 qAF a.u.). In conclusion, both clinically affected and unaffected eyes from patients with posterior uveitis demonstrated increased fundus autofluorescence. The results of our study could indicate subclinical inflammation in currently inactive and (yet) unaffected eyes of posterior uveitis patients. This could be caused by accumulation of fluorophores or an increased metabolic activity generated by low-grade inflammation. As these changes may precede future inflammation in yet unaffected eyes, additional longitudinal studies including analysis of eyes with active disease are warranted.
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Affiliation(s)
- Robert P Finger
- Department of Ophthalmology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
- Department of Ophthalmology, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Julie Jungblut
- Department of Ophthalmology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Marie D Just
- Department of Ophthalmology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Jan H Terheyden
- Department of Ophthalmology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Frank G Holz
- Department of Ophthalmology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Raffael Liegl
- Department of Ophthalmology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Thomas Ach
- Department of Ophthalmology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Maximilian W M Wintergerst
- Department of Ophthalmology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.
- Augenzentrum Grischun, Chur, Switzerland.
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Anitha V, Patwardhan V, Ravindran M. Long-term prognosis of penetrating keratoplasty in a patient with limited form of Scleroderma- a case report. Eur J Ophthalmol 2025; 35:NP1-NP4. [PMID: 39275841 DOI: 10.1177/11206721241284405] [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] [Indexed: 09/16/2024]
Abstract
PURPOSE To explore the challenges of managing recurrent graft rejections in patients with Macular Corneal Dystrophy (MCD) undergoing Penetrating Keratoplasty (PKP) who also have an underlying diagnosis of Systemic Sclerosis, specifically the limited form known as CREST syndrome. METHODS The case of a 47-year-old female diagnosed with MCD who underwent multiple PKPs over a 13 year period was reviewed. The patients treatment included extensive surgical interventions (PKPs, amniotic membrane transplatation, tarsorrhaphy) and medical management involving systemic and topical steroids and immunosuppressive therapy (Tacrolimus ointment). RESULTS Initial PKP surgeries improved the patients vision, but subsequently graft rejections,both acute and chronic, required further surgical and medical interventions. Despite aggressive management, the patient experienced multiple graft failures, with the final visual outcome being significantly compromised (vision 6/60). the presence of CREST syndrome complicated the management and prognosis of graft survival. CONCLUSION This case illustrates the significant impact of systemic autoimmune disorders like CREST syndrome on the prognosis of PKP in patients with MCD. It highlights the necessity for diligent systemic evaluation and possibly more aggressive immunosuppresive strategies to manage graft rejections and prolong graft survival in such complex clinical scenarios.
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Affiliation(s)
- Venugopal Anitha
- Cornea and Refractive Services, Aravind Eye Hospital and Post graduate Institute of Ophthalmology, Tirunelveli, India
| | - Veena Patwardhan
- Cornea and Refractive Services, Aravind Eye Hospital and Post graduate Institute of Ophthalmology, Tirunelveli, India
| | - Meenakshi Ravindran
- Chief Medical Officer, Paediatric and Strabismus surgery, Aravind Eye Hospital and Post graduate Institute of Ophthalmology, Tirunelveli, India
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3
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Wang K, Liu Y, Li S, Zhao N, Qin F, Tao Y, Song Z. Unveiling the therapeutic potential and mechanisms of stanniocalcin-1 in retinal degeneration. Surv Ophthalmol 2025; 70:106-120. [PMID: 39270826 DOI: 10.1016/j.survophthal.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 07/30/2024] [Accepted: 08/16/2024] [Indexed: 09/15/2024]
Abstract
Retinal degeneration (RD) is a group of ocular diseases characterized by progressive photoreceptor apoptosis and visual impairment. Mitochondrial malfunction, excessive oxidative stress, and chronic activation of neuroglia collectively contribute to the development of RD. Currently, there is a lack of efficacious therapeutic interventions for RD. Stanniocalcin-1 (STC-1) is a promising candidate molecule to decelerate photoreceptor cell death. STC-1 is a secreted calcium/phosphorus regulatory protein that exerts diverse protective effects. Accumulating evidence suggests that STC-1 protects retinal cells from ischemic injury, oxidative stress, and excessive apoptosis through enhancing the expression of uncoupling protein-2 (UCP-2). Furthermore, STC-1 exerts its antiinflammatory effects by inhibiting the activation of microglia and macrophages, as well as the synthesis and secretion of proinflammatory cytokines, such as TNF-α, IL-1, and IL-6. By employing these mechanisms, STC-1 effectively shields the retinal photoreceptors and optic nerve, thereby slowing down the progression of RD. We summarize the STC-1-mediated therapeutic effects on the degenerating retina, with a particular focus on its underlying mechanisms. These findings highlight that STC-1 may act as a versatile molecule to treat degenerative retinopathy. Further research on STC-1 is imperative to establish optimal protocols for its clinical use.
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Affiliation(s)
- Kexin Wang
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Yashuang Liu
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Siyu Li
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China
| | - Na Zhao
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China
| | - Fangyuan Qin
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Ye Tao
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China.
| | - Zongming Song
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China.
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4
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Hyttinen JMT, Koskela A, Blasiak J, Kaarniranta K. Autophagy in drusen biogenesis secondary to age-related macular degeneration. Acta Ophthalmol 2024; 102:759-772. [PMID: 39087629 DOI: 10.1111/aos.16744] [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: 03/25/2024] [Accepted: 07/11/2024] [Indexed: 08/02/2024]
Abstract
Age-related macular degeneration (AMD) is an emerging cause of blindness in aged people worldwide. One of the key signs of AMD is the degeneration of the retinal pigment epithelium (RPE), which is indispensable for the maintenance of the adjacent photoreceptors. Because of impaired energy metabolism resulting from constant light exposure, hypoxia, and oxidative stress, accumulation of drusen in AMD-affected eyes is observed. Drusen contain damaged cellular proteins, lipoprotein particles, lipids and carbohydrates and they are related to impaired protein clearance, inflammation, and extracellular matrix modification. When autophagy, a major cellular proteostasis pathway, is impaired, the accumulations of intracellular lipofuscin and extracellular drusen are detected. As these aggregates grow over time, they finally cause the disorganisation and destruction of the RPE and photoreceptors leading to visual loss. In this review, the role of autophagy in drusen biogenesis is discussed since impairment in removing cellular waste in RPE cells plays a key role in AMD progression. In the future, means which improve intracellular clearance might be of use in AMD therapy to slow the progression of drusen formation.
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Affiliation(s)
- Juha M T Hyttinen
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Ali Koskela
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Janusz Blasiak
- Faculty of Medicine, Collegium Medicum, Mazovian Academy in Plock, Plock, Poland
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
- Department of Molecular Genetics, University of Lodz, Lodz, Poland
- Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
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5
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Arya D, Jaggi U, Wang S, Tormanen K, Che M, Mahov S, Jin L, Ghiasi H. A novel GFP-based strategy to quantitate cellular spatial associations in HSV-1 viral pathogenesis. mBio 2024; 15:e0145424. [PMID: 39248563 PMCID: PMC11481894 DOI: 10.1128/mbio.01454-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 08/13/2024] [Indexed: 09/10/2024] Open
Abstract
Periodic reactivation of herpes simplex virus type 1 (HSV-1) triggers immune responses that result in corneal scarring (CS), known as herpes stromal keratitis (HSK). Despite considerable research, fully understanding HSK and eliminating it remains challenging due to a lack of comprehensive analysis of HSV-1-infected immune cells in both corneas and trigeminal ganglia (TG). We engineered a recombinant HSV-1 expressing green fluorescent protein (GFP) in the virulent McKrae virus strain that does not require corneal scarification for efficient virus replication (GFP-McKrae). Next-generation sequencing (NGS) analysis, along with in vitro and in vivo assays, showed that GFP-McKrae virus was similar to WT-McKrae virus. Furthermore, corneal cells infected with GFP-McKrae were quantitatively analyzed using image mass cytometry (IMC). The single-cell reconstruction data generated cellular maps of corneas based on the expression of 25 immune cell markers in GFP-McKrae-infected mice. Corneas from mock control mice showed the presence of T cells and macrophages, whereas corneas from GFP-McKrae-infected mice on days 3 and 5 post-infection (PI) exhibited increased immune cells. Notably, on day 3 PI, increased GFP expression was observed in closely situated clusters of DCs, macrophages, and epithelial cells. By day 5 PI, macrophages and T cells became prominent. Finally, immunostaining methods detected HSV-1 or GFP and gD proteins in latently infected TG. This study presents a valuable strategy for identifying cellular spatial associations in viral pathogenesis and holds promise for future therapeutic applications.IMPORTANCEThe goal of this study was to establish quantitative approaches to analyze immune cell markers in HSV-1-infected intact corneas and trigeminal ganglia from primary and latently infected mice. This allowed us to define spatial and temporal interactions between specific immune cells and their potential roles in virus replication and latency. To accomplish this important goal, we took advantage of the utility of GFP-McKrae virus as a valuable research tool while also highlighting its potential to uncover previously unrecognized cell types that play pivotal roles in HSV-1 replication and latency. Such insights will pave the way for developing targeted therapeutic approaches to tackle HSV-1 infections more effectively.
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Affiliation(s)
- Deepak Arya
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ujjaldeep Jaggi
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Shaohui Wang
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Kati Tormanen
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Mingtian Che
- Applied Genomics, Computation, and Translational Core, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Simeon Mahov
- Applied Genomics, Computation, and Translational Core, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ling Jin
- Department of Biomedical Sciences, Oregon State University, College of Veterinary Medicine, Corvallis, Oregon, USA
| | - Homayon Ghiasi
- Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Masalkhi M, Ong J, Waisberg E, Lee AG. Ocular immunology and inflammation under microgravity conditions and the pathogenesis of spaceflight associated neuro-ocular syndrome (SANS). Eye (Lond) 2024; 38:1799-1801. [PMID: 38443543 PMCID: PMC11226705 DOI: 10.1038/s41433-024-03005-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 02/02/2024] [Accepted: 02/28/2024] [Indexed: 03/07/2024] Open
Affiliation(s)
- Mouayad Masalkhi
- University College Dublin School of Medicine, Belfield, Dublin, Ireland.
| | - Joshua Ong
- Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, MI, USA
| | - Ethan Waisberg
- Department of Ophthalmology, University of Cambridge, Cambridge, UK
| | - Andrew G Lee
- Center for Space Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USA
- The Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA
- Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medicine, New York, NY, USA
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX, USA
- University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Texas A&M College of Medicine, Bryan, TX, USA
- Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA
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7
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Yang SN, Shi Y, Berggren PO. The anterior chamber of the eye technology and its anatomical, optical, and immunological bases. Physiol Rev 2024; 104:881-929. [PMID: 38206586 PMCID: PMC11381035 DOI: 10.1152/physrev.00024.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 11/30/2023] [Accepted: 01/05/2024] [Indexed: 01/12/2024] Open
Abstract
The anterior chamber of the eye (ACE) is distinct in its anatomy, optics, and immunology. This guarantees that the eye perceives visual information in the context of physiology even when encountering adverse incidents like inflammation. In addition, this endows the ACE with the special nursery bed iris enriched in vasculatures and nerves. The ACE constitutes a confined space enclosing an oxygen/nutrient-rich, immune-privileged, and less stressful milieu as well as an optically transparent medium. Therefore, aside from visual perception, the ACE unexpectedly serves as an excellent transplantation site for different body parts and a unique platform for noninvasive, longitudinal, and intravital microimaging of different grafts. On the basis of these merits, the ACE technology has evolved from the prototypical through the conventional to the advanced version. Studies using this technology as a versatile biomedical research platform have led to a diverse range of basic knowledge and in-depth understanding of a variety of cells, tissues, and organs as well as artificial biomaterials, pharmaceuticals, and abiotic substances. Remarkably, the technology turns in vivo dynamic imaging of the morphological characteristics, organotypic features, developmental fates, and specific functions of intracameral grafts into reality under physiological and pathological conditions. Here we review the anatomical, optical, and immunological bases as well as technical details of the ACE technology. Moreover, we discuss major achievements obtained and potential prospective avenues for this technology.
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Affiliation(s)
- Shao-Nian Yang
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Yue Shi
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
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8
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Fucito M, Spedicato M, Felletti S, Yu AC, Busin M, Pasti L, Franchina FA, Cavazzini A, De Luca C, Catani M. A Look into Ocular Diseases: The Pivotal Role of Omics Sciences in Ophthalmology Research. ACS MEASUREMENT SCIENCE AU 2024; 4:247-259. [PMID: 38910860 PMCID: PMC11191728 DOI: 10.1021/acsmeasuresciau.3c00067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 06/25/2024]
Abstract
Precision medicine is a new medical approach which considers both population characteristics and individual variability to provide customized healthcare. The transition from traditional reactive medicine to personalized medicine is based on a biomarker-driven process and a deep knowledge of biological mechanisms according to which the development of diseases occurs. In this context, the advancements in high-throughput omics technologies represent a unique opportunity to discover novel biomarkers and to provide an unbiased picture of the biological system. One of the medical fields in which omics science has started to be recently applied is that of ophthalmology. Ocular diseases are very common, and some of them could be highly disabling, thus leading to vision loss and blindness. The pathogenic mechanism of most ocular diseases may be dependent on various genetic and environmental factors, whose effect has not been yet completely understood. In this context, large-scale omics approaches are fundamental to have a comprehensive evaluation of the whole system and represent an essential tool for the development of novel therapies. This Review summarizes the recent advancements in omics science applied to ophthalmology in the last ten years, in particular by focusing on proteomics, metabolomics and lipidomics applications from an analytical perspective. The role of high-efficiency separation techniques coupled to (high-resolution) mass spectrometry ((HR)MS) is also discussed, as well as the impact of sampling, sample preparation and data analysis as integrating parts of the analytical workflow.
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Affiliation(s)
- Maurine Fucito
- Department
of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, via L. Borsari 46, 44121 Ferrara, Italy
| | - Matteo Spedicato
- Department
of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, via L. Borsari 46, 44121 Ferrara, Italy
| | - Simona Felletti
- Department
of Environmental and Prevention Sciences, University of Ferrara, via L. Borsari 46, Ferrara 44121, Italy
| | - Angeli Christy Yu
- Department
of Translational Medicine and for Romagna, University of Ferrara, via Aldo Moro 8, 44124 Ferrara, Italy
| | - Massimo Busin
- Department
of Translational Medicine and for Romagna, University of Ferrara, via Aldo Moro 8, 44124 Ferrara, Italy
| | - Luisa Pasti
- Department
of Environmental and Prevention Sciences, University of Ferrara, via L. Borsari 46, Ferrara 44121, Italy
| | - Flavio A. Franchina
- Department
of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, via L. Borsari 46, 44121 Ferrara, Italy
| | - Alberto Cavazzini
- Department
of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, via L. Borsari 46, 44121 Ferrara, Italy
- Council
for Agricultural Research and Economics, via della Navicella 2/4, Rome 00184, Italy
| | - Chiara De Luca
- Department
of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, via L. Borsari 46, 44121 Ferrara, Italy
| | - Martina Catani
- Department
of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, via L. Borsari 46, 44121 Ferrara, Italy
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Cakir Ince BA, Kucukevcilioglu M, Yucel C, Durukan AH. Examining the correlation of lymphangiogenesis biomarkers with clinical condition in Age-Related Macular Degeneration (AMD). Exp Eye Res 2024; 243:109891. [PMID: 38615832 DOI: 10.1016/j.exer.2024.109891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 04/01/2024] [Accepted: 04/11/2024] [Indexed: 04/16/2024]
Abstract
The aim of this study is to investigate the relationship between age-related macular degeneration (AMD) and lymphangiogenesis biomarkers, namely LYVE-1, Podoplanin, VEGF-C, VEGFR-2 and VEGFR-3. This prospective and interventional study includes 30 patients with AMD which may be dry or wet type and 30 controls for whom vitrectomy and phacoemulsification was indicated due to additional pathologies (epiretinal membrane, macular hole, retinal detachment, and cataract). 0.1-0,2 ml of aqueous humor and 0.5-1 ml of vitreous sample was taken during the operations. Before the operations 1 tube serum was also taken. All the lymphangiogenesis biomarkers in the study are examined by ELISA method. LYVE-1 (p = 0.001) and Podoplanin (p = 0.004) levels in the vitreous for the patient group are found to be significantly lower than the control group. Serum (p = 0.019), vitreous (p = 0.001), aqueous (p < 0.001) levels of VEGF-C for the patient group are significantly higher than the control group. VEGF-C/VEGFR-2 (p < 0.001), VEGF-C/VEGFR-3 (p < 0.001) ratios in the vitreous for the patient group are found to be significantly higher than the control group. Especially in wet AMD patients, LYVE-1 level is significantly lower in the vitreous (p = 0.002) and aqueous (p = 0.002) than the control group. In addition, Podoplanin level is observed as significantly lower in the vitreous (p = 0.014) and serum (p = 0.002) in comparison to control group. In the wet AMD group, VEGF-C level in the vitreous (p < 0.001), aqueous (p < 0.001) and serum (p = 0.001) is higher than the control group. The result of this study indicates a valid relationship between the weakening of lymphangiogenesis and the pathophysiology of AMD, especially for the wet type. It is observed that the levels of receptors that bind VEGF-C (VEGFR-2 and VEGFR-3) do not increase at the same rate as VEGF-C to compensate for the increase in VEGF-C. The absence of an increase in VEGFR-3, which is especially necessary for lymphangiogenesis, also suggests that lymphangiogenesis is weakened or decreased in AMD. In the future interventional studies with larger series, examination of lymphangiogenic biomarkers in inflammatory retinal diseases and glaucoma may reveal unexplored details.
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Affiliation(s)
| | - Murat Kucukevcilioglu
- Department of Ophthalmology, Gulhane School of Medicine, University of Health Sciences, Ankara, Turkey
| | - Cigdem Yucel
- Department of Clinical Biochemistry, Gulhane School of Medicine, University of Health Sciences, Ankara, Turkey
| | - Ali Hakan Durukan
- Department of Ophthalmology, Gulhane School of Medicine, University of Health Sciences, Ankara, Turkey
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10
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Lee SJ, Lee SH, Koh A, Kim KW. EGF-conditioned M1 macrophages Convey reduced inflammation into corneal endothelial cells through exosomes. Heliyon 2024; 10:e26800. [PMID: 38434401 PMCID: PMC10906407 DOI: 10.1016/j.heliyon.2024.e26800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/20/2024] [Accepted: 02/20/2024] [Indexed: 03/05/2024] Open
Abstract
Epidermal Growth Factor (EGF), a protein pivotal in cell proliferation and survival, has recently shown promise in alleviating inflammation. This study investigates EGF's impact on M1 macrophages, exploring its potential for anti-inflammatory and anti-vasculogenic interactions with corneal endothelial cells (CECs). Polarized M1 macrophages treated with EGF exhibited a suppression of gene expressions related to inflammatory and vasculogenic signals. The anti-inflammatory effects of EGF were observed in co-culture systems with human CECs (HCECs), showcasing its ability to alter macrophage phenotypes. Exosomes derived from EGF-treated M1 macrophages demonstrated enriched proteomic profiles related to immune system regulation and inflammation inhibition. When applied as eye drops in murine corneas, EGF-conditioned M1 macrophage-derived exosomes effectively reduced inflammation and increased M2-related ARG1 expression. This study highlights EGF's potential in mitigating inflammation in M1 macrophages and its delivery through exosomes to cultured HCECs and murine corneas, suggesting a novel therapeutic avenue for ocular surface anti-inflammatory treatments.
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Affiliation(s)
- Soo Jin Lee
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
| | - Seung Hyeun Lee
- Department of Ophthalmology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - Ahra Koh
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
- Chung-Ang University Graduate School, Republic of Korea
| | - Kyoung Woo Kim
- Chung-Ang Ocular Surface Restoration via Immune-inflammation Alleviation (CORIA) Laboratory, Seoul, Republic of Korea
- Department of Ophthalmology, Chung-Ang University College of Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea
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11
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Eteghadi A, Ebrahimi M, Keshel SH. New immunotherapy approaches as the most effective treatment for uveal melanoma. Crit Rev Oncol Hematol 2024; 194:104260. [PMID: 38199429 DOI: 10.1016/j.critrevonc.2024.104260] [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: 07/02/2023] [Revised: 11/26/2023] [Accepted: 01/04/2024] [Indexed: 01/12/2024] Open
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Conventional methods of UM treatment are based on chemotherapy and radiotherapy, which have been able to control tumor growth in a limited way. But due to the inadequacy and many side effects of these treatments, many UM patients die during treatment, and approximately 50% of patients develop metastasis. Meanwhile, the 2-year survival rate of these patients from the time of metastasis is 8%. Since immunotherapy has the potential to be the most specific and efficient method in the treatment of tumors, it is considered an attractive and promising research field in the treatment of UM. This review highlights recent advances in UM immunotherapy and provides new immunological approaches on how to overcome the challenges of UM immunotherapy.
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Affiliation(s)
- Atefeh Eteghadi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Ebrahimi
- Medical Nanotechnology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanotechnology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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12
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Ma S, Huis in't Veld RV, Hao Y, Gu Z, Rich C, Gelmi MC, Mulder AA, van Veelen PA, Vu TKH, van Hall T, Ossendorp FA, Jager MJ. Tumor Pigmentation Does Not Affect Light-Activated Belzupacap Sarotalocan Treatment but Influences Macrophage Polarization in a Murine Melanoma Model. Invest Ophthalmol Vis Sci 2024; 65:42. [PMID: 38271187 PMCID: PMC10829805 DOI: 10.1167/iovs.65.1.42] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 12/21/2023] [Indexed: 01/27/2024] Open
Abstract
Purpose Pigmentation in uveal melanoma is associated with increased malignancy and is known as a barrier for photodynamic therapy. We investigated the role of pigmentation in tumor behavior and the response to light-activated Belzupacap sarotalocan (Bel-sar) treatment in a pigmented (wild type) and nonpigmented (tyrosinase knock-out [TYR knock-out]) cell line in vitro and in a murine model. Methods The B16F10 (TYR knock-out) was developed using CRISPR/Cas9. After the treatment with light-activated Bel-sar, cytotoxicity and exposure of damage-associated molecular patterns (DAMPs) were measured by flow cytometry. Treated tumor cells were co-cultured with bone marrow-derived macrophages (BMDMs) and dendritic cells (DCs) to assess phagocytosis and activation. Both cell lines were injected subcutaneously in syngeneic C57BL/6 mice. Results Knock-out of the tyrosinase gene in B16F10 led to loss of pigmentation and immature melanosomes. Pigmented tumors contained more M1 and fewer M2 macrophages compared with amelanotic tumors. Bel-sar treatment induced near complete cell death, accompanied with enhanced exposure of DAMPs in both cell lines, resulting in enhanced phagocytosis of BMDMs and maturation of DCs. Bel-sar treatment induced a shift to M1 macrophages and delayed tumor growth in both in vivo tumor models. Following treatment, especially the pigmented tumors and their draining lymph nodes contained IFN-gamma positive CD8+T cells. Conclusions Pigmentation influenced the type of infiltrating macrophages in the tumor, with more M1 macrophages in pigmented tumors. Belzupacap sarotalocan treatment induced immunogenic cell death and tumor growth delay in pigmented as well as in nonpigmented models and stimulated M1 macrophage influx in both models.
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Affiliation(s)
- Sen Ma
- Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Ruben V. Huis in't Veld
- Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department of Radiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department of Immunology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Yang Hao
- Department of Radiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department of Laboratory Animals, College of Animal Sciences, Jilin University, Changchun, China
| | - Zili Gu
- Department of Radiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Cadmus Rich
- Aura Biosciences, Inc., Boston, Massachusetts, United States
| | - Maria Chiara Gelmi
- Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Aat A. Mulder
- Department of Electron Microscopy, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Peter A. van Veelen
- Center for Proteomics and Metabolomics, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - T. Khanh H. Vu
- Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Oncology Institute, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Ferry A. Ossendorp
- Department of Immunology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Martine J. Jager
- Department of Ophthalmology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
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13
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Giacalone JC, Parkinson DH, Balikov DA, Rajesh CR. AMD and Stem Cell-Based Therapies. Int Ophthalmol Clin 2024; 64:21-33. [PMID: 38146879 PMCID: PMC10783850 DOI: 10.1097/iio.0000000000000510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2023]
Abstract
Age-related macular degeneration (AMD) is a prevalent and complex disease leading to severe vision loss. Stem cells offer promising prospects for AMD treatment as they can be differentiated into critical retinal cell types that could replace lost host retinal cells or provide trophic support to promote host retinal cell survival. However, challenges such as immune rejection, concerns regarding tumorigenicity, and genomic integrity must be addressed. Clinical trials with stem cell-derived retinal pigment epithelial cells have shown preliminary safety in treating dry AMD, but improvements in manufacturing and surgical techniques cell delivery are needed. Late-stage AMD poses additional hurdles, possibly requiring multi-layered grafts. Advancements in automation technologies and gene correction strategies show potential to enhance iPSC-based therapies. Stem cell-based treatments offer hope for AMD management, but further research and optimization are essential for successful clinical implementation.
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Affiliation(s)
- Joseph C. Giacalone
- Department of Ophthalmology and Visual Science, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA
| | - David H. Parkinson
- Department of Ophthalmology and Visual Science, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA
| | - Daniel A. Balikov
- Department of Ophthalmology and Visual Science, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA
| | - C. Rao Rajesh
- Department of Ophthalmology and Visual Science, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI, USA
- A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI, USA
- Division of Ophthalmology, Surgical Service, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI, USA
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14
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Turhan SA, Karlsson P, Ozun Y, Gunes H, Surucu S, Toker E, Isak B. Identification of corneal and intra-epidermal axonal swellings in amyotrophic lateral sclerosis. Muscle Nerve 2024; 69:78-86. [PMID: 37983951 DOI: 10.1002/mus.27995] [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: 01/18/2023] [Revised: 10/07/2023] [Accepted: 10/15/2023] [Indexed: 11/22/2023]
Abstract
INTRODUCTION/AIMS In patients with amyotrophic lateral sclerosis (ALS), axonal spheroids in motor axons have been identified in post-mortem studies. In this study, axonal spheroids and swellings on C-fibers of ALS patients were investigated using corneal confocal microscopy (CCM) and skin biopsy, respectively. METHODS Thirty-one ALS patients and 20 healthy subjects were evaluated with CCM to assess corneal nerve-fiber length (CNFL), -fiber density (CNFD), -branch density (CNBD), dendritic cell (DC) density, and axonal spheroids originating from C-fibers (>100 μm2 ). In addition, intraepidermal nerve fiber density (IENFD) and axonal swellings (>1.5 μm) were assessed in skin biopsies obtained from the arms and legs of 22 patients and 17 controls. RESULTS In ALS patients, IENFD, CNFD, CNFL, and CNBD were not different from controls. The density of DCs and the number of patients with increased DC density were higher in ALS patients than controls (p = .0005 and p = .008). The number of patients with axonal spheroids was higher than controls (p = .03). DISCUSSION Evaluation of DCs and axonal bulbs in C-fibers of ALS patients could provide insights into pathophysiology or potentially serve as biomarkers in ALS.
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Affiliation(s)
| | - Pall Karlsson
- Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Yuksel Ozun
- Department of Neurology, Marmara University Hospital, Istanbul, Turkey
| | - Hande Gunes
- Department of Pathology, Kartal Research and Education Hospital, University of Medical Sciences, Istanbul, Turkey
| | - Selcuk Surucu
- Department of Anatomy, Faculty of Medicine, Koç University, Istanbul, Turkey
| | - Ebru Toker
- Department of Ophthalmology and Visual Sciences, West Virginia University Eye Institute, Morgantown, West Virginia, USA
| | - Baris Isak
- Department of Neurology, Marmara University Hospital, Istanbul, Turkey
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15
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Hoshi K, Kunikata H, Aizawa N, Yasuda M, Okabe T, Takizawa H, Abe T, Nakazawa T. Baseline characteristics associated with the incidence of intraocular inflammation after the intravitreous injection of brolucizumab. Int Ophthalmol 2023; 43:4701-4709. [PMID: 38044420 DOI: 10.1007/s10792-023-02870-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 08/20/2023] [Indexed: 12/05/2023]
Abstract
PURPOSE To investigate baseline characteristics associated with the incidence of intraocular inflammation (IOI) after the intravitreal injection of brolucizumab (IVBr) for the treatment of neovascular age-related macular degeneration (nAMD). METHODS This retrospective study included 66 eyes of 62 consecutive patients with nAMD who received IVBr (18 eyes were treatment naïve and 48 eyes had switched from other anti-vascular endothelial growth factor [VEGF] therapy). Baseline clinical characteristics were compared in non-IOI and IOI groups. RESULTS Although a dry macula was achieved at a high rate even 6 months after IVBr, IOI occurred in 8 of 66 eyes (12.1%; all had switched therapy) during the study period. Baseline characteristics including age, sex, nAMD type, lens status, visual acuity, central macular thickness, and a history of diabetes did not differ between the groups. The number of previous anti-VEGF injections before IVBr was greater in the IOI group (P = 0.004), and the ratio of patients with a laser flare-cell photometry (LFCP) value over 15 photon count per millisecond (pc/ms) was higher in the IOI group (P = 0.017). Multivariate logistic regression analysis showed that a greater number of previous anti-VEGF injections (odds ratio [OR]: 1.12, P = 0.006; area under the curve: 0.82, cut-off score: 14.0) and an LFCP value over 15 pc/ms (OR: 81.6, P = 0.031) were significantly associated with the incidence of IOI after IVBr. CONCLUSION A number of previous anti-VEGF injections greater than 14 and an LFCP value more than 15 pc/ms might be useful predictors of the incidence of IOI after IVBr in eyes with nAMD.
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Affiliation(s)
- Keisuke Hoshi
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Hiroshi Kunikata
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan.
- Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Naoko Aizawa
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Masayuki Yasuda
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Tatsu Okabe
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Hiroki Takizawa
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Toshiaki Abe
- Division of Clinical Cell Therapy Center for Advanced Medical Research and Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toru Nakazawa
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
- Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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16
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Li S, Guo Y, Zhao X, Lang D, Zhou Z. Biomechanical and tissue reaction: the effects of varying sutures size on canine abdominal wall stitching. Front Vet Sci 2023; 10:1254998. [PMID: 38026614 PMCID: PMC10667435 DOI: 10.3389/fvets.2023.1254998] [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: 07/08/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Objective Larger diameter sutures can provide sufficient tensile strength to surgical incisions but may exacerbate the inflammatory response caused by the amount of implanted foreign material. This experiment aims to investigate the differences in biomechanical stability and tissue reactivity after suturing canine midline abdominal incisions with different suture sizes. Method Assessing the biomechanical differences between USP 2-0, 3-0, and 4-0 PGA sutures using uniaxial tensile testing on ex vivo canine midline skin and fascial muscle tissues using either a simple continuous or simple interrupted technique. mRNA and protein expression levels of inflammatory factors were measured through RT-PCR and ELISA. Tissue reactivity was evaluated using a semi-quantitative scoring system. Result For strains below 30% in skin and below 50% in muscle, there were no significant differences among groups. The results of skin biomechanical testing showed that the USP 4-0 PGA suture group demonstrated significantly lower maximum tensile strength compared to the USP 2-0 PGA or USP 3-0 PGA suture groups. However, it remained capable of providing at least 56.3 N (1.03 MPa) tensile strength for canine skin incisions, matching the tensile strength requirements of general canine abdominal wall surgical incisions. In addition, there were no statistically significant differences observed in the maximum tensile strength among different size of sutures according to the data of biomechanical testing in muscle. Larger diameter sutures led to increased levels of inflammatory factors (IL-1β, IL-6, TNF-ɑ) and tissue reactivity. Simple interrupted sutures caused higher levels of inflammatory factors in muscular tissue compared to simple continuous sutures. Conclusion USP 4-0 PGA sutures provide sufficient biomechanical stability for suturing canine abdominal skin and linea alba. Suture size significantly influences tissue reactivity after suturing, with smaller gauge sutures reducing early tissue inflammatory response. Thus, USP 4-0 PGA suture has more advantages to suturing canine abdominal surgical incisions.
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Affiliation(s)
| | | | | | | | - Zhenlei Zhou
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
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17
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Wildner G, Bansal R, Ayyadurai N, Thurau S, Basu S. Pathogenesis of Bacterial Uveitis. Ocul Immunol Inflamm 2023; 31:1396-1404. [PMID: 36622856 DOI: 10.1080/09273948.2022.2155842] [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: 07/13/2022] [Revised: 09/02/2022] [Accepted: 12/02/2022] [Indexed: 01/10/2023]
Abstract
PURPOSE To describe the pathogenesis and the general immune mechanisms of the most frequent causes of bacterial uveitis. METHODOLOGY Narrative review. RESULTS Both extra- and intracellular bacteria can induce uveitis, whereas intracellular bacteria are generally transported into the inner eye via cells of the innate immune system, mainly macrophages. Systemic adaptive immunity is usually induced before the bacteria are localized to the inner eye, and once T and B cells have detected the pathogens behind the blood-eye barriers they elicit an acute and/or chronic inflammatory response deteriorating visual acuity that can severely affect the non-regenerating, intraocular tissues. CONCLUSIONS An understanding of pathogenic mechanisms, and its correlation with clinical and imaging features, can facilitate early recognition of microbial factors and institution of appropriate therapy.
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Affiliation(s)
- Gerhild Wildner
- Department of Ophthalmology, University Hospital, LMU, Munich, Germany
| | - Reema Bansal
- Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Nikitha Ayyadurai
- Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Stephan Thurau
- Department of Ophthalmology, University Hospital, LMU, Munich, Germany
| | - Soumyava Basu
- Prof Brien Holden Eye Research Center, LV Prasad Eye Institute, Hyderabad, India
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18
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Clahsen T, Hadrian K, Notara M, Schlereth SL, Howaldt A, Prokosch V, Volatier T, Hos D, Schroedl F, Kaser-Eichberger A, Heindl LM, Steven P, Bosch JJ, Steinkasserer A, Rokohl AC, Liu H, Mestanoglu M, Kashkar H, Schumacher B, Kiefer F, Schulte-Merker S, Matthaei M, Hou Y, Fassbender S, Jantsch J, Zhang W, Enders P, Bachmann B, Bock F, Cursiefen C. The novel role of lymphatic vessels in the pathogenesis of ocular diseases. Prog Retin Eye Res 2023; 96:101157. [PMID: 36759312 DOI: 10.1016/j.preteyeres.2022.101157] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 02/10/2023]
Abstract
Historically, the eye has been considered as an organ free of lymphatic vessels. In recent years, however, it became evident, that lymphatic vessels or lymphatic-like vessels contribute to several ocular pathologies at various peri- and intraocular locations. The aim of this review is to outline the pathogenetic role of ocular lymphatics, the respective molecular mechanisms and to discuss current and future therapeutic options based thereon. We will give an overview on the vascular anatomy of the healthy ocular surface and the molecular mechanisms contributing to corneal (lymph)angiogenic privilege. In addition, we present (i) current insights into the cellular and molecular mechanisms occurring during pathological neovascularization of the cornea triggered e.g. by inflammation or trauma, (ii) the role of lymphatic vessels in different ocular surface pathologies such as dry eye disease, corneal graft rejection, ocular graft versus host disease, allergy, and pterygium, (iii) the involvement of lymphatic vessels in ocular tumors and metastasis, and (iv) the novel role of the lymphatic-like structure of Schlemm's canal in glaucoma. Identification of the underlying molecular mechanisms and of novel modulators of lymphangiogenesis will contribute to the development of new therapeutic targets for the treatment of ocular diseases associated with pathological lymphangiogenesis in the future. The preclinical data presented here outline novel therapeutic concepts for promoting transplant survival, inhibiting metastasis of ocular tumors, reducing inflammation of the ocular surface, and treating glaucoma. Initial data from clinical trials suggest first success of novel treatment strategies to promote transplant survival based on pretransplant corneal lymphangioregression.
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Affiliation(s)
- Thomas Clahsen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Karina Hadrian
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Maria Notara
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Simona L Schlereth
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Antonia Howaldt
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Verena Prokosch
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thomas Volatier
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Deniz Hos
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Falk Schroedl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Alexandra Kaser-Eichberger
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Ludwig M Heindl
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Philipp Steven
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany
| | - Jacobus J Bosch
- Centre for Human Drug Research and Leiden University Medical Center, Leiden, the Netherlands
| | | | - Alexander C Rokohl
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hanhan Liu
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Mert Mestanoglu
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hamid Kashkar
- Institute for Molecular Immunology, Center for Molecular Medicine Cologne (CMMC), CECAD Research Center, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Björn Schumacher
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany
| | - Friedemann Kiefer
- European Institute for Molecular Imaging (EIMI), University of Münster, 48149, Münster, Germany
| | - Stefan Schulte-Merker
- Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Münster, Germany
| | - Mario Matthaei
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Yanhong Hou
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, China
| | - Sonja Fassbender
- IUF‒Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany; Immunology and Environment, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Jonathan Jantsch
- Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Wei Zhang
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Philip Enders
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Björn Bachmann
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany.
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19
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Shamshad A, Kang C, Jenny LA, Persad-Paisley EM, Tsang SH. Translatability barriers between preclinical and clinical trials of AAV gene therapy in inherited retinal diseases. Vision Res 2023; 210:108258. [PMID: 37244011 PMCID: PMC10526971 DOI: 10.1016/j.visres.2023.108258] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 05/29/2023]
Abstract
Inherited retinal diseases (IRDs) are progressive degenerative diseases which cause gradual vision loss or complete blindness. As over 270 gene mutations have been identified in the underlying pathology of IRDs, gene therapy as a treatment modality has been an increasingly active realm of investigation. Currently, the most common vehicle of ocular gene delivery is the adeno-associated virus (AAV) vector. This is injected into the immune-privileged subretinal space to mediate transgene expression in retinal cells. Although numerous animal models of IRDs have demonstrated successful outcomes following AAV-mediated gene delivery, many of these studies fail to translate into successful outcomes in clinical trials. The purpose of this review is to A) comparatively assess preclinical and clinical IRD trials in which the success of AAV-mediated therapy failed to translate between animal and human participants B) discuss factors which may complicate the translatability of gene therapy in animals to results in humans.
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Affiliation(s)
| | - Chaerim Kang
- Warren Alpert Medical School of Brown University, USA
| | - Laura A Jenny
- Edward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY, USA; Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, NY, USA
| | | | - Stephen H Tsang
- Edward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, NY, USA; Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA; Department of Biomedical Engineering, Columbia University, New York, NY, USA; Columbia Stem Cell Initiative, Columbia University, New York, NY, USA; Insitute of Human Nutrition, Columbia University, New York, NY, USA
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20
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Wang X, Wang T, Lam E, Alvarez D, Sun Y. Ocular Vascular Diseases: From Retinal Immune Privilege to Inflammation. Int J Mol Sci 2023; 24:12090. [PMID: 37569464 PMCID: PMC10418793 DOI: 10.3390/ijms241512090] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/21/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
The eye is an immune privileged tissue that insulates the visual system from local and systemic immune provocation to preserve homeostatic functions of highly specialized retinal neural cells. If immune privilege is breached, immune stimuli will invade the eye and subsequently trigger acute inflammatory responses. Local resident microglia become active and release numerous immunological factors to protect the integrity of retinal neural cells. Although acute inflammatory responses are necessary to control and eradicate insults to the eye, chronic inflammation can cause retinal tissue damage and cell dysfunction, leading to ocular disease and vision loss. In this review, we summarized features of immune privilege in the retina and the key inflammatory responses, factors, and intracellular pathways activated when retinal immune privilege fails, as well as a highlight of the recent clinical and research advances in ocular immunity and ocular vascular diseases including retinopathy of prematurity, age-related macular degeneration, and diabetic retinopathy.
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Affiliation(s)
- Xudong Wang
- Department of Ophthalmology, Harvard Medical School, Boston Children’s Hospital, Boston, MA 02115, USA; (X.W.)
| | - Tianxi Wang
- Department of Ophthalmology, Harvard Medical School, Boston Children’s Hospital, Boston, MA 02115, USA; (X.W.)
| | - Enton Lam
- Department of Ophthalmology, Harvard Medical School, Boston Children’s Hospital, Boston, MA 02115, USA; (X.W.)
| | - David Alvarez
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Ye Sun
- Department of Ophthalmology, Harvard Medical School, Boston Children’s Hospital, Boston, MA 02115, USA; (X.W.)
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21
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Jiang B, Luo Y, Yan N, Shen Z, Li W, Hou C, Xiao L, Ma C, Zhang L, Chen Y, Cheng X, Lian M, Ji C, Zhu Z, Wang Z. An X-ray inactivated vaccine against Pseudomonas aeruginosa Keratitis in mice. Vaccine 2023:S0264-410X(23)00627-8. [PMID: 37353454 DOI: 10.1016/j.vaccine.2023.05.066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/25/2023]
Abstract
Pseudomonas aeruginosa (P. aeruginosa) is one of the most prevalent pathogens of bacterial keratitis. Bacterial keratitis is a major cause of blindness worldwide. The rising incidence of multidrug resistance of P. aeruginosa precludes treatment with conventional antibiotics. Herein, we evaluated the protective efficiency and explored the possible underlying mechanism of an X-ray inactivated vaccine (XPa) using a murine P. aeruginosa keratitis model. Mice immunized with XPa exhibit reduced corneal bacterial loads and pathology scores. XPa vaccination induced corneal macrophage polarization toward M2, averting an excessive inflammatory reaction. Furthermore, histological observations indicated that XPa vaccination suppressed corneal fibroblast activation and prevented irreversible visual impairment. The potency of XPa against keratitis highlights its potential utility as an effective and promising vaccine candidate for P. aeruginosa.
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Affiliation(s)
- Boguang Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Yingjie Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Naihong Yan
- Research Laboratory of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhixue Shen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Wenfang Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Chen Hou
- Research Laboratory of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lirong Xiao
- Research Laboratory of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Cuicui Ma
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Li Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Yanwei Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Xingjun Cheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Mao Lian
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Chengjie Ji
- Department of Laboratory Medicine, The People's Hospital of Jianyang City, Chengdu 641400, China
| | - Ziyi Zhu
- Department of Laboratory Medicine, The People's Hospital of Jianyang City, Chengdu 641400, China
| | - Zhenling Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
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22
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Ostrin LA, Harb E, Nickla DL, Read SA, Alonso-Caneiro D, Schroedl F, Kaser-Eichberger A, Zhou X, Wildsoet CF. IMI-The Dynamic Choroid: New Insights, Challenges, and Potential Significance for Human Myopia. Invest Ophthalmol Vis Sci 2023; 64:4. [PMID: 37126359 PMCID: PMC10153586 DOI: 10.1167/iovs.64.6.4] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 02/07/2023] [Indexed: 05/02/2023] Open
Abstract
The choroid is the richly vascular layer of the eye located between the sclera and Bruch's membrane. Early studies in animals, as well as more recent studies in humans, have demonstrated that the choroid is a dynamic, multifunctional structure, with its thickness directly and indirectly subject to modulation by a variety of physiologic and visual stimuli. In this review, the anatomy and function of the choroid are summarized and links between the choroid, eye growth regulation, and myopia, as demonstrated in animal models, discussed. Methods for quantifying choroidal thickness in the human eye and associated challenges are described, the literature examining choroidal changes in response to various visual stimuli and refractive error-related differences are summarized, and the potential implications of the latter for myopia are considered. This review also allowed for the reexamination of the hypothesis that short-term changes in choroidal thickness induced by pharmacologic, optical, or environmental stimuli are predictive of future long-term changes in axial elongation, and the speculation that short-term choroidal thickening can be used as a biomarker of treatment efficacy for myopia control therapies, with the general conclusion that current evidence is not sufficient.
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Affiliation(s)
- Lisa A Ostrin
- University of Houston College of Optometry, Houston, Texas, United States
| | - Elise Harb
- Herbert Wertheim School of Optometry and Vision Science, University of California Berkeley, Berkeley, California, United States
| | - Debora L Nickla
- Department of Biomedical Sciences and Disease, New England College of Optometry, Boston, Massachusetts, United States
| | - Scott A Read
- Contact Lens and Visual Optics Laboratory, Centre for Vision and Eye Research, School of Optometry and Vision Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - David Alonso-Caneiro
- Contact Lens and Visual Optics Laboratory, Centre for Vision and Eye Research, School of Optometry and Vision Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Falk Schroedl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology-Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Alexandra Kaser-Eichberger
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology-Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Xiangtian Zhou
- Eye Hospital and School of Optometry and Ophthalmology, National Clinical Research Center for Ocular Diseases, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Christine F Wildsoet
- Herbert Wertheim School of Optometry and Vision Science, University of California Berkeley, Berkeley, California, United States
- Centre for Vision and Eye Research, School of Optometry and Vision Science, Queensland University of Technology, Brisbane, Queensland, Australia
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23
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Abbondante S, Leal SM, Clark HL, Ratitong B, Sun Y, Ma LJ, Pearlman E. Immunity to pathogenic fungi in the eye. Semin Immunol 2023; 67:101753. [PMID: 37060806 PMCID: PMC10508057 DOI: 10.1016/j.smim.2023.101753] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Indexed: 04/17/2023]
Abstract
Fusarium, Aspergillus and Candida are important fungal pathogens that cause visual impairment and blindness in the USA and worldwide. This review will summarize the epidemiology and clinical features of corneal infections and discuss the immune and inflammatory responses that play an important role in clinical disease. In addition, we describe fungal virulence factors that are required for survival in infected corneas, and the activities of neutrophils in fungal killing, tissue damage and cytokine production.
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Affiliation(s)
- Serena Abbondante
- Department of Ophthalmology, and Department of Physiology and Biophysics, University of California, Irvine, CA, USA
| | - Sixto M Leal
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Bridget Ratitong
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yan Sun
- Department of Ophthalmic Research, Cole Eye Institute and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Li-Jun Ma
- Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, USA
| | - Eric Pearlman
- Department of Ophthalmology, and Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
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24
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Huang Z, Zhang Y. Iris metastasis as resistance mechanism to atezolizumab, carboplatin, and etoposide but responds to additional irinotecan and anlotinib in a small cell lung cancer patient. Thorac Cancer 2023; 14:779-782. [PMID: 36747371 PMCID: PMC10008681 DOI: 10.1111/1759-7714.14818] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 01/24/2023] [Accepted: 01/25/2023] [Indexed: 02/08/2023] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy associated with poor prognosis. Metastasis to sites outside the chest at the time of initial diagnosis, such as bone, brain, and liver metastasis have been found in most SCLC patients. Iris metastases from SCLC have rarely been previously reported, and often cause eye pain and blindness in patients. Here, we report a patient with SCLC who presented with iris metastasis in the right eye and metastasis in the left adrenal gland due to disease progression on first-line therapy, which subsequently caused pain and blindness in the right eye. The patient was treated with second-line irinotecan combined with anlotinib and atezolizumab and did not receive any local treatment in the right eye. After only one cycle of treatment, the iris metastases in the right eye were smaller than before, and the visual acuity in the right eye recovered. At the same time, her left adrenal metastases were also significantly smaller than before. Our case suggests that systemic therapy with effective treatment options can similarly improve iris metastases in patients.
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Affiliation(s)
- Zhe Huang
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China.,Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yongchang Zhang
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, China.,Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
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25
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Du Y, Yan B. Ocular immune privilege and retinal pigment epithelial cells. J Leukoc Biol 2023; 113:288-304. [PMID: 36805720 DOI: 10.1093/jleuko/qiac016] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Indexed: 02/04/2023] Open
Abstract
The ocular tissue microenvironment is immune-privileged and uses multiple immunosuppressive mechanisms to prevent the induction of inflammation. The retinal pigment epithelium plays an essential role in ocular immune privilege. In addition to serving as a blood barrier separating the fenestrated choriocapillaris from the retina, the retinal pigment epithelium is a source of immunosuppressive cytokines and membrane-bound negative regulators that modulate the activity of immune cells within the retina. This article reviews the current understanding of how retinal pigment epithelium cells mediate immune regulation, focusing on the changes under pathologic conditions.
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Affiliation(s)
- Yuxiang Du
- Institute of Precision Medicine, Jining Medical University, No. 133, Hehua Road, Taibaihu New District, Jining, Shandong 272067, People's Republic of China
| | - Bo Yan
- Institute of Precision Medicine, Jining Medical University, No. 133, Hehua Road, Taibaihu New District, Jining, Shandong 272067, People's Republic of China
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26
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DeDreu J, Le PM, Menko AS. The ciliary zonules provide a pathway for immune cells to populate the avascular lens during eye development. Exp Biol Med (Maywood) 2022; 247:2251-2273. [PMID: 36633170 PMCID: PMC9899985 DOI: 10.1177/15353702221140411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/20/2022] [Indexed: 01/13/2023] Open
Abstract
The eye is an immune-privileged site, with both vasculature and lymphatics absent from the central light path. Unique adaptations have made it possible for immune cells to be recruited to this region of the eye in response to ocular injuries and pathogenic insults. The induction of such immune responses is typically activated by tissue resident immune cells, considered the sentinels of the immune system. We discovered that, despite the absence of an embedded vasculature, the embryonic lens becomes populated by resident immune cells. The paths by which they travel to the lens during development were not known. However, our previous studies show that in response to corneal wounding immune cells travel to the lens from the vascular-rich ciliary body across the zonules that link these two tissues. We now examined whether the zonule fibers provide a path for immune cells to the embryonic lens, and the zonule-associated matrix molecules that could promote immune cell migration. The vitreous also was examined as a potential source of lens resident immune cells. This matrix-rich site in the posterior of the eye harbors hyalocytes, an immune cell type with macrophage-like properties. We found that both the zonules and the vitreous of the embryonic eye contained fibrillin-2-based networks and that migration-promoting matrix proteins like fibronectin and tenascin-C were linked to these fibrils. Immune cells were seen emerging from the ciliary body, migrating along the ciliary zonules to the lens, and invading through the lens capsule at its equator. This is just adjacent to where immune cells take up residence in the embryonic lens. In contrast, the immune cells of the vitreous were not detected in the region of the lens. These results strongly suggest that the ciliary zonules are a primary path of immune cell delivery to the developing lens.
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Affiliation(s)
- JodiRae DeDreu
- Department of Pathology and Genomic
Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia,
PA 19107, USA
| | - Phuong M Le
- Department of Pathology and Genomic
Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia,
PA 19107, USA
| | - A. Sue Menko
- Department of Pathology and Genomic
Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia,
PA 19107, USA
- Department of Ophthalmology, Sidney
Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107,
USA
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27
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Matzinger P. Autoimmunity: Are we asking the right question? Front Immunol 2022; 13:864633. [PMID: 36405714 PMCID: PMC9671104 DOI: 10.3389/fimmu.2022.864633] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 09/20/2022] [Indexed: 09/07/2023] Open
Abstract
For decades, the main question immunologists have asked about autoimmunity is "what causes a break in self-tolerance?" We have not found good answers to that question, and I believe we are still so ignorant because it's the wrong question. Rather than a break in self-tolerance, I suggest that many autoimmune diseases might be due to defects in normal tissue physiology.
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Affiliation(s)
- Polly Matzinger
- Ghost Lab, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States
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28
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Antigenic mimicry – The key to autoimmunity in immune privileged organs. J Autoimmun 2022:102942. [DOI: 10.1016/j.jaut.2022.102942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 10/17/2022] [Indexed: 11/09/2022]
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29
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Immunological consequences of compromised ocular immune privilege accelerate retinal degeneration in retinitis pigmentosa. Orphanet J Rare Dis 2022; 17:378. [PMID: 36253797 PMCID: PMC9575261 DOI: 10.1186/s13023-022-02528-x] [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: 01/11/2022] [Accepted: 10/02/2022] [Indexed: 11/26/2022] Open
Abstract
Background Retinitis pigmentosa (RP) is a hereditary retinal disease which leads to visual impairment. The onset and progression of RP has physiological consequences that affects the ocular environment. Some of the key non-genetic factors which hasten the retinal degeneration in RP include oxidative stress, hypoxia and ocular inflammation. In this study, we investigated the status of the ocular immune privilege during retinal degeneration and the effect of ocular immune changes on the peripheral immune system in RP. We assessed the peripheral blood mononuclear cell stimulation by retinal antigens and their immune response status in RP patients. Subsequently, we examined alterations in ocular immune privilege machineries which may contribute to ocular inflammation and disease progression in rd1 mouse model. Results In RP patients, we observed a suppressed anti-inflammatory response to self-retinal antigens, thereby indicating a deviated response to self-antigens. The ocular milieu in rd1 mouse model indicated a significant decrease in immune suppressive ligands and cytokine TGF-B1, and higher pro-inflammatory ocular protein levels. Further, blood–retinal-barrier breakdown due to decrease in the expression of tight junction proteins was observed. The retinal breach potentiated pro-inflammatory peripheral immune activation against retinal antigens and caused infiltration of the peripheral immune cells into the ocular tissue. Conclusions Our studies with RP patients and rd1 mouse model suggest that immunological consequences in RP is a contributing factor in the progression of retinal degeneration. The ocular inflammation in the RP alters the ocular immune privilege mechanisms and peripheral immune response. These aberrations in turn create an auto-reactive immune environment and accelerate retinal degeneration.
Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02528-x.
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30
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Yu WS, Aquili L, Wong KH, Lo ACY, Chan LLH, Chan YS, Lim LW. Transcorneal electrical stimulation enhances cognitive functions in aged and 5XFAD mouse models. Ann N Y Acad Sci 2022; 1515:249-265. [PMID: 35751874 DOI: 10.1111/nyas.14850] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dementia is a major burden on global health for which there are no effective treatments. The use of noninvasive visual stimulation to ameliorate cognitive deficits is a novel concept that may be applicable for treating dementia. In this study, we investigated the effects of transcorneal electrical stimulation (TES) on memory enhancement using two mouse models, in aged mice and in the 5XFAD model of Alzheimer's disease. After 3 weeks of TES treatment, mice were subjected to Y-maze and Morris water maze tests to assess hippocampal-dependent learning and memory. Immunostaining of the hippocampus of 5XFAD mice was also performed to examine the effects of TES on amyloid plaque pathology. The results showed that TES improved the performance of both aged and 5XFAD mice in memory tests. TES also reduced hippocampal plaque deposition in male, but not female, 5XFAD mice. Moreover, TES significantly reversed the downregulated level of postsynaptic protein 95 in the hippocampus of male 5XFAD mice, suggesting the effects of TES involve a postsynaptic mechanism. Overall, these findings support further investigation of TES as a potential treatment for cognitive dysfunction and mechanistic studies of TES effects in other dementia models.
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Affiliation(s)
- Wing Shan Yu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Luca Aquili
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,Discipline of Psychology, College of Science, Health, Engineering and Education, Murdoch University, Perth, Western Australia, Australia
| | - Kah Hui Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,Faculty of Medicine, Department of Anatomy, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Amy Cheuk Yin Lo
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Leanne Lai Hang Chan
- Department of Electrical Engineering, City University of Hong Kong, Hong Kong SAR, China
| | - Ying-Shing Chan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Lee Wei Lim
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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31
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Lambuk L, Ahmad S, Sadikan MZ, Nordin NA, Kadir R, Nasir NAA, Chen X, Boer J, Plebanski M, Mohamud R. Targeting Differential Roles of Tumor Necrosis Factor Receptors as a Therapeutic Strategy for Glaucoma. Front Immunol 2022; 13:857812. [PMID: 35651608 PMCID: PMC9149562 DOI: 10.3389/fimmu.2022.857812] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
Glaucoma is an irreversible sight-threatening disorder primarily due to elevated intraocular pressure (IOP), leading to retinal ganglion cell (RGC) death by apoptosis with subsequent loss of optic nerve fibers. A considerable amount of empirical evidence has shown the significant association between tumor necrosis factor cytokine (TNF; TNFα) and glaucoma; however, the exact role of TNF in glaucoma progression remains unclear. Total inhibition of TNF against its receptors can cause side effects, although this is not the case when using selective inhibitors. In addition, TNF exerts its antithetic roles via stimulation of two receptors, TNF receptor I (TNFR1) and TNF receptor II (TNFR2). The pro-inflammatory responses and proapoptotic signaling pathways predominantly mediated through TNFR1, while neuroprotective and anti-apoptotic signals induced by TNFR2. In this review, we attempt to discuss the involvement of TNF receptors (TNFRs) and their signaling pathway in ocular tissues with focus on RGC and glial cells in glaucoma. This review also outlines the potential application TNFRs agonist and/or antagonists as neuroprotective strategy from a therapeutic standpoint. Taken together, a better understanding of the function of TNFRs may lead to the development of a treatment for glaucoma.
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Affiliation(s)
- Lidawani Lambuk
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Suhana Ahmad
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Muhammad Zulfiqah Sadikan
- Centre for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Malaysia
| | - Nor Asyikin Nordin
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Ramlah Kadir
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
| | - Nurul Alimah Abdul Nasir
- Centre for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Malaysia
| | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
| | - Jennifer Boer
- School of Health and Biomedical Sciences, Royal Melbourne Institute Technology (RMIT) University, Bundoora, VIC, Australia
| | - Magdalena Plebanski
- School of Health and Biomedical Sciences, Royal Melbourne Institute Technology (RMIT) University, Bundoora, VIC, Australia
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia
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32
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Loi JK, Alexandre YO, Senthil K, Schienstock D, Sandford S, Devi S, Christo SN, Mackay LK, Chinnery HR, Osborne PB, Downie LE, Sloan EK, Mueller SN. Corneal tissue-resident memory T cells form a unique immune compartment at the ocular surface. Cell Rep 2022; 39:110852. [PMID: 35613584 DOI: 10.1016/j.celrep.2022.110852] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 03/27/2022] [Accepted: 04/29/2022] [Indexed: 11/03/2022] Open
Abstract
The eye is considered immune privileged such that immune responses are dampened to protect vision. As the most anterior compartment of the eye, the cornea is exposed to pathogens and can mount immune responses that recruit effector T cells. However, presence of immune memory in the cornea is not defined. Here, we use intravital 2-photon microscopy to examine T cell responses in the cornea in mice. We show that recruitment of CD8+ T cells in response to ocular virus infection results in the formation of tissue-resident memory T (TRM) cells. Motile corneal TRM cells patrol the cornea and rapidly respond in situ to antigen rechallenge. CD103+ TRM cell generation requires antigen and transforming growth factor β. In vivo imaging in humans also reveals highly motile cells that patrol the healthy cornea. Our study finds that TRM cells form in the cornea where they can provide local protective immunity.
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Affiliation(s)
- Joon Keit Loi
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Yannick O Alexandre
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Kirthana Senthil
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Dominik Schienstock
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Sarah Sandford
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Sapna Devi
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Susan N Christo
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Laura K Mackay
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Holly R Chinnery
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC, Australia
| | - Peregrine B Osborne
- Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, VIC, Australia
| | - Laura E Downie
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC, Australia
| | - Erica K Sloan
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; Division of Surgery, Peter MacCallum Cancer Center, Melbourne, VIC, Australia
| | - Scott N Mueller
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
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33
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Mitchell JL, MacDougall L, Dobromylskyj MJ, Smith K, Stavinohova R, Gunn-Moore DA, Hope JC, Scurrell E. Ocular mycobacterial lesions in cats. Vet Pathol 2022; 59:792-805. [PMID: 35587045 PMCID: PMC9358306 DOI: 10.1177/03009858221098431] [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] [Indexed: 11/16/2022]
Abstract
Ocular mycobacterial infections are an under-recognized cause of morbidity in the
domestic cat. This study aimed to explore the distribution, histopathological
appearance, and severity of feline ocular mycobacterial lesions, and to
characterize the immune cell population with immunohistochemistry. Routine
histological staining with hematoxylin and eosin, and Masson’s trichrome, was
performed to identify ocular lesions and assign an inflammation score based on
the number of cells present. Acid-fast bacilli were detected with Ziehl-Neelsen,
and immunohistochemistry for ionized calcium-binding adaptor protein-1 (Iba1),
calprotectin, cluster of differentiation 3 (CD3), and Pax5 was undertaken on
formalin-fixed paraffin-embedded tissue samples from 24 cases of ocular
mycobacteriosis. Posterior or panuveitis with concurrent retinitis was
identified in 20/24 cases (83%), with retinal detachment in 16/20 (80%) of these
cases. Choroidal lesions had the highest median inflammation score.
Ziehl-Neelsen-positive organisms were detected in 20/24 cases (83%), with the
highest prevalence of acid-fast bacilli detected in choroidal lesions (16/20,
80%). Lesions were typically granulomatous to pyogranulomatous, characterized by
abundant numbers of Iba1-positive macrophages, followed by calprotectin-positive
granulocytes and monocytes, fewer T cells, and rarer B cells. However, where
iritis was identified, inflammation was typically lymphoplasmacytic (11/16
cases, 69%). Where diagnostic testing was performed, tuberculosis (ie, infection
with Mycobacterium bovis, Mycobacterium
microti, or a nonspeciated Mycobacterium
tuberculosis-complex pathogen) was diagnosed in 20/22 cats (91%),
with Mycobacterium lepraemurium infection identified in the
other 2/22 cats (9%). These results suggest the choroid is the primary site of
lesion development in most cases of feline ocular mycobacteriosis, and
inflammatory changes are associated with the presence of mycobacteria localized
to ocular tissues.
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Affiliation(s)
| | | | | | - Ken Smith
- Royal Veterinary College, Hatfield, UK
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Zhang W, Schönberg A, Bock F, Cursiefen C. Posttransplant VEGFR1R2 Trap Eye Drops Inhibit Corneal (Lymph)angiogenesis and Improve Corneal Allograft Survival in Eyes at High Risk of Rejection. Transl Vis Sci Technol 2022; 11:6. [PMID: 35533080 PMCID: PMC9100603 DOI: 10.1167/tvst.11.5.6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose To assess whether topical application of VEGFR1R2 Trap after corneal transplantation can impair corneal (lymph)angiogenesis and promote murine corneal allograft survival in eyes at high risk of rejection. Methods We used the murine model of suture-induced neovascularization and subsequent keratoplasty in eyes at high risk of rejection, which is an established model for local drug application. After transplantation, the mice were treated with either VEGFR1R2 Trap (aflibercept) or human IgG Fc as eye drops for 2 weeks (three times/d). Deposition of VEGFR1R2 Trap in corneal tissue was detected by immunohistochemistry. Two and 8 weeks after transplantation, corneal (lymph)angiogenesis was assessed morphometrically. Dendritic cells (DCs) and regulatory T cells (Tregs) in the draining lymph nodes (dLNs) were examined by flow cytometry. Allograft survival was determined by corneal graft opacity scores. Results Topically applied VEGFR1R2 Trap penetrated into corneal host and graft stroma after keratoplasty in eyes at high risk of rejection. Additional postsurgical corneal hemangiogenesis (P < 0.0001) and lymphangiogenesis (P < 0.01) as well as infiltrating CD45+ leukocytes (P < 0.001) and macrophages (P < 0.01) were significantly reduced in the VEGFR1R2 Trap group compared to controls. VEGFR1R2 Trap eye drops significantly decreased the frequency of total CD11c+ DCs (P < 0.01), as well as activated CD11c+MHC II+ DCs (P < 0.01) and CD11c+CD40+ DCs (P < 0.05). In contrast, the frequency of CD200R+ regulatory DCs (P < 0.05) and Tregs in dLNs (P < 0.01) was enhanced. Moreover, long-term allograft survival was also improved (P < 0.05). Conclusions Temporary, topical application of VEGFR1R2 Trap after corneal transplantation can achieve sufficient anti-VEGF activity, inhibit additional (lymph)angiogenesis, and significantly improve corneal allograft survival in eyes at high risk of rejection. Translational Relevance VEGFR1R2 Trap eye drops after transplantation present a new therapeutic option for patients undergoing corneal transplantation and are at high risk of graft rejection.
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Affiliation(s)
- Wei Zhang
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Alfrun Schönberg
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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35
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Bonillo M, Pfromm J, Fischer MD. Challenges to Gene Editing Approaches in the Retina. Klin Monbl Augenheilkd 2022; 239:275-283. [PMID: 35316854 DOI: 10.1055/a-1757-9810] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Retinal gene therapy has recently been at the cutting edge of clinical development in the diverse field of genetic therapies. The retina is an attractive target for genetic therapies such as gene editing due to the distinctive anatomical and immunological features of the eye, known as immune privilege, so that inherited retinal diseases (IRDs) have been studied in several clinical studies. Thus, rapid strides are being made toward developing targeted treatments for IRDs. Gene editing in the retina faces a group of heterogenous challenges, including editing efficiencies, off-target effects, the anatomy of the target organ, immune responses, inactivation, and identifying optimal application methods. As clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated nuclease (Cas) based technologies are at the forefront of current gene editing advances, their specific editing efficiency challenges and potential off-target effects were assessed. The immune privilege of the eye reduces the likelihood of systemic immune responses following retinal gene therapy, but possible immune responses must not be discounted. Immune responses to gene editing in the retina may be humoral or cell mediated, with immunologically active cells, including microglia, implicated in facilitating possible immune responses to gene editing. Immunogenicity of gene therapeutics may also lead to the inactivation of edited cells, reducing potential therapeutic benefits. This review outlines the broad spectrum of potential challenges currently facing retinal gene editing, with the goal of facilitating further advances in the safety and efficacy of gene editing therapies.
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Affiliation(s)
- Mario Bonillo
- Clinic of Ophthalmology, University Eye Hospital, University Hospital Tübingen, Tübingen, Germany.,Clinic of Ophthalmology, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany
| | - Julia Pfromm
- Clinic of Ophthalmology, University Eye Hospital, University Hospital Tübingen, Tübingen, Germany.,Clinic of Ophthalmology, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany
| | - M Dominik Fischer
- Clinic of Ophthalmology, University Eye Hospital, University Hospital Tübingen, Tübingen, Germany.,Clinic of Ophthalmology, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany.,Oxford University NHS Foundation Trust, Oxford Eye Hospital, Oxford, United Kingdom of Great Britain and Northern Ireland.,Department of Clinical Neurosciences, University of Oxford Nuffield Laboratory of Ophthalmology, Oxford, United Kingdom of Great Britain and Northern Ireland
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36
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Busch M, Pfeil JM, Dähmcke M, Brauckmann T, Großjohann R, Chisci V, Hunfeld E, Eilts S, Omran W, Morawiec‐Kisiel E, Schulz D, Paul S, Tayar A, Bründer M, Grundel B, Küstner M, Stahl A. Anti-drug antibodies to brolucizumab and ranibizumab in serum and vitreous of patients with ocular disease. Acta Ophthalmol 2022; 100:903-910. [PMID: 35225432 DOI: 10.1111/aos.15124] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/26/2022] [Accepted: 02/18/2022] [Indexed: 12/15/2022]
Affiliation(s)
- Martin Busch
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Johanna M. Pfeil
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Merlin Dähmcke
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Tara Brauckmann
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Rico Großjohann
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Viola Chisci
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Elisabeth Hunfeld
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Sonja Eilts
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Wael Omran
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Ewa Morawiec‐Kisiel
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Daniel Schulz
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Sebastian Paul
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | - Allam Tayar
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | | | - Bastian Grundel
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
| | | | - Andreas Stahl
- Department of Ophthalmology University Medical Center Greifswald Greifswald Germany
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37
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Reinehr S, Mueller-Buehl AM, Tsai T, Joachim SC. Specific Biomarkers in the Aqueous Humour of Glaucoma Patients. Klin Monbl Augenheilkd 2022; 239:169-176. [PMID: 35211939 DOI: 10.1055/a-1690-7468] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Glaucoma, a multifactorial neurodegenerative disease, is the second most common cause of blindness. Since early diagnosis facilitates timely treatment, it is therefore essential to identify appropriate markers. In the future, so-called biomarkers could be helpful in early detection and follow-up. In glaucoma, these parameters could be obtained in the aqueous humour. Altered antibodies, proteins, microRNA (miRNA) and trace element levels have already been identified. This review provides insight into possible changes in the aqueous humour of patients with primary open-angle glaucoma (POAG), normal tension glaucoma (NTG) or pseudoexfoliation glaucoma (PEXG). Studies on antibody changes in POAG patients identified an upregulation of immune system associated antibodies such as heat shock protein (HSP) 27. HSP27 was also upregulated in PEXG patients but decreased in NTG. In POAG and PEXG samples, the levels of certain proteins, including interleukins and endothelin-1, were elevated. The vasoconstrictor endothelin-1 may play a role in regulating intraocular pressure. By contrast, proteins playing a role in the response to oxidative stress were downregulated. In NTG patients, proteins responsible for the elimination of toxic by-products from the respiratory chain were downregulated. In addition, the aqueous humour of POAG and PEXG patients contained several miRNAs that have been linked to tissue development, neurological disease and cellular organisation. Other miRNAs regulated in glaucoma play a role in extracellular matrix remodelling and thus may affect drainage resistance in the trabecular meshwork. It is also interesting to note that the aqueous humour of glaucoma patients showed changes in the levels of trace elements such as zinc and selenium. The elevated zinc levels could be responsible for the imbalance of intraocular matrix metalloproteinases and thus for increased intraocular pressure. All these studies demonstrate the complex changes in aqueous humour in glaucoma. Some of these biomarkers may be useful in the future for early diagnosis of the disease.
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Affiliation(s)
- Sabrina Reinehr
- Experimental Eye Research Institute, Ruhr-Universität Bochum, Deutschland
| | | | - Teresa Tsai
- Experimental Eye Research Institute, Ruhr-Universität Bochum, Deutschland
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38
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Mahaling B, Low SWY, Beck M, Kumar D, Ahmed S, Connor TB, Ahmad B, Chaurasia SS. Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders. Int J Mol Sci 2022; 23:ijms23052591. [PMID: 35269741 PMCID: PMC8910759 DOI: 10.3390/ijms23052591] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 12/13/2022] Open
Abstract
Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells. Recent evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, high glucose, oxidative stress, ischemia, mechanical trauma, stress, or environmental conditions, in retinal diseases. DAMPs activate the innate immune system, suggesting their role to be protective, but may promote pathological inflammation and angiogenesis in response to the chronic insult or injury. DAMPs are recognized by specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs) and the NOD-like receptor family (NLRs), and purine receptor 7 (P2X7), in systemic diseases. However, studies describing the role of DAMPs in retinal disorders are meager. Here, we extensively reviewed the role of DAMPs in retinal disorders, including endophthalmitis, uveitis, glaucoma, ocular cancer, ischemic retinopathies, diabetic retinopathy, age-related macular degeneration, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, and inherited retinal disorders. Finally, we discussed DAMPs as biomarkers, therapeutic targets, and therapeutic agents for retinal disorders.
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Affiliation(s)
- Binapani Mahaling
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Shermaine W. Y. Low
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Molly Beck
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Devesh Kumar
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Simrah Ahmed
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
| | - Thomas B. Connor
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
- Vitreoretinal Surgery, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Baseer Ahmad
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
- Vitreoretinal Surgery, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shyam S. Chaurasia
- Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Froedtert and MCW Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (B.M.); (S.W.Y.L.); (M.B.); (D.K.); (S.A.); (T.B.C.); (B.A.)
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence: ; Tel.: +1-414-955-2050
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39
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Endogenous Endophthalmitis-The Clinical Significance of the Primary Source of Infection. J Clin Med 2022; 11:jcm11051183. [PMID: 35268274 PMCID: PMC8911070 DOI: 10.3390/jcm11051183] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/05/2022] [Accepted: 02/21/2022] [Indexed: 02/01/2023] Open
Abstract
Endophthalmitis is a severe form of ocular inflammation. The source of pathogens in endogenous endophthalmitis is located inside the body, and infection spreads hematogenously. Although rare, endogenous endophthalmitis is a very serious condition, as this type of inflammation is very devastating for ocular tissues. Prognosis is very poor, and the patients are often in a serious general condition, so they require special care and an individual approach in the treatment process. Thanks to the knowledge of the risks associated with infections of individual tissues and organs as well as potential pathogens and the clinical picture, it is possible to make a correct diagnosis faster and implement the correct treatment. In the case of endogenous endophthalmitis, reaction time is absolutely crucial for prognosis. In this review, we focus primarily on the importance of the primary source of infection for the course of the disease and prognosis.
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40
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DeDreu J, Pal-Ghosh S, Mattapallil MJ, Caspi RR, Stepp MA, Menko AS. Uveitis-mediated immune cell invasion through the extracellular matrix of the lens capsule. FASEB J 2021; 36:e21995. [PMID: 34874579 PMCID: PMC9300120 DOI: 10.1096/fj.202101098r] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/20/2021] [Accepted: 10/04/2021] [Indexed: 12/05/2022]
Abstract
While the eye is considered an immune privileged site, its privilege is abrogated when immune cells are recruited from the surrounding vasculature in response to trauma, infection, aging, and autoimmune diseases like uveitis. Here, we investigate whether in uveitis immune cells become associated with the lens capsule and compromise its privilege in studies of C57BL/6J mice with experimental autoimmune uveitis. These studies show that at D14, the peak of uveitis in these mice, T cells, macrophages, and Ly6G/Ly6C+ immune cells associate with the lens basement membrane capsule, burrow into the capsule matrix, and remain integrated with the capsule as immune resolution is occurring at D26. 3D surface rendering image analytics of confocal z‐stacks and scanning electron microscopy imaging of the lens surface show the degradation of the lens capsule as these lens‐associated immune cells integrate with and invade the lens capsule, with a subset infiltrating both epithelial and fiber cell regions of lens tissue, abrogating its immune privilege. Those immune cells that remain on the surface often become entwined with a fibrillar net‐like structure. Immune cell invasion of the lens capsule in uveitis has not been described previously and may play a role in induction of lens and other eye pathologies associated with autoimmunity.
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Affiliation(s)
- JodiRae DeDreu
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Sonali Pal-Ghosh
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Mary J Mattapallil
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Rachel R Caspi
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mary Ann Stepp
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.,Department of Ophthalmology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - A Sue Menko
- Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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41
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Rodrigo MJ, Subías M, Montolío A, Méndez-Martínez S, Martínez-Rincón T, Arias L, García-Herranz D, Bravo-Osuna I, Garcia-Feijoo J, Pablo L, Cegoñino J, Herrero-Vanrell R, Carretero A, Ruberte J, Garcia-Martin E, Pérez del Palomar A. Analysis of Parainflammation in Chronic Glaucoma Using Vitreous-OCT Imaging. Biomedicines 2021; 9:biomedicines9121792. [PMID: 34944608 PMCID: PMC8698891 DOI: 10.3390/biomedicines9121792] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/22/2021] [Accepted: 11/25/2021] [Indexed: 11/25/2022] Open
Abstract
Glaucoma causes blindness due to the progressive death of retinal ganglion cells. The immune response chronically and subclinically mediates a homeostatic role. In current clinical practice, it is impossible to analyse neuroinflammation non-invasively. However, analysis of vitreous images using optical coherence tomography detects the immune response as hyperreflective opacities. This study monitors vitreous parainflammation in two animal models of glaucoma, comparing both healthy controls and sexes over six months. Computational analysis characterizes in vivo the hyperreflective opacities, identified histologically as hyalocyte-like Iba-1+ (microglial marker) cells. Glaucomatous eyes showed greater intensity and number of vitreous opacities as well as dynamic fluctuations in the percentage of activated cells (50–250 microns2) vs. non-activated cells (10–50 microns2), isolated cells (10 microns2) and complexes (>250 microns2). Smaller opacities (isolated cells) showed the highest mean intensity (intracellular machinery), were the most rounded at earlier stages (recruitment) and showed the greatest change in orientation (motility). Study of vitreous parainflammation could be a biomarker of glaucoma onset and progression.
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Affiliation(s)
- María Jesús Rodrigo
- Department of Ophthalmology, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (M.S.); (S.M.-M.); (T.M.-R.); (L.A.); (L.P.); (E.G.-M.)
- Miguel Servet Ophthalmology Research Group (GIMSO), Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain
- National Ocular Pathology Network (OFTARED), Carlos III Health Institute, 28040 Madrid, Spain;
- Correspondence: ; Tel.: +34-976765558; Fax: +34-976566234
| | - Manuel Subías
- Department of Ophthalmology, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (M.S.); (S.M.-M.); (T.M.-R.); (L.A.); (L.P.); (E.G.-M.)
- Miguel Servet Ophthalmology Research Group (GIMSO), Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain
| | - Alberto Montolío
- Biomaterials Group, Aragon Engineering Research Institute (I3A), University of Zaragoza, 50018 Zaragoza, Spain; (A.M.); (J.C.); (A.P.d.P.)
- Department of Mechanical Engineering, University of Zaragoza, 50018 Zaragoza, Spain
| | - Silvia Méndez-Martínez
- Department of Ophthalmology, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (M.S.); (S.M.-M.); (T.M.-R.); (L.A.); (L.P.); (E.G.-M.)
- Miguel Servet Ophthalmology Research Group (GIMSO), Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain
| | - Teresa Martínez-Rincón
- Department of Ophthalmology, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (M.S.); (S.M.-M.); (T.M.-R.); (L.A.); (L.P.); (E.G.-M.)
- Miguel Servet Ophthalmology Research Group (GIMSO), Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain
| | - Lorena Arias
- Department of Ophthalmology, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (M.S.); (S.M.-M.); (T.M.-R.); (L.A.); (L.P.); (E.G.-M.)
- Miguel Servet Ophthalmology Research Group (GIMSO), Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain
| | - David García-Herranz
- Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal) Research Group, UCM 920415, Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid (UCM), 28040 Madrid, Spain;
- Health Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain
- University Institute of Industrial Pharmacy (IUFI), School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Irene Bravo-Osuna
- University Institute of Industrial Pharmacy (IUFI), School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Julian Garcia-Feijoo
- Department of Ophthalmology, San Carlos Clinical Hospital, UCM, 28040 Madrid, Spain;
| | - Luis Pablo
- Department of Ophthalmology, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (M.S.); (S.M.-M.); (T.M.-R.); (L.A.); (L.P.); (E.G.-M.)
- Miguel Servet Ophthalmology Research Group (GIMSO), Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain
- National Ocular Pathology Network (OFTARED), Carlos III Health Institute, 28040 Madrid, Spain;
| | - José Cegoñino
- Biomaterials Group, Aragon Engineering Research Institute (I3A), University of Zaragoza, 50018 Zaragoza, Spain; (A.M.); (J.C.); (A.P.d.P.)
- Department of Mechanical Engineering, University of Zaragoza, 50018 Zaragoza, Spain
| | - Rocio Herrero-Vanrell
- National Ocular Pathology Network (OFTARED), Carlos III Health Institute, 28040 Madrid, Spain;
- University Institute of Industrial Pharmacy (IUFI), School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Ana Carretero
- Centre for Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; (A.C.); (J.R.)
- CIBER for Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain
- Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Jesus Ruberte
- Centre for Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; (A.C.); (J.R.)
- CIBER for Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain
- Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Elena Garcia-Martin
- Department of Ophthalmology, Miguel Servet University Hospital, 50009 Zaragoza, Spain; (M.S.); (S.M.-M.); (T.M.-R.); (L.A.); (L.P.); (E.G.-M.)
- Miguel Servet Ophthalmology Research Group (GIMSO), Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain
- National Ocular Pathology Network (OFTARED), Carlos III Health Institute, 28040 Madrid, Spain;
| | - Amaya Pérez del Palomar
- Biomaterials Group, Aragon Engineering Research Institute (I3A), University of Zaragoza, 50018 Zaragoza, Spain; (A.M.); (J.C.); (A.P.d.P.)
- Department of Mechanical Engineering, University of Zaragoza, 50018 Zaragoza, Spain
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Zhang W, Schönberg A, Hamdorf M, Georgiev T, Cursiefen C, Bock F. Preincubation of donor tissue with a VEGF cytokine trap promotes subsequent high-risk corneal transplant survival. Br J Ophthalmol 2021; 106:1617-1626. [PMID: 34810177 DOI: 10.1136/bjophthalmol-2021-319745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 09/07/2021] [Indexed: 11/03/2022]
Abstract
AIMS Pathological neovascularisation of the host bed and the transplant itself is the main risk factor for graft rejection after corneal transplantation. This study aims to prevent this process by preincubation of the corneal donor tissue ex vivo with an antivascular endothelial growth factor (VEGF) cytokine trap blocking additional postsurgical hemangiogenesis and lymphangiogenesis to promote high-risk graft survival. METHODS The donor tissue was preincubated with a VEGFR1R2 cytokine trap for 24 hours prior to murine high-risk corneal transplantation (human IgG Fc was used as the control). The distribution of VEGFR1R2 Trap in the cornea was investigated by immunohistochemistry. Corneas were excised to quantify the blood vessels (BVs) and lymphatic vessels (LVs) and draining lymph nodes (dLNs) were harvested to analyse the phenotype of dendritic cells (DCs) and T cells at week 1, 2 and 8 post-transplantation. Graft survival was compared between preincubation with VEGFR1R2 Trap and human IgG Fc in high-risk recipients. RESULTS VEGFR1R2 Trap was present in the graft for at least 2 weeks after surgery and additionally diffused into the corneal recipient. BVs, LVs and macrophages in the whole cornea were significantly decreased 1-week and 2-week post-transplantation (p<0.05). In dLNs the frequency of CD11c+DCs was significantly reduced, whereas CD200R+ regulatory DCs were significantly increased after keratoplasty (p<0.05). Furthermore, long-term high-risk graft survival was significantly improved (p<0.01). CONCLUSIONS Preincubation of corneal donor tissue with a VEGFR1R2 cytokine trap can significantly promote subsequent high-risk corneal transplant survival and thereby opens new treatment avenues for high-risk corneal transplantation.
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Affiliation(s)
- Wei Zhang
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.,Department of Ophthalmology, Hebei Eye Hospital, Xingtai, Hebei, China
| | - Alfrun Schönberg
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Matthias Hamdorf
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Tihomir Georgiev
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany .,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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McDonald T, Muhammad F, Peters K, Lee DJ. Combined Deficiency of the Melanocortin 5 Receptor and Adenosine 2A Receptor Unexpectedly Provides Resistance to Autoimmune Disease in a CD8 + T Cell-Dependent Manner. Front Immunol 2021; 12:742154. [PMID: 34867964 PMCID: PMC8634946 DOI: 10.3389/fimmu.2021.742154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/28/2021] [Indexed: 12/15/2022] Open
Abstract
Regulatory immunity that provides resistance to relapse emerges during resolution of experimental autoimmune uveitis (EAU). This post-EAU regulatory immunity requires a melanocortin 5 receptor (MC5r)-dependent suppressor antigen presenting cell (APC), as shown using a MC5r single knock-out mouse. The MC5r-dependent APC activates an adenosine 2A receptor (A2Ar)-dependent regulatory Treg cell, as shown using an A2Ar single knock-out mouse. Unexpectedly, when MC5r-/- post-EAU APC were used to activate A2Ar-/- post-EAU T cells the combination of cells significantly suppressed EAU, when transferred to EAU mice. In contrast, transfer of the reciprocal activation scheme did not suppress EAU. In order to explain this finding, MC5r-/-A2Ar-/- double knock-out (DKO) mice were bred. Naïve DKO mice had no differences in the APC populations, or inflammatory T cell subsets, but did have significantly more Treg cells. When we examined the number of CD4 and CD8 T cell subsets, we found significantly fewer CD8 T cells in the DKO mice compared to WT and both single knock-out mice. DKO mice also had significantly reduced EAU severity and accelerated resolution. In order to determine if the CD8 T cell deficiency contributed to the resistance to EAU in the DKO mice, we transferred naïve CD8 T cells from WT mice, that were immunized for EAU. Susceptibility to EAU was restored in DKO mice that received a CD8 T cell transfer. While the mechanism that contributed to the CD8 T cell deficiency in the DKO mice remains to be determined, these observations indicate an importance of CD8 T cells in the initiation of EAU. The involvement of CD4 and CD8 T cells suggests that both class I and class II antigen presentation can trigger an autoimmune response, suggesting a much wider range of antigens may trigger autoimmune disease.
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Affiliation(s)
- Trisha McDonald
- Dean McGee Eye Institute, Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Fauziyya Muhammad
- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Kayleigh Peters
- Dean McGee Eye Institute, Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Darren J. Lee
- Dean McGee Eye Institute, Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States,Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States,*Correspondence: Darren J. Lee,
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Abstract
Childhood noninfectious uveitis leads to sight-threatening complications. Idiopathic chronic anterior uveitis and juvenile idiopathic arthritis-associated uveitis are most common. Inflammation arises from an immune response against antigens within the eye. Ophthalmic work-up evaluates anatomic involvement, disease activity, ocular complications, and disease course. Local and/or systemic glucocorticoids are initial treatment, but not as long-term sole therapy to avoid glucocorticoids-induced toxicity or persistent ocular inflammation. Children with recurrent, refractory, or severe disease require systemic immunosuppression with methotrexate and/or anti-tumor necrosis factor monoclonal antibody medications (adalimumab, infliximab). Goals of early detection and treatment are to optimize vision in childhood uveitis.
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Affiliation(s)
- Margaret H Chang
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Fegan 6, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Jessica G Shantha
- Department of Ophthalmology, Emory University, Emory Eye Center, 1365 Clifton Road, Clinic Building B, Atlanta, GA 30326, USA
| | - Jacob J Fondriest
- Department of Internal Medicine, Summa Health System, Internal Medicine Center, 55 Arch Street, Suite 1B, Akron, OH 44304, USA; Rush Eye Center, 1725 West Harrison Street, Suite 945, Chicago, IL 60612, USA
| | - Mindy S Lo
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Fegan 6, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Sheila T Angeles-Han
- Division of Rheumatology, Cincinnati Children's Hospital Medical Center, 3333 Burnett Avenue, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA; Division of Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, USA.
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German OL, Vallese-Maurizi H, Soto TB, Rotstein NP, Politi LE. Retina stem cells, hopes and obstacles. World J Stem Cells 2021; 13:1446-1479. [PMID: 34786153 PMCID: PMC8567457 DOI: 10.4252/wjsc.v13.i10.1446] [Citation(s) in RCA: 8] [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: 04/28/2021] [Revised: 07/14/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023] Open
Abstract
Retinal degeneration is a major contributor to visual dysfunction worldwide. Although it comprises several eye diseases, loss of retinal pigment epithelial (RPE) and photoreceptor cells are the major contributors to their pathogenesis. Early therapies included diverse treatments, such as provision of anti-vascular endothelial growth factor and many survival and trophic factors that, in some cases, slow down the progression of the degeneration, but do not effectively prevent it. The finding of stem cells (SC) in the eye has led to the proposal of cell replacement strategies for retina degeneration. Therapies using different types of SC, such as retinal progenitor cells (RPCs), embryonic SC, pluripotent SCs (PSCs), induced PSCs (iPSCs), and mesenchymal stromal cells, capable of self-renewal and of differentiating into multiple cell types, have gained ample support. Numerous preclinical studies have assessed transplantation of SC in animal models, with encouraging results. The aim of this work is to revise the different preclinical and clinical approaches, analyzing the SC type used, their efficacy, safety, cell attachment and integration, absence of tumor formation and immunorejection, in order to establish which were the most relevant and successful. In addition, we examine the questions and concerns still open in the field. The data demonstrate the existence of two main approaches, aimed at replacing either RPE cells or photoreceptors. Emerging evidence suggests that RPCs and iPSC are the best candidates, presenting no ethical concerns and a low risk of immunorejection. Clinical trials have already supported the safety and efficacy of SC treatments. Serious concerns are pending, such as the risk of tumor formation, lack of attachment or integration of transplanted cells into host retinas, immunorejection, cell death, and also ethical. However, the amazing progress in the field in the last few years makes it possible to envisage safe and effective treatments to restore vision loss in a near future.
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Affiliation(s)
- Olga L German
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Harmonie Vallese-Maurizi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Tamara B Soto
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Nora P Rotstein
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Luis Enrique Politi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
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Soliman AM, Sim RH, Das S, Mahakkanukrauh P. Therapeutic Targeting of Inflammatory Pathways with Emphasis on NLRP3 Inflammasomes by Natural Products: A Novel Approach for the Treatment of Inflammatory Eye Diseases. Curr Med Chem 2021; 29:2891-2912. [PMID: 34514977 DOI: 10.2174/0929867328666210910154330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/15/2021] [Accepted: 07/23/2021] [Indexed: 11/22/2022]
Abstract
There is an increase in the incidence of inflammatory eye diseases worldwide. Several dysregulated inflammatory pathways, including the NOD-like receptor protein 3 (NLRP3) inflammasome, have been reported to contribute significantly to the pathogenesis and progression of ophthalmic diseases. Although the available allopathic/conventional medicine has demonstrated effectiveness in managing eye diseases, there is an ongoing global demand for alternative therapeutics with minimal adverse drug reactions, easy availability, increase in patient-compliance, and better disease outcome. Therefore, several studies are investigating the utilization of natural products and herbal formulations in impeding inflammatory pathways, including the NLRP3 inflammasome, in order to prevent or manage eye diseases. In the present review, we highlight the recently reported inflammatory pathways with special emphasis on NLRP3 Inflammasomes involved in the development of eye diseases. Furthermore, we present a variety of natural products and phytochemicals that were reported to interfere with these pathways and their underlying mechanisms of action. These natural products represent potential therapeutic applications for the treatment of several inflammatory eye diseases.
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Affiliation(s)
- Amro M Soliman
- Department of Biological Sciences-Physiology, Cell and Developmental Biology, University of Alberta, Edmonton, AB T6G 2R3. Canada
| | - Ru Hui Sim
- Tanglin Health Clinic, 50480 Kuala Lumpu. Malaysia
| | - Srijit Das
- Department of Human & Clinical Anatomy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat. Oman
| | - Pasuk Mahakkanukrauh
- Department of Anatomy & Excellence Center of Osteology Research and Training, Cadaveric Surgical and Training Center, Chiang Mai University. Thailand
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Armento A, Schmidt TL, Sonntag I, Merle DA, Jarboui MA, Kilger E, Clark SJ, Ueffing M. CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway. Int J Mol Sci 2021; 22:ijms22168727. [PMID: 34445430 PMCID: PMC8396051 DOI: 10.3390/ijms22168727] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.
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Affiliation(s)
- Angela Armento
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; (T.L.S.); (I.S.); (D.A.M.); (M.A.J.); (E.K.); (S.J.C.)
- Correspondence: (A.A.); (M.U.); Tel.: +49-7071-29-84953 (A.A.)
| | - Tiziana L. Schmidt
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; (T.L.S.); (I.S.); (D.A.M.); (M.A.J.); (E.K.); (S.J.C.)
| | - Inga Sonntag
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; (T.L.S.); (I.S.); (D.A.M.); (M.A.J.); (E.K.); (S.J.C.)
| | - David A. Merle
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; (T.L.S.); (I.S.); (D.A.M.); (M.A.J.); (E.K.); (S.J.C.)
- Department of Ophthalmology, Medical University of Graz, 8036 Graz, Austria
| | - Mohamed Ali Jarboui
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; (T.L.S.); (I.S.); (D.A.M.); (M.A.J.); (E.K.); (S.J.C.)
| | - Ellen Kilger
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; (T.L.S.); (I.S.); (D.A.M.); (M.A.J.); (E.K.); (S.J.C.)
| | - Simon J. Clark
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; (T.L.S.); (I.S.); (D.A.M.); (M.A.J.); (E.K.); (S.J.C.)
- Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Marius Ueffing
- Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; (T.L.S.); (I.S.); (D.A.M.); (M.A.J.); (E.K.); (S.J.C.)
- Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
- Correspondence: (A.A.); (M.U.); Tel.: +49-7071-29-84953 (A.A.)
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Local and systemic gene expression levels of IL-10, IL-17 and TGF-β in active ocular toxoplasmosis in humans. Cytokine 2021; 146:155643. [PMID: 34332275 DOI: 10.1016/j.cyto.2021.155643] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND To compare mRNA expression of interleukin 10 (IL-10), interleukin 17 (IL-17) and Transforming Growth Factor-β (TGF-β) in aqueous humor (AH) and peripheral blood mononuclear cells (PBMCs) in human ocular toxoplasmosis (OT) and controls. METHOD RNA isolation, cDNA synthesis and real-time polymerase chain reaction were performed on AH sediments and PBMCs of 16 patients with active OT and 21 controls at the Khatam-al-Anbia Eye Hospital, Iran. For comparison, Mann Whitney U test was used at a discrimination level of p < 0.05. Pearson and Spearman rank correlation test were applied for correlation with clinical parameters. RESULTS The expression for IL-10 and IL-17 in the AH was 3.7- and 88.0-fold higher in OT than in controls (P = 0.04 and P = 0.03, respectively) whereas that of TGF-β was 7.7-fold lower (P < 0.001). The expression levels for these cytokines in PBMC followed a similar pattern (IL-10 13.8-fold down-regulated (P = 0.001), IL-17 with 1.9-fold insignificantly upregulated (p = 0.43), TGF-β 452.8-fold down-regulated (P = 0.002). Compared to PBMC, IL-10 coding mRNA was 1876-fold higher in the almost cell-free AH in OT (39.2-fold in controls), IL-17 coding mRNA was 9.4-fold higher (17.7-fold down-regulated in controls), and that coding for TGF-β 207-fold higher in OT (7x105-fold in controls). The expression for IL-10, IL-17 and TGF-β in AH thus followed an opposite pattern compared to that in PBMC. CONCLUSION OT induces a highly-specific local immunoregulatory process as evidenced by an intraocular up-regulation of IL-10 and down-regulation of TGF-β mRNA. This could indicate an attempt to prevent unnecessary tissue damage which is in line with a moderate local mRNA up-regulation for IL-17 which seems sufficient to control parasite proliferation. That this regulation is opposite to that in PBMC may be linked to intraocular immune deviation in the course of disease.
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49
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Wildner G. Tumors, tumor therapies, autoimmunity and the eye. Autoimmun Rev 2021; 20:102892. [PMID: 34229046 DOI: 10.1016/j.autrev.2021.102892] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 04/25/2021] [Indexed: 12/12/2022]
Abstract
The eye as an immune privileged organ is mostly spared from (auto)immune attacks. Intraocular inflammation like autoimmune uveitis is a rare event. Nevertheless, tumor-related destructive autoimmune responses can affect the eye, as observed in the case of cancer- associated retinopathy (CAR), an autoantibody-mediated destruction of retinal cells induced by the ectopic expression of ocular antigens by peripheral tumors. The new tumor therapies targeting immune checkpoints to enhance anti-tumor responses can also induce autoimmune responses and result in autoimmune diseases even in immune privileged organs like the eyes. Even MEK/BRAF-inhibitor therapies using small molecules to block tumor-specific signal transduction molecules have turned out to not just inhibit tumor growth and survival and render tumors more susceptible for immune recognition, but to have additional toxic effects on non-dividing retinal cells, destroying and making them potential targets of autoimmunity.
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Affiliation(s)
- Gerhild Wildner
- Department of Ophthalmology, University Hospital, LMU Munich, Mathildenstr. 8, 80336 Munich, Germany.
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50
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Heindl LM, Platzl C, Wolfmeier H, Herwig-Carl MC, Kaser-Eichberger A, Strohmaier C, Schroedl F. Choroidal melanocytes: subpopulations of different origin? Ann Anat 2021; 238:151775. [PMID: 34082079 DOI: 10.1016/j.aanat.2021.151775] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The human choroid derives from the mesectoderm, except the melanocytes originating from the neuroectoderm. To date, it is unclear whether all choroidal melanocytes share the same origin or might have different origins. The purpose of this study was to screen immunohistochemically for mesenchymal elements in the adult healthy human choroid, in the malignant melanoma of the choroid, as well as in the developing human fetal choroid. METHODS Human choroids were obtained from cornea donors and prepared as flat whole mounts for paraffin- and cryoembedding. Globes enucleated for choroidal melanoma and eyes from human fetuses between 11 and 20 weeks of gestation were also embedded in paraffin. Sections were processed for immunohistochemistry of the mesenchymal marker vimentin, the melanocyte marker Melan-A, and the macrophage marker CD68, followed by light-, fluorescence-, and confocal laser scanning-microscopy. RESULTS The normal choroid contained 499 ± 139 vimentin, 384 ± 78 Melan-A, and 129 ± 57 CD68 immunoreactive cells/mm2. The vimentin immunopositive cell density was significantly higher than the density of Melan-A and CD68 immunopositive cells (p < 0.001, respectively). By confocal microscopy, 24 ± 8% of all choroidal melanocytes displayed vimentin immunoreactivity. In choroidal melanomas, numerous melanoma cells of the epithelioid and spindle cell type revealed immunopositivity for both vimentin and Melan-A. The intratumoral density of vimentin immunoreactive cells was 1758 ± 106 cells/mm2, significantly higher than the density of Melan-A and CD68 immunopositive cells (p < 0.001, respectively). Comparing to healthy choroidal tissue, the choroidal melanomas revealed significantly higher densities of vimentin, Melan-A, and CD68 immunoreactive cells (p < 0.001, respectively). In the developing human fetal choroid, numerous vimentin and Melan-A immunopositive cells were detected not before the 16th week of gestation, with some of them showing colocalization of vimentin and Melan-A. CONCLUSIONS The adult healthy human choroid is endowed with a significant number of vimentin immunopositive mesenchymal structures, including a subpopulation of vimentin immunoreactive choroidal melanocytes. These vimentin immunopositive melanocytic cells are also present in choroidal melanomas as well as in the developing human fetal choroid. Therefore, different embryologic origins can be considered for choroidal melanocytes.
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Affiliation(s)
- Ludwig M Heindl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria; Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
| | - Christian Platzl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria.
| | - Heidi Wolfmeier
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria.
| | - Martina C Herwig-Carl
- Department of Ophthalmology, Division of Ophthalmic Pathology, University Hospital Bonn, Bonn, Germany.
| | - Alexandra Kaser-Eichberger
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria.
| | - Clemens Strohmaier
- Department of Ophthalmology and Optometry, Johannes Kepler University, Linz, Austria.
| | - Falk Schroedl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria.
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