Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.8
5.6
Journals
IJMS
Special Issues
Mechanisms of Dry Eye Diseases
ijms-logo
Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Mechanisms of Dry Eye Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 68383

Special Issue Editors

Dr. Cintia S. De Paiva

E-Mail Website
Guest Editor
Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
Interests: Sjögren syndrome; dry eye; lacrimal gland; aging; microbiome; dendritic cells; CD4+ T cells; goblet cells
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Stephen C. Pflugfelder

E-Mail Website
Guest Editor
Cullen Eye Institute, Houston, TX, USA
Interests: dry eye; ocular surface; autoimmunity; Sjogren syndrome; conjunctiva; goblet cells; dendritic cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Dry eye is one of the most prevalent diseases affecting tens of millions worldwide, and it is among the most common reasons to seek eye care. Clinically, patients often report ocular discomfort or pain and decreased functional vision. More severe cases may develop sight-threatening corneal complications. Dry eye disease is a multifactorial disease that destabilizes the tear film and causes epithelial disease and inflammation. Although our understanding of the pathological mechanisms has increased in the past 20 years, there is still much to discover about mechanisms causing inflammation, glandular and mucosal disease, and tear instability.

In this Special Issue of IJMS, we are seeking articles that provide new insights into the underlying mechanisms of dry eye disease, including molecular and cellular mechanisms involved in the initiation and perpetuation of inflammation and epithelial disease, new diagnostic tools/biomarkers, and new therapies and treatment options. We are looking for both clinical and preclinical studies with an emphasis on molecular biology; animal models of disease are encouraged.

Assoc. Prof. Cintia S. de Paiva
Prof. Stephen C. Pflugfelder
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • dry eye
  • corneal barrier function
  • goblet cells
  • lacrimal gland
  • animal models of dry eye
  • biomarkers
  • inflammation

Related Special Issue

Published Papers (18 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

19 pages, 3402 KiB  
Article
Characterization of Type I Interferon-Associated Chemokines and Cytokines in Lacrimal Glands of Nonobese Diabetic Mice
by Merri-Grace Allred, Michael S. Chimenti, Ashley E. Ciecko, Yi-Guang Chen and Scott M. Lieberman
Int. J. Mol. Sci. 2021, 22(7), 3767; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073767 - 05 Apr 2021
Cited by 7 | Viewed by 2307
Abstract
Type I interferons (IFNs) are required for spontaneous lacrimal gland inflammation in the nonobese diabetic (NOD) mouse model of Sjögren’s disease, but the consequences of type I IFN signaling are not well-defined. Here, we use RNA sequencing to define cytokine and chemokine genes [...] Read more.
Type I interferons (IFNs) are required for spontaneous lacrimal gland inflammation in the nonobese diabetic (NOD) mouse model of Sjögren’s disease, but the consequences of type I IFN signaling are not well-defined. Here, we use RNA sequencing to define cytokine and chemokine genes upregulated in lacrimal glands of NOD mice in a type I IFN-dependent manner. Interleukin (IL)-21 was the highest differentially expressed cytokine gene, and Il21 knockout NOD mice were relatively protected from lacrimal gland inflammation. We defined a set of chemokines upregulated early in disease including Cxcl9 and Cxcl10, which share a receptor, CXCR3. CXCR3+ T cells were enriched in lacrimal glands with a dominant proportion of CXCR3+ regulatory T cells. Together these data define the early cytokine and chemokine signals associated with type I IFN-signaling in the development of lacrimal gland inflammation in NOD mice providing insight into the role of type I IFN in autoimmunity development. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

11 pages, 2236 KiB  
Article
Blue Light Induces Impaired Autophagy through Nucleotide-Binding Oligomerization Domain 2 Activation on the Mouse Ocular Surface
by Ying Li, Rujun Jin, Lan Li, Ji Suk Choi, Jonghwa Kim, Hyeon Jeong Yoon, Jong Hwan Park and Kyung Chul Yoon
Int. J. Mol. Sci. 2021, 22(4), 2015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042015 - 18 Feb 2021
Cited by 8 | Viewed by 2046
Abstract
In this study, we investigated the effects of blue light exposure on nucleotide-binding oligomerization domain 2 (NOD2) expression on the mouse ocular surface and evaluated the role of NOD2 activation in light-induced cell death. Mice were divided into wild-type (WT), NOD2-knock out (KO), [...] Read more.
In this study, we investigated the effects of blue light exposure on nucleotide-binding oligomerization domain 2 (NOD2) expression on the mouse ocular surface and evaluated the role of NOD2 activation in light-induced cell death. Mice were divided into wild-type (WT), NOD2-knock out (KO), WT + blue light (WT + BL), and NOD2-KO + blue light (NOD2-KO + BL) groups, and the mice in the WT+BL and NOD2-KO + BL groups were exposed to blue light for 10 days. After 10 days of blue light exposure, increased reactive oxygen species and malondialdehyde were observed in the WT + BL and NOD2-KO + BL groups, and the WT + BL group showed a higher expression of NOD2 and autophagy related 16 like 1. Although both WT+BL and NOD2-KO + BL groups showed an increase in the expression of light chain 3-II, NOD2-KO + BL mice had a significantly lower p62 expression than WT + BL mice. In addition, NOD2-KO+BL mice had significantly lower corneal epithelial damage and apoptosis than WT + BL mice. In conclusion, blue light exposure can induce impaired autophagy by activation of NOD2 on the ocular surface. In addition, the reactive oxygen species (ROS)–NOD2–autophagy related 16 like 1 (ATG16L) signaling pathway may be involved in the blue-light-induced autophagy responses, resulting in corneal epithelial apoptosis. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

21 pages, 4289 KiB  
Article
Rab27a Contributes to Cathepsin S Secretion in Lacrimal Gland Acinar Cells
by Runzhong Fu, Maria C. Edman and Sarah F. Hamm-Alvarez
Int. J. Mol. Sci. 2021, 22(4), 1630; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041630 - 05 Feb 2021
Cited by 5 | Viewed by 2691
Abstract
Altered lacrimal gland (LG) secretion is a feature of autoimmune dacryoadenitis in Sjögren’s syndrome (SS). Cathepsin S (CTSS) is increased in tears of SS patients, which may contribute to disease. Rab3D and Rab27a/b isoforms are effectors of exocytosis in LG, but Rab27a is [...] Read more.
Altered lacrimal gland (LG) secretion is a feature of autoimmune dacryoadenitis in Sjögren’s syndrome (SS). Cathepsin S (CTSS) is increased in tears of SS patients, which may contribute to disease. Rab3D and Rab27a/b isoforms are effectors of exocytosis in LG, but Rab27a is poorly studied. To investigate whether Rab27a mediates CTSS secretion, we utilized quantitative confocal fluorescence microscopy of LG from SS-model male NOD and control male BALB/c mice, showing that Rab27a-enriched vesicles containing CTSS were increased in NOD mouse LG. Live-cell imaging of cultured lacrimal gland acinar cells (LGAC) transduced with adenovirus encoding wild-type (WT) mCFP-Rab27a revealed carbachol-stimulated fusion and depletion of mCFP-Rab27a-enriched vesicles. LGAC transduced with dominant-negative (DN) mCFP-Rab27a exhibited significantly reduced carbachol-stimulated CTSS secretion by 0.5-fold and β-hexosaminidase by 0.3-fold, relative to stimulated LGAC transduced with WT mCFP-Rab27a. Colocalization of Rab27a and endolysosomal markers (Rab7, Lamp2) with the apical membrane was increased in both stimulated BALB/c and NOD mouse LG, but the extent of colocalization was much greater in NOD mouse LG. Following stimulation, Rab27a colocalization with endolysosomal membranes was decreased. In conclusion, Rab27a participates in CTSS secretion in LGAC though the major regulated pathway, and through a novel endolysosomal pathway that is increased in SS. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

11 pages, 2015 KiB  
Article
Retinoid Regulation of Ocular Surface Innate Inflammation
by Jehan Alam, Zhiyuan Yu, Cintia S. de Paiva and Stephen C. Pflugfelder
Int. J. Mol. Sci. 2021, 22(3), 1092; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031092 - 22 Jan 2021
Cited by 12 | Viewed by 3105
Abstract
Corneal and conjunctival inflammation and dry eye develop in systemic vitamin A deficiency (VAD). The objective of this study was to investigate the lacrimal ocular surface retinoid axis, particularly immunomodulatory effects of retinoic acid (RA) and change in conjunctival myeloid cell number and [...] Read more.
Corneal and conjunctival inflammation and dry eye develop in systemic vitamin A deficiency (VAD). The objective of this study was to investigate the lacrimal ocular surface retinoid axis, particularly immunomodulatory effects of retinoic acid (RA) and change in conjunctival myeloid cell number and phenotype in VAD. We discovered that ocular surface epithelial and myeloid cells express retinoid receptors. Both all trans- and 9-cis-RA suppressed production of dry eye relevant inflammatory mediators [interleukin(IL)-1β, IL-12, regulated upon activation, normal T cell expressed and secreted (RANTES)] by myeloid cells. Systemic VAD was associated with significant goblet cell loss and an increased number of CD45+ immune cells in the conjunctiva. MHCII−CD11b+ classical monocytes were significantly increased in the conjunctiva of VAD C57BL/6 and RXR-α mutated Pinkie strains. RNA seq revealed significantly increased expression of innate immune/inflammatory genes in the Pinkie conjunctiva. These findings indicate that retinoids are essential for maintaining a healthy, well-lubricated ocular surface and have immunomodulatory effects in the conjunctiva that are mediated in part via RXR-α signaling. Perturbation of the homeostatic retinoid axis could potentiate inflammation on the ocular surface. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

19 pages, 2639 KiB  
Article
Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Development in Male Nonobese Diabetic Mice
by Ivy L. Debreceni, Michael S. Chimenti, David V. Serreze, Aron M. Geurts, Yi-Guang Chen and Scott M. Lieberman
Int. J. Mol. Sci. 2020, 21(24), 9478; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249478 - 13 Dec 2020
Cited by 11 | Viewed by 2524
Abstract
Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. [...] Read more.
Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation. Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice. RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands. Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

15 pages, 1870 KiB  
Article
Bioelectric Responses of Conjunctival Goblet Cells to Dry Eye: Impact of Ion Channels on Exocytotic Function and Viability
by Donald G. Puro
Int. J. Mol. Sci. 2020, 21(24), 9415; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249415 - 10 Dec 2020
Cited by 3 | Viewed by 1718
Abstract
How ion channels impact the response of the ocular surface to dry eye is only beginning to be explored. Here, we review recent progress and provide new experimental data clarifying the exocytosis-altering actions of ion channels in conjunctival goblet cells whose release of [...] Read more.
How ion channels impact the response of the ocular surface to dry eye is only beginning to be explored. Here, we review recent progress and provide new experimental data clarifying the exocytosis-altering actions of ion channels in conjunctival goblet cells whose release of tear-stabilizing mucin is a key adaptive response to the pre-ocular hyperosmolarity that characterizes dry eye. Patch-clamp recordings of goblet cells located in freshly excised rat conjunctiva reveal that these mucin-releasing cells respond to sustained hyperosmolarity by sequentially activating their ATP-sensitive potassium (KATP), nonspecific cation (NSC), voltage-gated calcium (VGCC), and P2X7 channels; each of which modulates exocytosis. Based on these and other new findings, we now identify four stages in the bioelectric response of conjunctival goblet cells to extracellular hyperosmolarity. To better characterize these stages, we report that high-resolution membrane capacitance (Cm) measurements of the exocytotic activity of single goblet cells demonstrate that the replenishment of mucin-filled granules after neural-evoked exocytosis is a multi-hour process, which VGCCs markedly accelerate. Yet, we also discovered that VGCC activation is high-risk since hyperosmotic-induced goblet cell death is boosted. With dry eye treatments being far from optimal, elucidating the physiologic and pathobiologic impact of the KATP/NSC/VGCC/P2X7 pathway provides a new opportunity to identify novel therapeutic strategies. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

13 pages, 2272 KiB  
Article
Autophagy Activation Protects Ocular Surface from Inflammation in a Dry Eye Model In Vitro
by Zhao Liu, Ding Chen, Xin Chen, Fang Bian, Ning Gao, Jinmiao Li, Stephen C. Pflugfelder and De-Quan Li
Int. J. Mol. Sci. 2020, 21(23), 8966; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238966 - 26 Nov 2020
Cited by 29 | Viewed by 2311
Abstract
Inflammation is the main pathophysiology of dry eye, characterized by tear film instability and hyperosmolarity. The aim of this study was to investigate the association of inflammation and cellular autophagy using an in vitro dry eye model with primary cultured human corneal epithelial [...] Read more.
Inflammation is the main pathophysiology of dry eye, characterized by tear film instability and hyperosmolarity. The aim of this study was to investigate the association of inflammation and cellular autophagy using an in vitro dry eye model with primary cultured human corneal epithelial cells (HCECs). Primary HCECs cultured with fresh limbal explants from donors were switched to a hyperosmotic medium (450 mOsM) by adding sodium chloride into the culture medium. We observed the stimulated inflammatory mediators, TNF-α, IL-1β, IL-6 and IL-8, as well as the increased expression of autophagy related genes, Ulk1, Beclin1, Atg5 and LC3B, as evaluated by RT-qPCR and ELISA. The immunofluorescent staining of LC3B and Western blotting revealed the activated autophagosome formation and autophagic flux, as evidenced by the increased LC3B autophagic cells with activated Beclin1, Atg5, Atg7 and LC3B proteins, and the decreased levels of P62 protein in HCECs. Interestingly, the autophagy activation was later at 24 h than inflammation induced at 4 h in HCECs exposed to 450 mOsM. Furthermore, application of rapamycin enhanced autophagy activation also reduced the inflammatory mediators and restored cell viability in HCECs exposed to the hyperosmotic medium. Our findings for the first time demonstrate that the autophagy activation is a late phase response to hyperosmotic stress, and is enhanced by rapamycin, which protects HCECs by suppressing inflammation and promoting cells survival, suggesting a new therapeutic potential to treat dry eye diseases. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

17 pages, 8894 KiB  
Article
Rapamycin Eyedrops Increased CD4+Foxp3+ Cells and Prevented Goblet Cell Loss in the Aged Ocular Surface
by Claudia M. Trujillo-Vargas, Shallu Kutlehria, Humberto Hernandez, Rodrigo G. de Souza, Andrea Lee, Zhiyuan Yu, Stephen C. Pflugfelder, Mandip Singh and Cintia S. de Paiva
Int. J. Mol. Sci. 2020, 21(23), 8890; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238890 - 24 Nov 2020
Cited by 9 | Viewed by 2869
Abstract
Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan [...] Read more.
Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan of several species. Here, we compared the effects of daily instillation of eyedrops containing rapamycin or empty micelles for three months on the aged mice. Tear cytokine/chemokine profile showed a pronounced increase in vascular endothelial cell growth factor-A (VEGF-A) and a trend towards decreased concentration of Interferon gamma (IFN)-γ in rapamycin-treated groups. A significant decrease in inflammatory markers in the lacrimal gland was also evident (IFN-γ, IL-12, CIITA and Ctss); this was accompanied by slightly diminished Unc-51 Like Autophagy Activating Kinase 1 (ULK1) transcripts. In the lacrimal gland and draining lymph nodes, we also observed a significant increase in the CD45+CD4+Foxp3+ cells in the rapamycin-treated mice. More importantly, rapamycin eyedrops increased conjunctival goblet cell density and area compared to the empty micelles. Taken together, evidence from these studies indicates that topical rapamycin has therapeutic efficacy for age-associated ocular surface inflammation and goblet cell loss and opens the venue for new investigations on its role in the aging process of the eye. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

21 pages, 2460 KiB  
Article
TRPM8: A Therapeutic Target for Neuroinflammatory Symptoms Induced by Severe Dry Eye Disease
by Darine Fakih, Christophe Baudouin, Annabelle Réaux-Le Goazigo and Stéphane Mélik Parsadaniantz
Int. J. Mol. Sci. 2020, 21(22), 8756; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228756 - 19 Nov 2020
Cited by 20 | Viewed by 3409
Abstract
Dry eye disease (DED) is commonly associated with ocular surface inflammation and pain. In this study, we evaluated the effectiveness of repeated instillations of transient receptor potential melastatin 8 (TRPM8) ion channel antagonist M8-B on a mouse model of severe DED induced by [...] Read more.
Dry eye disease (DED) is commonly associated with ocular surface inflammation and pain. In this study, we evaluated the effectiveness of repeated instillations of transient receptor potential melastatin 8 (TRPM8) ion channel antagonist M8-B on a mouse model of severe DED induced by the excision of extra-orbital lacrimal and Harderian glands. M8-B was topically administered twice a day from day 7 until day 21 after surgery. Cold and mechanical corneal sensitivities and spontaneous ocular pain were monitored at day 21. Ongoing and cold-evoked ciliary nerve activities were next evaluated by electrophysiological multi-unit extracellular recording. Corneal inflammation and expression of genes related to neuropathic pain and inflammation were assessed in the trigeminal ganglion. We found that DED mice developed a cold allodynia consistent with higher TRPM8 mRNA expression in the trigeminal ganglion (TG). Chronic M8-B instillations markedly reversed both the corneal mechanical allodynia and spontaneous ocular pain commonly associated with persistent DED. M8-B instillations also diminished the sustained spontaneous and cold-evoked ciliary nerve activities observed in DED mice as well as inflammation in the cornea and TG. Overall, our study provides new insight into the effectiveness of TRPM8 blockade for alleviating corneal pain syndrome associated with severe DED, opening a new avenue for ocular pain management. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

14 pages, 30196 KiB  
Article
Disease-Specific Expression of Conjunctiva Associated Lymphoid Tissue (CALT) in Mouse Models of Dry Eye Disease and Ocular Allergy
by Philipp Steven, Sebastian Schwab, Anne Kiesewetter, Daniel R. Saban, Michael E. Stern and Uta Gehlsen
Int. J. Mol. Sci. 2020, 21(20), 7514; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207514 - 12 Oct 2020
Cited by 10 | Viewed by 2504
Abstract
Conjunctiva-associated tissue (CALT) is assumed to play a crucial role in the immune system of the ocular surface. Its function in several ocular surface diseases (OSD) is still not fully understood. This study investigates the function of CALT in mouse models of dry-eye [...] Read more.
Conjunctiva-associated tissue (CALT) is assumed to play a crucial role in the immune system of the ocular surface. Its function in several ocular surface diseases (OSD) is still not fully understood. This study investigates the function of CALT in mouse models of dry-eye disease and ocular allergy. Since antigen-presentation is the central similarity in the pathologies, this study focuses on antigen-presentation in CALT Morphology and the expression of CALT, which was investigated in mice after induction of dry-eye, ocular allergy, topical antigen-stimulation, and after local depletion of phagocytic cells. Antigen uptake was investigated after the application of fluorescent ovalbumin (OVA). OSD influences the appearance and morphology of CALT in a disease-dependent manner. Ocular allergy leads to an increase and dry-eye disease to a decrease in number and size of CALT. The development of CALT is dependent on the presence of APCs. Professional APCs are present in CALT, and soluble antigen is transported into the follicle. CALT appearance is disease-specific and indicative of differing functions. Although the specific involvement of CALT in OSD needs further study, the existence of functional APCS and antigen-uptake supports the hypothesis that CALT is an immunological key player at the ocular surface. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

16 pages, 3380 KiB  
Article
Parity Attenuates Intraepithelial Corneal Sensory Nerve Loss in Female Mice
by Mary Ann Stepp, Sonali Pal-Ghosh, Gauri Tadvalkar and Cintia S. de Paiva
Int. J. Mol. Sci. 2020, 21(14), 5172; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145172 - 21 Jul 2020
Cited by 4 | Viewed by 2502
Abstract
Aging impacts the ocular surface and reduces intraepithelial corneal nerve (ICN) density in male and female mice. Many researchers use retired breeders to study naturally aged female mice. Yet, the impact of parity and the length of time since breeders were retired on [...] Read more.
Aging impacts the ocular surface and reduces intraepithelial corneal nerve (ICN) density in male and female mice. Many researchers use retired breeders to study naturally aged female mice. Yet, the impact of parity and the length of time since breeders were retired on age-related changes in the intraepithelial corneal nerves is not known. Here we study 2 month (M) nulliparous (NP) females as well as 9M, 10M, and 11M NP and multiparous (MP) female mice to determine whether parity impacts the age-related decline seen in corneal axon density; 9M male mice are also included in these assessments. After showing that parity attenuates age-related loss in axon density, we also assess the impact of parity on corneal epithelial cell proliferation and find that it impacts cell proliferation and axon density normalized by cell proliferation. Stromal nerve arborization is also impacted by aging with parity enhancing stromal nerves in older mice. qPCR was performed on 20 genes implicated in ICN density using corneal epithelial RNA isolated from 10M NP and MP mice and showed that NGF expression was significantly elevated in MP corneal epithelium. Corneal sensitivity was significantly higher in 9M MP mice compared to NP mice and increased sensitivity in MP mice was accompanied by increased nerve terminals in the apical and middle cell layers. Together, these data show that parity in mice attenuates several aspects of the age-related decline seen on the ocular surface by retaining sensory axons and corneal sensitivity as mice age. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

Review

Jump to: Research

17 pages, 1329 KiB  
Review
The Role of Endogenous Antimicrobial Peptides in Modulating Innate Immunity of the Ocular Surface in Dry Eye Diseases
by Youssof Eshac, Rachel L. Redfern and Vinay Kumar Aakalu
Int. J. Mol. Sci. 2021, 22(2), 721; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020721 - 13 Jan 2021
Cited by 6 | Viewed by 3096
Abstract
The ocular surface has the challenging responsibility of maintaining a clear moist refractive surface while protecting the eye from exogenous pathogens and the environment. Homeostasis of the ocular surface, including its innate immune components, is altered in ocular surface disease states. In this [...] Read more.
The ocular surface has the challenging responsibility of maintaining a clear moist refractive surface while protecting the eye from exogenous pathogens and the environment. Homeostasis of the ocular surface, including its innate immune components, is altered in ocular surface disease states. In this review, we focus on antimicrobial peptides and the role they play in the immune response of the ocular surface during healthy states and dry eye diseases. Antimicrobial peptides are of special interest to the study of the ocular surface because of their various roles that include microbial threat neutralization, wound healing, and immune modulation. This review explores current literature on antimicrobial peptides in ocular surface diseases and discusses their therapeutic potential in ocular surface diseases and dry eye. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

15 pages, 1182 KiB  
Review
Therapeutic Potential of the Molecular Chaperone and Matrix Metalloproteinase Inhibitor Clusterin for Dry Eye
by M. Elizabeth Fini, Shinwu Jeong and Mark R. Wilson
Int. J. Mol. Sci. 2021, 22(1), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010116 - 24 Dec 2020
Cited by 12 | Viewed by 3001
Abstract
Evidence is presented herein supporting the potential of the natural homeostatic glycoprotein CLU (clusterin) as a novel therapeutic for the treatment of dry eye. This idea began with the demonstration that matrix metalloproteinase MMP9 is required for damage to the ocular surface in [...] Read more.
Evidence is presented herein supporting the potential of the natural homeostatic glycoprotein CLU (clusterin) as a novel therapeutic for the treatment of dry eye. This idea began with the demonstration that matrix metalloproteinase MMP9 is required for damage to the ocular surface in mouse dry eye. Damage was characterized by degradation of OCLN (occludin), a known substrate of MMP9 and a key component of the paracellular barrier. Following up on this finding, a yeast two-hybrid screen was conducted using MMP9 as the bait to identify other proteins involved. CLU emerged as a strong interacting protein that inhibits the enzymatic activity of MMP9. Previously characterized as a molecular chaperone, CLU is expressed prominently by epithelia at fluid-tissue interfaces and secreted into bodily fluids, where it protects cells and tissues against damaging stress. It was demonstrated that CLU also protects the ocular surface in mouse dry eye when applied topically to replace the natural protein depleted from the dysfunctional tears. CLU is similarly depleted from tears in human dry eye. The most novel and interesting finding was that CLU binds selectively to the damaged ocular surface. In this position, CLU protects against epithelial cell death and barrier proteolysis, and dampens the autoimmune response, while the apical epithelial cell layer is renewed. When present at high enough concentration, CLU also blocks staining by vital dyes used clinically to diagnose dry eye. None of the current therapeutics have this combination of properties to “protect, seal, and heal”. Future work will be directed towards human clinical trials to investigate the therapeutic promise of CLU. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

24 pages, 1126 KiB  
Review
Defining Dry Eye from a Clinical Perspective
by Kazuo Tsubota, Stephen C. Pflugfelder, Zuguo Liu, Christophe Baudouin, Hyo Myung Kim, Elisabeth M. Messmer, Friedrich Kruse, Lingyi Liang, Jimena Tatiana Carreno-Galeano, Maurizio Rolando, Norihiko Yokoi, Shigeru Kinoshita and Reza Dana
Int. J. Mol. Sci. 2020, 21(23), 9271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239271 - 04 Dec 2020
Cited by 121 | Viewed by 13447
Abstract
Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many [...] Read more.
Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: “Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities.” The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

43 pages, 6925 KiB  
Review
Innate Immunity and Biological Therapies for the Treatment of Sjögren’s Syndrome
by Amrita Srivastava and Helen P. Makarenkova
Int. J. Mol. Sci. 2020, 21(23), 9172; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239172 - 01 Dec 2020
Cited by 27 | Viewed by 5197
Abstract
Sjögren’s syndrome (SS) is a systemic autoimmune disorder affecting approximately 3% of the population in the United States. This disease has a female predilection and affects exocrine glands, including lacrimal and salivary glands. Dry eyes and dry mouths are the most common symptoms [...] Read more.
Sjögren’s syndrome (SS) is a systemic autoimmune disorder affecting approximately 3% of the population in the United States. This disease has a female predilection and affects exocrine glands, including lacrimal and salivary glands. Dry eyes and dry mouths are the most common symptoms due to the loss of salivary and lacrimal gland function. Symptoms become more severe in secondary SS, where SS is present along with other autoimmune diseases like systemic lupus erythematosus, systemic sclerosis, or rheumatoid arthritis. It is known that aberrant activation of immune cells plays an important role in disease progression, however, the mechanism for these pathological changes in the immune system remains largely unknown. This review highlights the role of different immune cells in disease development, therapeutic treatments, and future strategies that are available to target various immune cells to cure the disease. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

19 pages, 3704 KiB  
Review
Mouse Models of Sjögren’s Syndrome with Ocular Surface Disease
by Sharmila Masli and Darlene A. Dartt
Int. J. Mol. Sci. 2020, 21(23), 9112; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239112 - 30 Nov 2020
Cited by 13 | Viewed by 2751
Abstract
Sjögren’s syndrome (SS) is a systemic rheumatic disease that predominantly affects salivary and lacrimal glands resulting in oral and ocular dryness, respectively, referred to as sicca symptoms. The clinical presentation of ocular dryness includes keratoconjunctivitis sicca (KCS), resulting from the inflammatory damage to [...] Read more.
Sjögren’s syndrome (SS) is a systemic rheumatic disease that predominantly affects salivary and lacrimal glands resulting in oral and ocular dryness, respectively, referred to as sicca symptoms. The clinical presentation of ocular dryness includes keratoconjunctivitis sicca (KCS), resulting from the inflammatory damage to the ocular surface tissues of cornea and conjunctiva. The diagnostic evaluation of KCS is a critical component of the classification criteria used by clinicians worldwide to confirm SS diagnosis. Therapeutic management of SS requires both topical and systemic treatments. Several mouse models of SS have contributed to our current understanding of immunopathologic mechanisms underlying the disease. This information also helps develop novel therapeutic interventions. Although these models address glandular aspects of SS pathology, their impact on ocular surface tissues is addressed only in a few models such as thrombospondin (TSP)-1 deficient, C57BL/6.NOD.Aec1Aec2, NOD.H2b, NOD.Aire KO, and IL-2Rα (CD25) KO mice. While corneal and/or conjunctival damage is reported in most of these models, the characteristic SS specific autoantibodies are only reported in the TSP-1 deficient mouse model, which is also validated as a preclinical model. This review summarizes valuable insights provided by investigations on the ocular spectrum of the SS pathology in these models. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

25 pages, 583 KiB  
Review
Meibomian Gland Dysfunction: What Have Animal Models Taught Us?
by Mingxia Sun, Isabel Y. Moreno, Michelle Dang and Vivien J. Coulson-Thomas
Int. J. Mol. Sci. 2020, 21(22), 8822; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228822 - 21 Nov 2020
Cited by 26 | Viewed by 4511
Abstract
Studies have estimated that currently 344 million people worldwide and 16.4 million adults in the US have some form of dry eye disease (DED). It is believed that approximately 70% of DED cases are due to some form of evaporative dry eye, for [...] Read more.
Studies have estimated that currently 344 million people worldwide and 16.4 million adults in the US have some form of dry eye disease (DED). It is believed that approximately 70% of DED cases are due to some form of evaporative dry eye, for which Meibomian gland dysfunction (MGD) is the major cause. Unfortunately, currently there is no effective treatment for MGD, and solely palliative care is available. Given the importance of MGD in DED, there has been a growing interest in studying Meibomian gland development, homeostasis and pathology, and, also, in developing therapies for treating and/or preventing MGD. For such, animal models have shown to be a vital tool. Much of what is known today about the Meibomian gland and MGD was learnt from these important animal models. In particular, canine and rabbit models have been essential for studying the physiopathology and progression of DED, and the mouse model, which includes different knockout strains, has enabled the identification of specific pathways potentially involved in MGD. Herein, we provide a bibliographic review on the various animal models that have been used to study Meibomian gland development, Meibomian gland homeostasis and MGD, primarily focusing on publications between 2000 and 2020. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

28 pages, 1533 KiB  
Review
Can Gut Microbiota Affect Dry Eye Syndrome?
by Jayoon Moon, Chang Ho Yoon, Se Hyun Choi and Mee Kum Kim
Int. J. Mol. Sci. 2020, 21(22), 8443; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228443 - 10 Nov 2020
Cited by 40 | Viewed by 6743
Abstract
Using metagenomics, continuing evidence has elicited how intestinal microbiota trigger distant autoimmunity. Sjögren’s syndrome (SS) is an autoimmune disease that affects the ocular surface, with frequently unmet therapeutic needs requiring new interventions for dry eye management. Current studies also suggest the possible relation [...] Read more.
Using metagenomics, continuing evidence has elicited how intestinal microbiota trigger distant autoimmunity. Sjögren’s syndrome (SS) is an autoimmune disease that affects the ocular surface, with frequently unmet therapeutic needs requiring new interventions for dry eye management. Current studies also suggest the possible relation of autoimmune dry eye with gut microbiota. Herein, we review the current knowledge of how the gut microbiota interact with the immune system in homeostasis as well as its influence on rheumatic and ocular autoimmune diseases, and compare their characteristics with SS. Both rodent and human studies regarding gut microbiota in SS and environmental dry eye are explored, and the effects of prebiotics and probiotics on dry eye are discussed. Recent clinical studies have commonly observed a correlation between gut dysbiosis and clinical manifestations of SS, while environmental dry eye portrays characteristics in between normal and autoimmune. Moreover, a decrease in both the Firmicutes/Bacteroidetes ratio and genus Faecalibacterium have most commonly been observed in SS subjects. The presumable pathways forming the “gut dysbiosis–ocular surface–lacrimal gland axis” are introduced. This review may provide perspectives into the link between the gut microbiome and dry eye, enhance our understanding of the pathogenesis in autoimmune dry eye, and be useful in the development of future interventions. Full article
(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-18
Back to TopTop