Corneal application of SOCS1/3 peptides for the treatment of eye diseases mediated by inflammation and oxidative stress.

Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic. The production of inflammatory cytokines and their activities are regulated by a class of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS1 and SOCS3 are known to dampen signaling via pathways employing Janus kinases and signal transducer and activator of transcription proteins (JAK/STAT), Toll-like Receptors (TLR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen activated kinase (MAPK) and NLR family pyrin domain containing 3 (NLRP3). We have developed cell-penetrating peptides from the kinase inhibitory region of the SOCS1 and SOCS3 (denoted as R9-SOCS1-KIR and R9-SOCS3-KIR) and tested them in retinal pigment epithelium (RPE) cells and in macrophage cell lines. SOCS-KIR peptides exhibited anti-inflammatory, anti-oxidant and anti-angiogenic properties. In cell culture, both Th1 and Th17 cells were suppressed together with the inhibition of other inflammatory markers. We also observed a decrease in oxidants and a simultaneous rise in neuroprotective and anti-oxidant effectors. In addition, treatment prevented the loss of gap junction proteins and the ensuing drop in transepithelial electrical resistance in RPE cells. When tested in mouse models by eye drop instillation, they showed protection against autoimmune uveitis, as a prophylactic as well as a therapeutic. Mice with endotoxin-induced uveitis were protected by eye drop administration as well. R9-SOCS3-KIR was particularly effective against the pathways acting through STAT3, e.g. IL-6 and VEGF-A mediated responses that lead to macular degeneration. Eye drop administration of R9-SOCS3-KIR stimulated production of antioxidant effectors and reduced clinical symptoms in mouse model of oxidative stress that replicates the RPE injury occurring in AMD. Because these peptides suppress multiple pathogenic stimuli and because they can be delivered topically to the cornea, they are attractive candidates for therapeutics for uveitis, macular degeneration, diabetic retinopathy and glaucoma.

Neutrophils in Ocular Diseases.

Neutrophils, traditionally viewed as first responders to infection or tissue damage, exhibit dynamic and diverse roles in ocular health and disease. This review elaborates on previous findings that showed how neutrophils contribute to ocular diseases. In ocular infections, neutrophils play a pivotal role in host defense by orchestrating inflammatory responses to combat pathogens. Furthermore, in optic nerve neuropathies and retinal degenerative diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR), neutrophils are implicated in neuroinflammation and tissue damage owing to their ability to undergo neutrophil extracellular trap formation (NETosis) and secretion of inflammatory molecules. Targeting neutrophil-dependent processes holds promise as a therapeutic strategy, offering potential avenues for intervention in ocular infections, cancers, and retinal degenerative diseases. Understanding the multifaceted roles of neutrophils in ocular diseases is crucial for developing targeted therapies to improve patient outcomes.

Immunopeptides: immunomodulatory strategies and prospects for ocular immunity applications.

Immunopeptides have low toxicity, low immunogenicity and targeting, and broad application prospects in drug delivery and assembly, which are diverse in application strategies and drug combinations. Immunopeptides are particularly important for regulating ocular immune homeostasis, as the eye is an immune-privileged organ. Immunopeptides have advantages in adaptive immunity and innate immunity, treating eye immune-related diseases by regulating T cells, B cells, immune checkpoints, and cytokines. This article summarizes the application strategies of immunopeptides in innate immunity and adaptive immunity, including autoimmunity, infection, vaccine strategies, and tumors. Furthermore, it focuses on the mechanisms of immunopeptides in mediating ocular immunity (autoimmune diseases, inflammatory storms, and tumors). Moreover, it reviews immunopeptides' application strategies and the therapeutic potential of immunopeptides in the eye. We expect the immune peptide to get attention in treating eye diseases and to provide a direction for eye disease immune peptide research.

Clinical features of ocular damage in systemic lupus erythematosus and risk factors for hydroxychloroquine-related complications.

Ocular damage in systemic lupus erythematosus (SLE) may cause insidious visual impairment, but its clinical features and the risk of hydroxychloroquine (HCQ)-related complications are still controversial. We performed a meta-analysis to evaluate ocular damage in SLE, the correlation between eye and systemic involvement, and the ocular side effects of treatment. The database PubMed, Embase, and Ovid were used for literature from reception to July, 2023, and the calculation was carried out with R. About 48,693 patients from 66 studies were included. The results indicated that ocular damage in SLE was insidious, appearing in 28 % of patients with no complaints. The most common symptoms and manifestations were dry eye (30 %) and keratoconjunctivitis sicca (26 %). Retinopathy was detected in 10 % of patients and was related to antiphospholipid antibodies (25 % versus 8 %). The proportion of retinopathy also significantly increased in patients with lupus nephropathy or neuropsychiatric systemic lupus erythematosus (risk ratio of 2.29 and 1.95, respectively). HCQ was used in 82 % of patients, of which 4 % suffered from ocular toxicity. HCQ-related retinopathy was dose-dependent. Dosage below 5 mg/kg/d was relatively effective and safe for long-term use, while routine examination was recommended.

Vaccines and the Eye: Current Understanding of the Molecular and Immunological Effects of Vaccination on the Eye.

Vaccination is a public health cornerstone that protects against numerous infectious diseases. Despite its benefits, immunization implications on ocular health warrant thorough investigation, particularly in the context of vaccine-induced ocular inflammation. This review aimed to elucidate the complex interplay between vaccination and the eye, focusing on the molecular and immunological pathways implicated in vaccine-associated ocular adverse effects. Through an in-depth analysis of recent advancements and the existing literature, we explored various mechanisms of vaccine-induced ocular inflammation, such as direct infection by live attenuated vaccines, immune complex formation, adjuvant-induced autoimmunity, molecular mimicry, hypersensitivity reactions, PEG-induced allergic reactions, Type 1 IFN activation, free extracellular RNA, and specific components. We further examined the specific ocular conditions associated with vaccination, such as uveitis, optic neuritis, and retinitis, and discussed the potential impact of novel vaccines, including those against SARS-CoV-2. This review sheds light on the intricate relationships between vaccination, the immune system, and ocular tissues, offering insights into informed discussions and future research directions aimed at optimizing vaccine safety and ophthalmological care. Our analysis underscores the importance of vigilance and further research to understand and mitigate the ocular side effects of vaccines, thereby ensuring the continued success of vaccination programs, while preserving ocular health.

Approach to Immune-mediated Ocular Diseases.

Immune-mediated ocular inflammation is a common clinical diagnosis reached for horses with keratitis and uveitis. This diagnosis is made as a diagnosis of exclusion following a thorough effort to rule out an underlying cause for the inflammation, most importantly infectious and neoplastic disease. Practically, response to ophthalmic and systemic anti-inflammatory or immunomodulatory medications is used to support a diagnosis of immune-mediated ocular inflammation; however, such medications are often contraindicated in the face of infection or neoplasia. This article will summarize our current understanding and approach to the diagnosis and management of immune-mediated keratitis and recurrent or insidious uveitis in horses.

Immunopathological mechanisms and clinical manifestations of ocular graft-versus-host disease following hematopoietic stem cell transplantation.

Graft-versus-host disease is among the most common clinical complications following allogeneic hematopoietic stem cell transplantation. It causes inflammation-mediated destruction and dysfunction of various organ systems including ocular tissues in 60-90% of the patients and is termed ocular GVHD (oGVHD). In oGVHD, donor-derived T-cells recognize host antigens as foreign, resulting in immune dysregulation, inflammation and fibrosis of lacrimal glands, meibomian glands, cornea, and conjunctiva. The clinical presentation in oGVHD patients range from mild dry eye symptoms to catastrophic inflammation mediated pathological changes which can cause corneal perforation and blindness. In this review article, we provide detailed insights into the impact of mucosal barrier disruption, the afferent and efferent phases of immunological response involving activation of antigen presenting cells and T cells, respectively. We evaluate the evidence outlining the effector phase of the disease leading to cellular destruction and eventually fibrosis in patients with oGVHD. Finally, we discuss the well-established criteria for the diagnosis of oGVHD.

Profiles, Distribution, and Functions of Gamma Delta T Cells in Ocular Surface Homeostasis and Diseases.

The ocular surface microenvironment, containing the cornea, conjunctiva, and lacrimal gland, constitutes the mucosal frontline of the eye and houses a myriad of immune cells. As a part of unconventional T cells, gamma delta (γδ) T cells differ in the development and functions from canonical alpha beta (αß) T cells. They are predominantly situated in mucosal sites throughout the body, including ocular surface tissues. Recent research has elucidated that γδ T cells serve as the primary interleukin-17A (IL-17A) source in the conjunctiva. They play a pivotal role in preserving ocular surface homeostasis and exhibit both protective and pathogenic roles in ocular surface diseases. This review delves into the general profiles of γδ T cells, their distribution in ocular surface tissues, and consolidates current insights into their functions in different conditions including dry eye disease, infectious keratitis, corneal wound healing, anterior chamber-associated immune deviation, allergic conjunctival disease, and diabetic ocular surface disease. The aim is to provide a systemic perspective on γδ T cells in the ocular surface microenvironment and outline potential directions for future studies.

Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.

Ocular Involvement in Graft-versus-Host Disease. / Augenbeteiligung bei Graft-versus-Host-Erkrankung.

In ocular graft-versus-host disease (GVHD), an inflammatory reaction occurs at the ocular surface after transplantation of allogeneic hematopoietic stem cells. Self-reactive T cells of the donor are particularly responsible for this. This can lead to a pronounced wetting disorder of the ocular surface, conjunctival hyperemia, and corneal ulceration up to perforation. The ocular GVHD is associated with a high degree of suffering, such as pain, photophobia, and reduction in visual acuity. This review provides an overview of typical ophthalmological findings, topical and systemic therapeutic approaches, and concomitant measures (e.g., scleral lenses, punctum plugs) and the appropriate management of complications.

The Role of Symptom Duration and Serologic Factors in the Relapse of IgG4-Related Ophthalmic Disease following Surgery: A Retrospective Cohort Study.

IgG4-related disease (IgG4-RD) affects multiple organs and is characterized by immune-mediated inflammation and fibrosis; IgG-RD affecting orbital tissue is known as IgG4-related ophthalmic disease (IgG4-ROD). This research is aimed at exploring whether symptom duration and common serologic factors, such as IgG, IgE, and eosinophils, are potential risk factors for IgG4-ROD patient relapse after surgery and identifying possible causes of the positive correlation between symptom duration and relapse. This retrospective cohort study included 40 IgG4-ROD patients after surgery. Auxiliary inspection results were obtained before surgery and during follow-up, and relapse risk factors were identified based on previous studies. We used the Spearman rank correlation test to reveal the relationship between symptom duration and relapse time and identified the optimal cutoff value for symptom duration by X-tile. Then, we divided the patients into the long-duration and short-duration groups. Kaplan-Meier survival analyses and log-rank tests were performed to identify the relationship between symptom duration and relapse using X-tile software. Finally, we studied the relationship between previously studied relapse risk factors and symptom duration. The survival curves of the long-duration and short-duration groups were obviously different, and the baseline serum IgG, IgE, and eosinophil levels and asthma concomitant rate were significantly different between the long-duration and short-duration groups. Furthermore, the baseline serum IgG (r = 0.485, P = 0.002), IgE (r = 0.350, P = 0.037), and eosinophil (r = 0.6535, P < 0.0001) levels were positively correlated with symptom duration. Our study shows that IgG4-ROD symptom duration is significantly positively correlated with relapse rate and negatively correlated with relapse time. Symptom duration was positively correlated with serum baseline IgG4, IgE, and eosinophil levels and asthma history, which were potential risk factors for disease relapse. We recommended that IgG4-ROD patients with symptom durations greater than 96 months continue to receive maintenance steroid therapy longer than 1 year postsurgery to reduce the relapse rate.

Ophthalmologic manifestations in patients with antiphospholipid antibodies: Beware of iatrogenic complications.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by several clinical manifestations such as venous and arterial thrombosis associated with persistent antiphospholipid antibodies (aPL). Several studies confirmed that retinal vein occlusion was the most common APS ocular manifestation. The purpose of this study was to identify ophthalmologic manifestations in a homogeneous cohort of well-defined persistently aPL-positive patients and to determine variables associated with these manifestations. METHODS: APL-positive patients were selected from two research programs. All ophthalmologic manifestations including those related to APS were recorded. RESULTS: A total of 117 patients were included and 10 of them had APS-related ophthalmologic manifestations (glaucoma, hydroxychloroquine-related maculopathy, anterior acute uveitis, anterior ischemic optic neuropathy). Systemic Lupus Erythematosus (SLE) (OR = 3.4[95%CI; 0.9-12.7), corticosteroids (OR = 9.0 [95%CI; 2.2-37.7]) and aPL-related nephropathy (OR = 7.1 [95%CI; 1.7-30.0]) were significatively associated with the risk of APS-related ophthalmologic manifestations. CONCLUSION: Most of ocular manifestations in this study were iatrogenic related to corticosteroids or hydroxychloroquine. Patients with SLE, small vessel thrombosis in general, or with aPL-related nephropathy in particular, seemed at higher risk to develop APS-related ophthalmologic manifestations thus deserving adequate monitoring.

Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models.

Rosacea is a chronic inflammatory disease that affects the face skin. It is clinically classified into the following four subgroups depending on its location and severity: erythematotelangiectatic, papulopustular, phymatous, and ocular. Rosacea is a multifactorial disease triggered by favoring factors, the pathogenesis of which remains imperfectly understood. Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of skin sebaceous glands and ocular meibomian glands. Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors. In this paper, we review the common and specific molecular mechanisms involved in the pathogenesis of cutaneous and ocular rosacea and discuss laboratory and clinical studies, as well as experimental models.

Therapy of ocular complications in ANCA+ associated vasculitis.

ANCA+ associated vasculitis (AAV) is a group of rare diseases with potentially vision-threatening complications. Ocular and orbital complications of these diseases are caused by vasculitis of the small vessels of the eye or by granulomatous mass formation. ANCA (anti-neutrophil cytoplasmic antibodies) represent a key component of pathophysiological pathways as well as a diagnostic marker. Various manifestations are reported in literature, scleritis and episcleritis being the most common, followed by pseudotumor orbitae. In vision-threatening orbital or ocular disease, aggressive systemic treatment with a combination of high-dose glucocorticoids and either cyclophosphamide or rituximab is needed. Certain cases require locoregional surgical management to preserve ocular integrity or vision. Ocular involvement of AAV remains a challenge in clinical practice, requiring multi-specialty cooperation in order to ensure the best possible visual outcome. Abbreviations: AAV = ANCA+ associated vasculitis, ANCA = anti-neutrophil cytoplasmic antibodies, GPA = granulomatosis with polyangiitis, EGPA = eosinophilic granulomatosis with polyangiitis, MPA = microscopic polyangiitis.

Age-related changes in ocular mucosal tolerance: Lessons learned from gut and respiratory tract immunity.

The ocular surface is the part of the visual system directly exposed to the environment, and it comprises the cornea, the first refractive tissue layer and its surrounding structures. The ocular surface has evolved to keep the cornea smooth and wet, a prerequisite for proper sight, and also protected. To this aim, the ocular surface is a bona fide mucosal niche with an immune system capable of fighting against dangerous pathogens. However, due to the potential harmful effects of uncontrolled inflammation, the ocular surface has several mechanisms to keep the immune response in check. Specifically, the ocular surface is maintained inflammation-free and functional by a particular form of peripheral tolerance known as mucosal tolerance, markedly different from the immune privilege of intraocular structures. Remarkably, conjunctival tolerance is akin to the oral and respiratory tolerance mechanisms found in the gut and airways, respectively. And also similarly, this form of immunoregulation in the eye is affected by ageing just as it is in the digestive and respiratory tracts. With ageing comes an increased prevalence of immune-based ocular surface disorders, which could be related to an age-related impairment of conjunctival tolerance. The purpose of this review was to summarize the present knowledge of ocular mucosal tolerance and how it is affected by the ageing process in the light of the current literature on mucosal immunoregulation of the gut and airways.

Drops of Lactiplantibacillus plantarum CRL 759 culture supernatant attenuates eyes inflammation induced by lipopolysaccharide.

Anti-inflammatory effect of soluble secreted compounds of probiotic bacteria was widely demonstrated as therapy for different inflammatory diseases, but was not investigated in inflammatory eye disorders. The aim of this study was to determine whether Lactiplantibacillus plantarum CRL759 cell-free supernatant reduced inflammatory parameters and clinical signs in ocular inflammations. First, we evaluated the effect of L. plantarum CRL759 supernatant in vitro on human retinal cell line, ARPE-19 cells, stimulated with lipopolysaccharide (LPS). Then, we investigated in vivo its capacity to decrease inflammation by local administration on the eyes of mice with endotoxin induced inflammation. In vitro assays demonstrated that L. plantarum CRL759 supernatant reduced the production of interleukin (IL)-6, IL-8, nitric oxide and thiobarbituric acid reactive substances in LPS-stimulated ARPE-19 cells. Our in vivo data proved that L. plantarum supernatant significantly reduced the clinical score of endotoxin treated mice and diminished levels of tumour necrosis factor alpha, interferon gamma and protein concentration in aqueous humour. Histological examination showed reduction of infiltrating inflammatory cells in the posterior segment of the eyes. As far as we know, this is the first report showing that Lactobacillus spp. supernatant administered as drops reduces some parameters of ocular inflammation. This promising strategy is safe and could alleviate symptoms and signs of ocular inflammation in people that are refractories to the conventional therapies.

Toxicity Evaluation of a Novel Rapamycin Liposomal Formulation After Subconjunctival and Intravitreal Injection.

Purpose: Safety and toxicity evaluation of a novel, liposome-encapsulated rapamycin formulation, intended for autoimmune ocular disorders. Methods: The formulation was assessed by micronucleus polychromatic erythrocyte production, irritability by Hen's Egg Test-Chorioallantoic Membrane (HET CAM), sterility, and pyrogenicity testing. Subconjunctival (SCJ) and intravitreal (IVT) administration of the formulation were performed to evaluate subacute and acute toxicity, respectively. Differences between groups in biochemical and hematological parameters were evaluated by analysis of variance and t-tests. Numeric score was assigned to histopathological classification. Electroretinography (ERG) testing was also performed. Data were analyzed by a 1 way no parametric Kruskal-Wallis and the Mann-Whitney tests. Significance was considered when P < 0.05. Results: No significant toxicity directly related to the preparation was detected. Micronucleus count, mucous irritation score, and pyrogenicity results were negative. Pathology demonstrated no damage related to the formulation after SCJ injection. After IVT injection, only lens injury associated with technique was observed. Retinal function was also conserved in ERG. Conclusions: The preparation evaluated offers a good toxicity and safety profile when injected in a SCJ or IVT manner in an animal model. A clinical trial conducted in humans is highly warranted, as it could reveal an alternative immunosuppressive treatment for ophthalmological immune-mediated pathologies.