small molecules

2026-07-13 | Ocular Toxoplasmosis: Bridging Clinical Diagnosis and Evidence-Based Management

Background: Ocular toxoplasmosis is one of the most common infectious causes of posterior uveitis and may lead to recurrent inflammation and visual impairment. It most often presents as necrotizing retinochoroiditis, but the clinical picture depends on lesion location and immune status. Aim: This review summarizes current evidence on clinical manifestations, diagnosis and treatment of ocular toxoplasmosis. Material and methods: A narrative review of PubMed and Scopus publications from 2002–2025 was performed, focusing on clinical presentation, diagnostic methods and therapeutic management. Results: Ocular toxoplasmosis usually presents as focal retinochoroiditis with vitritis and, less commonly, anterior uveitis. Immunocompromised patients may develop bilateral, multifocal or extensive lesions. Diagnosis is primarily clinical and may be supported by serology, multimodal imaging, PCR testing and assessment of intraocular antibody production in uncertain cases. Conventional therapy with pyrimethamine, sulfadiazine and corticosteroids remains effective, while trimethoprim-sulfamethoxazole offers comparable efficacy with a more favorable safety profile. Intravitreal clindamycin with dexamethasone may be considered when systemic treatment is contraindicated. Conclusions: Early diagnosis and individualized treatment are essential to reduce irreversible retinal damage. Current therapies control active inflammation but do not eradicate latent infection or reliably prevent recurrence.

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2026-06-13 | Real-World Anatomical Outcomes of Suprachoroidal Triamcinolone Acetonide Injections in a Large Retinal Practice over a 4-Year Period.

To evaluate the clinical role, durability, anatomical response, and safety for suprachoroidal triamcinolone acetonide (SCTA) (Xipere) in routine clinical practice. Data were manually extracted from health records at a high-volume retina practice in Cleveland, Ohio. All patients with noninfectious inflammatory macular edema undergoing SCTA (≥1 billing code) between October 25, 2021, and July 17, 2025, were included. Patients with known systemic autoimmune or infectious associations were excluded. Unique eyes were defined by MRN + laterality, with "OU" entries split into OD/OS. Patient demographics, underlying diagnosis categorization, time between first and second injection (for eyes with ≥2 injections) were summarized. Pre- versus post-treatment central retinal thickness (CRT) and intraocular pressure (IOP) were compared via paired t-tests. A total of 177 patients (195 eyes) received 340 SCTA injections for macular edema associated with an underlying diagnosis of intermediate uveitis (10%), pseudophakic cystoid macular edema (31%), and posterior uveitis (59%). The time between first and second injection was approximately 5 months [SD ± 72.5; median 144 (min 35, max 427)]. From baseline to follow-up, mean CRT decreased by 103 µm [95% CI: (-122,-83.2), P < 0.001], while IOP increased minimally [mean difference 0.7 mmHg, 95% CI: (-0.02, 1.43), P = 0.057]; and was medically managed when elevated. In this real-world cohort, findings suggest that SCTA achieves robust anatomical improvement, a favorable IOP profile, and prolonged durability across patients with inflammation-related macular edema.

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2026-03-13 | Combined PCR Positivity for Mycobacterium tuberculosis Complex and Nontuberculous Mycobacterium Species in Patients Treated for Tubercular Panuveitis.

Intraocular dual infection by Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM) is rarely reported. This study describes the clinical features, aetiology, and treatment outcomes of patients with dual infection from MTBC and NTM-related uveitis. A retrospective study was conducted on 146 clinically suspected tubercular uveitis (TBU) patients who underwent diagnostic or therapeutic pars plana vitrectomy as plan of laboratory diagnosis-based management between June 2023 and December 2024. Undiluted vitreous samples were analysed with nested MTBC-NTM multiplex real-time PCR assay kit. Six out of 146 patients (4.11%) were found infected with dual infection from MTBC and NTM. All six cases showed severe clinical presentation characterised by bilateral panuveitis (5/6 patients), with significant structural sequelae. Optic atrophy was universal and occurred more frequently than in isolated TBU, while complicated cataract and hypotony-related maculopathy were also common. Despite the dual etiology, all patients achieved inflammatory resolution and visual recovery (mean BCVA improving from 20/400 to 20/100) following standard anti-tubercular therapy (ATT) and corticosteroids, with no recurrence during follow-up. Concurrent MTBC and NTM infection drives a distinct, aggressive form of panuveitis characterized by optic nerve pallor, anterior segment complications of complicated cataract or uveitic membranes and maculopathy. Despite this severity, standard ATT remained an effective first-line strategy, likely either due to therapeutic cross-coverage against NTM or MTBC being the primary driver of uveitis in the present study. The concurrent positivity also highlights the need for vitreous molecular profiling and further research in co-infections in infectious posterior uveitis.

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2025-10-01 | SOME ASPECTS OF THE EPIDEMIOLOGICAL CHARACTERISTICS OF UVEITIS AND UVEITIC GLAUCOMA IN THE REGIONS OF AZERBAIJAN

Purpose – to evaluate some aspects of the epidemiological characteristics of uveitis and uveitic glaucoma (UG) in the regions of Azerbaijan. Material and methods The study was conducted based on a retrospective clinical, epidemiological, and etio-pathogenetic analysis of the clinical and electronic databases (1C-EMS) of patients who presented with uveitis and UG to the National Ophthalmology Centre named after Academician Zarifa Aliyeva and its Masally, Ganja, and Sheki branches between 2008 and 2025. Methods of examination: ophthalmological, general clinical, laboratory, statistical. Results The analysis revealed that the majority of 2,877 patients diagnosed with uveitis who applied to the National Ophthalmology Centre named after Academician Zarifa Aliyeva and its branches during 2008-2025 were between the ages of 19 and 70 (91.4%) (35.5% in the acute stage, 64.5% in the chronic stage). Most of them applied to the Centre in Baku - 2,179 (75.7%), and 698 people (24.3%) applied to the branches. Overall, patients with uveitis accounted for 0.41% of all applications. Compared by the years, the highest number of patient applications with uveitis was recorded in Baku in 2018 and 2024, in Masally in 2017 and 2022, in Ganja in 2017 and 2024, and in Sheki in 2020. Men with uveitis applied more often to Baku (55.3%) and Masally (67.5%), while women applied more often to Ganja (62.4%) and Sheki (61.1%) branches. It was found that uveitis of non-infectious etiology (59.4%) and posterior anatomical localization (37.8%) were more frequent. Uveitic ocular hypertension (UOH) was detected in 837 (29.1%) of the 2,877 patients, and uveitic glaucoma (UG) was found in 346 (12.03%). UOH was mainly observed during anterior uveitis (in 657 patients, 78.5%), while UG was found in the chronic stage of uveitis (66.5%). The fact that 40.2% of patients with UG present at an extremely advanced stage of the disease necessitates the selection of radical surgical treatment methods. Any surgical intervention performed on patients with uveitis can also lead to exacerbation of the postoperative inflammatory process. Conclusion Most of the uveitis cases were of non-infectious etiology (59.4%) and posterior anatomical localization (37.8%), with UOH recorded in 29.1% and UG in 12.03%. The detection of UG in the primary chronic uveitis (66.5) and the extremely advanced stage (40.2%) forces the choice of radical surgical treatment methods. In order to reduce the risk of developing UG, it is advisable to choose a multidisciplinary approach to the dispanserization, examination, and treatment of patients with uveitis, to constantly monitor patients with UOH, and to provide appropriate hypotensive and neuroprotective complex treatment in a timely manner, in addition to anti-inflammatory treatment. Key words: uveitis, uveitic glaucoma, epidemiological characteristics

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2025-09-16 | Controversy and consensus on the management of ocular toxoplasmosis: A joint statement by the Asia-Pacific Society of Ocular Inflammation and Infection (APSOII), the Asia-Pacific Vitreo-Retina Society (APVRS), the Academy of Asia-Pacific Professors of Ophthalmology (AAPPO) and The Infectious Uveitis Treatment Algorithm Network (TITAN) Group.

This international consensus effort, convened by The Infectious Uveitis Treatment Algorithm Network (TITAN) group, brought together 103 uveitis experts to address long-standing controversies in the management of ocular toxoplasmosis (OT), a leading cause of infectious posterior uveitis worldwide. Despite the availability of advanced diagnostic tools, variability persists in clinical decision-making. Controversies were identified from previous surveys on OT management, which served as the foundation for developing the survey questions in this study. Using a two-round modified Delphi method, experts reviewed evidence and rated recommendations across three domains: diagnosis and investigations, treatment, and follow-up management. Key consensus findings include support for antiparasitic therapy in most active cases, selective use of polymerase chain reaction (PCR) testing for atypical presentations, and prophylactic therapy in high-risk scenarios. These expert-derived consensus provide a framework for best practices in OT clinical management and highlight priorities for future prospective studies.

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antibodies

2026-01-28 | [Ocular toxoplasmosis in adults : Refresher course].

Ocular toxoplasmosis is the leading cause of infectious posterior uveitis worldwide and a daily challenge for ophthalmologists. Most cases of ocular toxoplasmosis are acquired postnatally, mainly through ingestion of contaminated meat or contact with cat feces. The diagnosis relies on clinical findings such as focal retinochoroiditis, vitritis and retinal scarring. The treatment can include antiparasitic drugs and in selected cases requires the combination with corticosteroids. The recurrence rates are high, particularly in older or immunocompromised patients. Early diagnosis and individualized treatment strategies significantly improve the prognosis and visual function.

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2024-06-30 | Interleukins profile among patients infected with ocular toxoplasmosis in Baghdad city, Iraq

Toxoplasma gondii is an intracellular organism that causes serious illness in both animals and people all over the world. It is often asymptomatic, but in immunocompromised people, it can cause pneumonia, ocular toxoplasmosis, and even mis1carriages. Research into T. gondii in cancer patients is extensive. However, no one has yet discussed the implications of widespread parasite infection in this population. Ocular toxoplasmosis (OT) is the infection of the eye caused by toxoplasmosis. Toxoplasma gondii infection, which causes infectious posterior uveitis and consequent vision loss, is a significant health damage, particularly in developing nations.

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2024-01-17 | Unveiling the Web: Exploring the Multifaceted Role of Neutrophil Extracellular Traps in Ocular Health and Disease

Neutrophil extracellular traps (NETs) play an essential role in antimicrobial defense. However, NETs have also been shown to promote and mediate a wide spectrum of diseases, including cancer, diabetes mellitus, cardiovascular diseases, and ocular diseases. Data regarding NETs in ocular diseases remain limited. In physiological conditions, NETs protect the eye from debris and cleave proinflammatory cytokines, including several interleukins. On the other hand, NETs play a role in corneal diseases, such as dry eye disease and ocular graft-versus-host disease, where they promote acinar atrophy and delayed wound healing. Additionally, NET levels positively correlate with increased severity of uveitis. NETs have also been described in the context of diabetic retinopathy. Although increased NET biomarkers are associated with an increased risk of the disease, NETs also assist in the elimination of pathological blood vessels and the regeneration of normal vessels. Targeting NET pathways for the treatment of ocular diseases has shown promising outcomes; however, more studies are still needed in this regard. In this article, we summarize the literature on the protective roles of NETs in the eye. Then, we describe their pathogenetic effects in ocular diseases, including those of the cornea, uvea, and retinal blood vessels. Finally, we describe the therapeutic implications of targeting NETs in such conditions.

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2023-03-31 | Influence of killer immunoglobulin-like receptors genes on the recurrence rate of ocular toxoplasmosis in Brazil

Recurrence is a hallmark of ocular toxoplasmosis (OT), and conditions that influence its occurrence remain a challenge. Natural killer cells (NK) are effectors cells whose primary is cytotoxic function against many parasites, including Toxoplasma gondii. Among the NK cell receptors, immunoglobulin-like receptors (KIR) deserve attention due to their high polymorphism.This study aimed to analyse the influence of KIR gene polymorphism in the course of OT infection and its association with recurrences after an active episode.Ninety-six patients from the Ophthalmologic Clinic of the National Institute of Infectology Evandro Chagas were followed for up to five years. After DNA extraction, genotyping of the patients was performed by polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) utilising Luminex equipment for reading. During follow-up, 60.4% had a recurrence.We identified 25 KIR genotypes and found a higher frequency of genotype 1 (31.7%) with worldwide distribution. We note that the KIR2DL2 inhibitor gene and the gene activator KIR2DS2 were more frequent in patients without recurrence. Additionally, we observed that individuals who carry these genes progressed recurrence episodes slowly compared to individuals who do not carry these genes.The KIR2DL2 and KIR2DS2 are associated as possible protection markers against ocular toxoplasmosis recurrence (OTR).

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2023-03-07 | Potential relationships between uveitis and COVID-19: a bioinformatic study based on CEO database

Abstract Purpose Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a great impact on human survival and a great threat to public health in countries all over the world. The link between COVID-19 and ocular illness has received increasing attention due to SARS-CoV-2 infection can be transmitted through eye contact. Using bioinformatics methods, we sought to investigate the potential molecular mechanisms between uveitis and COVID-19, providing rationales and directions for further exploration. Methods Transcriptomic data of uveitis and COVID-19 patient blood samples were accessed from the Gene Expression Omnibus public database. Common differentially expressed genes were identified. Genetic Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, Protein-Protein Interaction network analysis were performed on intersected genes. We screened 5 hub genes by using the maximum clustering centrality algorithm. The Least Absolute Shrinkage and Selection Operator regression analysis identified the potential biomarkers for uveitis and COVID-19. Finally, the expression level and diagnostic value of the biomarker in the two diseases were determined. Results 50 intersected genes were extracted from differential expression analysis in uveitis and COVID-19. These genes were functionally enriched in cytokine-mediated signaling pathway, vesicle lumen, receptor ligand activity. Through KEGG analysis, these genes were found to be involved in viral protein interaction with cytokine and cytokine receptor, and cytokine-cytokine receptor interaction. HORMAD1 was obtained by Least Absolute Shrinkage and Selection Operator regression analysis, which was high expression in both uveitis and COVID-19 when compared to controls. Receiver Operating Characteristic values and AUC statistics indicated that HORMAD1 had diagnostic value for uveitis and COVID-19. Conclusions Bioinformatic analysis predicts HORMAD1 involvement in etiology and therapeutic targets of uveitis and COVID-19. However, additional clinical trials and studies are needed to confirm the role of HORMAD1.

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cell therapies

2023-06-02 | IL-27-containing exosomes secreted by innate B-1a cells suppress and ameliorate uveitis

IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize in-vivo to form biologically active IL-27 is unknown. Major impediment to clinical use of IL-27 derives from difficulty of determining exact amount of bioavailable heterodimeric IL-27 needed for therapy.To understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy.Contrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion.Use of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.

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2015-12-09 | Transforming growth factor-β2 increases the capacity of retinal pigment epithelial cells to induce the generation of regulatory T cells

The present study investigated the underlying mechanism of the induction of regulatory T cells (Tregs) by retinal pigment epithelial (RPE) cells and the characteristics of these Tregs. Human RPE cells were cultured in the presence or absence of transforming growth factor-β 2 (TGF-β2), and reverse-transcription quantitative PCR was performed to determine the mRNA expression of indoleamine 2,3-dioxygenase (IDO) and nuclear factor erythroid 2-related factor (Nrf2). Supernatants of RPE cell cultures were added to CD4+ T cells to induce Tregs. The RPE-induced Tregs were purified by two-step magnetic cell sorting. The natural Tregs were isolated from the peripheral blood mononuclear cells of healthy volunteers. Purified CD4+ CD25- T cells (2 x 10(5)/well) were cultured alone or with Tregs (various densities, natural or RPE-induced). The proliferation of CD4+ CD25- T cells was determined by 3H-thymidine incorporation. After 24 h of stimulation with TGF-β2, the mRNA expression of IDO in RPE cells was upregulated. The highest level of IDO mRNA expression was reached after 72 h of stimulation with TGF-β2. However, the Nrf2 mRNA expression was slightly decreased after 24 h of stimulation with TGF-β2 and significantly increased after 48-72 h of TGF-β2 stimulation. Increased levels of CD25 expression were observed on CD4+ T cells exposed to supernatants of RPE cell cultures treated with TGF-β2 and recombinant interleukin-2. The RPE-induced Tregs were more effective at suppressing the proliferation of CD4+ CD25- T cells compared with native Tregs. These findings suggested that IDO may be a signaling protein in RPE cells which is implicated in the induction of Tregs. RPE-induced Tregs have the potential to be applied for immunotherapy for ocular inflammatory diseases.

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2012-01-12 | The Living Eye “Disarms” Uncommitted Autoreactive T Cells by Converting Them to Foxp3+ Regulatory Cells following Local Antigen Recognition

Abstract Immune privilege is used by the eye, brain, reproductive organs, and gut to preserve structural and functional integrity in the face of inflammation. The eye is arguably the most vulnerable and, therefore, also the most “privileged” of tissues; paradoxically, it remains subject to destructive autoimmunity. It has been proposed, although never proven in vivo, that the eye can induce T regulatory cells (Tregs) locally. Using Foxp3-GFP reporter mice expressing a retina-specific TCR, we now show that uncommitted T cells rapidly convert in the living eye to Foxp3+ Tregs in a process involving retinal Ag recognition, de novo Foxp3 induction, and proliferation. This takes place within the ocular tissue and is supported by retinoic acid, which is normally present in the eye because of its function in the chemistry of vision. Nonconverted T cells showed evidence of priming but appeared restricted from expressing effector function in the eye. Pre-existing ocular inflammation impeded conversion of uncommitted T cells into Tregs. Importantly, retina-specific T cells primed in vivo before introduction into the eye were resistant to Treg conversion in the ocular environment and, instead, caused severe uveitis. Thus, uncommitted T cells can be disarmed, but immune privilege is unable to protect from uveitogenic T cells that have acquired effector function prior to entering the eye. These findings shed new light on the phenomenon of immune privilege and on its role, as well as its limitations, in actively controlling immune responses in the tissue.

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2009-03-01 | Immunopathology in ocular toxoplasmosis: facts and clues

Although parasite-mediated host cell lysis is deemed to be an important cause of tissue destruction in ocular toxoplasmosis (OT), the severity of the disease is probably correlated with hypersensitivity and inflammation. Notwithstanding, the mechanisms that regulate the inflammatory process in recurrent OT are poorly understood. Recent evidence has identified interleukin (IL) 17 as a marker for disease severity. The ocular and cerebral presence of this cytokine is generally associated with the induction of autoimmune responses in the brain and the eye. Indeed, there are indications that autoimmunity may contribute to clinical variability in the activity of OT. IL-23, which induces the proliferation of IL-17-producing cells and IL-27, which is a counterplayer to IL-17, may regulate T(H)-1-cell-mediated responses in OT. The importance of these cytokines in experimental models of uveitis and encephalitis has been recently reported. CD25(+) regulatory T-cells may control the local inflammatory response and protect the host against collateral inflammatory tissue damage. The responses of these cells to OT may be suitably tailored to cope with either an acquired or a congenital aetiology. Knowledge relating to immunoreactivity in OT has grown impressively during the past few years. Its characteristic and variable features have been identified and the potential relevance of autoimmunity has been assessed. In light of this knowledge, potential future treatment options have been considered.

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2009-01-26 | Human ocular-derived virus-specific CD4+ T cells control varicella zoster virus replication in human retinal pigment epithelial cells.

purpose. Varicella zoster virus (VZV)-induced retinitis is characterized by the presence of virus-infected cells in the retinal layer and the ocular infiltration of VZV-specific T cells. Herein, the susceptibility of human retinal pigment epithelial (RPE) cells to VZV infection and the ability of virus-specific CD4+ T cells to control VZV infection in RPE cells in vitro is addressed. methods. Human primary RPE cell cultures (n = 2) were infected with a VZV strain expressing green fluorescent protein. The infection and viability of infected RPE cells was monitored by flow cytometry or by a fluorescent imager on RPE monolayers. RPE cells, pretreated with or without interferon-γ (IFN-γ), were infected with VZV and subsequently cultured with VZV-specific CD4+ T-cell clones (TCCs; n = 3) recognizing disparate VZV proteins presented by different HLA class II alleles. IFN-γ production and cytotoxicity of the TCCs in response to VZV-infected RPE cells was determined by flow cytometry. results. Human RPE cells are permissive to a productive VZV infection. VZV-infected RPE cells presented the cognate antigen to the CD4+ TCCs only if the RPE cells were pretreated with IFN-γ and expressed the appropriate HLA class II allele. VZV-specific TCCs inhibited productive VZV infection in RPE cells, which was in part attributed to TCC-mediated killing of the VZV-infected RPE cells. conclusions. The results presented suggest that RPE cells may play a role as retina-resident antigen-presenting cells in the intraocular, VZV-specific, T cell-mediated inflammatory response of VZV-induced uveitis.

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proteins

2023-09-01 | Targeted delivery of autoantigen to dendritic cells prevents development of spontaneous uveitis

Restoration of immunological tolerance to self antigens has been a major drive in understanding the mechanisms of, and developing new treatments for, autoimmune and autoinflammatory disease. Sessile dendritic cells (DC) are considered the main instruments underpinning immunological tolerance particularly the CD205+ (DEC205+) cDC1 subset in contrast to DCIR2+ cDC2 which mediate immunogenicity. Targeting DC using autoantigen peptide-antibody fusion proteins has been a well explored methodology for inducing tolerance. Here we show that subcutaneous (s.c.) inoculation of hen-egg lysozyme (HEL)-DEC205 Ig fusion prevents the development of spontaneous uveoretinitis (experimental autoimmune uveoretinitis, EAU) in a transgenic mouse model generated by crossing interphotoreceptor retinol binding protein (IRBP)-HEL (sTg HEL) with HEL specific TCR (sTg TCR) mice. Prolonged suppression of EAU required injections of HEL-DEC205 Ig once weekly, reflecting the half life of s.c. DC. Interestingly, HEL-DCIR2 Ig also had a suppressive effect on development of EAU but less so than DEC205 Ig while it had minimal effect on preventing the retinal atrophy associated with EAU. In addition, HEL-DEC205 Ig was only effective when administered s.c. rather than systemically and had no effect on EAU induced by adoptive transfer of HEL-activated T cells. These data demonstrate the importance of systemic (lymph node) rather than local (eye) antigen presentation in the development of EAU as well as suggest a potential therapeutic approach to controlling sight-threatening immune-mediated uveitis provided relevant antigen(s) can be identified.

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2018-03-28 | Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

Lipocalin 2 (LCN2), an important mediator of a variety of cellular processes, is involved in regulating the inflammatory response, but its roles in different inflammatory diseases are controversial. Because the role of LCN2 in ocular inflammation has been unclear until now, we explored the function of LCN2 in lipopolysaccharide (LPS)-induced ocular inflammation in vivo and in vitro.Endotoxin-induced uveitis (EIU) was induced in male Sprague Dawley rats by the intravitreal injection of LPS. The expression and location of LCN2 in the retina were detected with western blotting and immunohistochemistry, respectively. We determined the clinical scores for anterior inflammation, quantified the infiltrated inflammatory cells, and measured the pro-inflammatory factors to determine the anti-inflammatory effects of LCN2 in EIU eyes. Cultured primary rat Müller cells were stimulated with LPS and the expression and secretion of LCN2 were measured with real-time PCR, western blotting, and an ELISA. After Müller cells were cotreated with LPS and LCN2 or PBS, the expression and secretion of TNF-α, IL-6, and MCP-1 were examined with realtime PCR, western blotting, and ELISAs. Western blotting and immunofluorescence were used to detect the phosphorylation and cellular distribution of nuclear factor kappaB (NF-κB) subunit p65.In EIU, the expression of LCN2 was significantly upregulated in the retina, especially in the outer nuclear layer (mainly composed of Müller cells). LPS stimulation of cultured Müller cells also markedly elevated LCN2 expression. Intravitreal injection of LCN2 significantly reduced the clinical scores, inflammatory infiltration, and protein leakage in EIU, which correlated with the reduced levels of proinflammatory factors in the aqueous humor and retina. LCN2 treatment also reduced the expression and secretion of TNF-α, IL-6, and MCP-1 in LPS-stimulated Müller cells. LCN2 inhibited the inflammatory response by inhibiting the phosphorylation and translocation of NF-κB p65.LCN2 protects against ocular inflammation, at least in part, by negatively regulating the activation of the NF-κB signaling pathway. LCN2 may be a promising anti-inflammatory therapy for ocular diseases, such as uveitis.

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2015-12-01 | Superoxide Dismutase 1 Nanozyme for Treatment of Eye Inflammation

Use of antioxidants to mitigate oxidative stress during ocular inflammatory diseases has shown therapeutic potential. This work examines a nanoscale therapeutic modality for the eye on the base of antioxidant enzyme, superoxide dismutase 1 (SOD1), termed “nanozyme.” The nanozyme is produced by electrostatic coupling of the SOD1 with a cationic block copolymer, poly(L‐lysine)‐poly(ethyleneglycol), followed by covalent cross‐linking of the complexes with 3,3′‐dithiobis(sulfosuccinimidylpropionate) sodium salt. The ability of SOD1 nanozyme as well as the native SOD1 to reduce inflammatory processes in the eye was examined in vivo in rabbits with immunogenic uveitis. Results suggested that topical instillations of both enzyme forms demonstrated anti‐inflammatory activity; however, the nanozyme was much more effective compared to the free enzyme in decreasing uveitis manifestations. In particular, we noted statistically significant differences in such inflammatory signs in the eye as the intensities of corneal and iris edema, hyperemia of conjunctiva, lens opacity, fibrin clots, and the protein content in aqueous humor. Clinical findings were confirmed by histological data. Thus, SOD1‐containing nanozyme is potentially useful therapeutic agent for the treatment of ocular inflammatory disorders.

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2014-09-17 | Oral Delivery of ACE2/Ang-(1–7) Bioencapsulated in Plant Cells Protects against Experimental Uveitis and Autoimmune Uveoretinitis

Hyperactivity of the renin-angiotensin system (RAS) resulting in elevated Angiotensin II (Ang II) contributes to all stages of inflammatory responses including ocular inflammation. The discovery of angiotensin-converting enzyme 2 (ACE2) has established a protective axis of RAS involving ACE2/Ang-(1–7)/Mas that counteracts the proinflammatory and hypertrophic effects of the deleterious ACE/AngII/AT1R axis. Here we investigated the hypothesis that enhancing the systemic and local activity of the protective axis of the RAS by oral delivery of ACE2 and Ang-(1–7) bioencapsulated in plant cells would confer protection against ocular inflammation. Both ACE2 and Ang-(1–7), fused with the non-toxic cholera toxin subunit B (CTB) were expressed in plant chloroplasts. Increased levels of ACE2 and Ang-(1–7) were observed in circulation and retina after oral administration of CTB-ACE2 and Ang-(1–7) expressing plant cells. Oral feeding of mice with bioencapsulated ACE2/Ang-(1–7) significantly reduced endotoxin-induced uveitis (EIU) in mice. Treatment with bioencapsulated ACE2/Ang-(1–7) also dramatically decreased cellular infiltration, retinal vasculitis, damage and folding in experimental autoimmune uveoretinitis (EAU). Thus, enhancing the protective axis of RAS by oral delivery of ACE2/Ang-(1–7) bioencapsulated in plant cells provide an innovative, highly efficient and cost-effective therapeutic strategy for ocular inflammatory diseases. Hyperactivity of the renin-angiotensin system (RAS) resulting in elevated Angiotensin II (Ang II) contributes to all stages of inflammatory responses including ocular inflammation. The discovery of angiotensin-converting enzyme 2 (ACE2) has established a protective axis of RAS involving ACE2/Ang-(1–7)/Mas that counteracts the proinflammatory and hypertrophic effects of the deleterious ACE/AngII/AT1R axis. Here we investigated the hypothesis that enhancing the systemic and local activity of the protective axis of the RAS by oral delivery of ACE2 and Ang-(1–7) bioencapsulated in plant cells would confer protection against ocular inflammation. Both ACE2 and Ang-(1–7), fused with the non-toxic cholera toxin subunit B (CTB) were expressed in plant chloroplasts. Increased levels of ACE2 and Ang-(1–7) were observed in circulation and retina after oral administration of CTB-ACE2 and Ang-(1–7) expressing plant cells. Oral feeding of mice with bioencapsulated ACE2/Ang-(1–7) significantly reduced endotoxin-induced uveitis (EIU) in mice. Treatment with bioencapsulated ACE2/Ang-(1–7) also dramatically decreased cellular infiltration, retinal vasculitis, damage and folding in experimental autoimmune uveoretinitis (EAU). Thus, enhancing the protective axis of RAS by oral delivery of ACE2/Ang-(1–7) bioencapsulated in plant cells provide an innovative, highly efficient and cost-effective therapeutic strategy for ocular inflammatory diseases.

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2014-04-17 | Interleukin-35 induces regulatory B cells that suppress autoimmune disease

Regulatory B (Breg) cells producing interleukin-10 (IL-10) suppress autoimmune disease, but the mechanisms mediating their induction remain unclear. Charles E. Egwuagu and colleagues report that IL-35 induces Breg cells and also promotes their production of IL-35. In vivo IL-35 suppresses autoimmune disease in an IL-35 receptor– and IL-10–dependent manner. Adoptive transfer of IL-35–induced Breg cells inhibits established autoimmune disease, suggesting that IL-35 and IL-35–producing Breg cells may be used to treat inflammatory disease. Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4+ T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35+ Breg cells and treat autoimmune and inflammatory disease.

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2022-12-01 | How study of naturally occurring ocular disease in animals improves ocular health globally

In this article, which is part of the Currents in One Health series, the role of naturally occurring ocular disease in animals is reviewed with emphasis on how the understanding of these ocular diseases contributes to one health initiatives, particularly the pathogenesis and treatment of ocular diseases common to animals and humans. Animals spontaneously develop ocular diseases that closely mimic those in humans, especially dry eye disease, herpes virus infection (cats), fungal keratitis (horses), bacterial keratoconjunctivitis, uveitis, and glaucoma. Both uveitis and glaucoma are common in domestic animals and humans, and many similarities exist in pathogenesis, genetics, and response to therapy. Furthermore, the study of inherited retinal disease in animals has particularly epitomized the one health concept, specifically the collaborative efforts of multiple disciplines working to attain optimal health for people and animals. Through this study of retinal disease in dogs, innovative therapies such as gene therapy have been developed. A unique opportunity exists to study ocular disease in shared environments to better understand the interplay between the environment, genetics, and ocular disease in both animals and humans. The companion Currents in One Health by Gilger, AJVR, December 2022, addresses in more detail recent studies of noninfectious immune-mediated animal ocular disease and their role in advancing ocular health globally.

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2022-10-28 | Rift Valley Fever Virus Infects the Posterior Segment of the Eye and Induces Inflammation in a Rat Model of Ocular Disease.

People infected with the mosquito-borne Rift Valley fever virus (RVFV) can suffer from eye-related problems resulting in ongoing vision issues or even permanent blindness. Despite ocular disease being the most frequently reported severe outcome, it is vastly understudied compared to other disease outcomes caused by RVFV. Ocular manifestations of RVFV include blurred vision, uveitis, and retinitis. When an infected individual develops macular or paramacular lesions, there is a 50% chance of permanent vision loss in one or both eyes. The cause of blinding ocular pathology remains unknown in part due to the lack of a tractable animal model. Using 3 relevant exposure routes, both subcutaneous (SC) and aerosol inoculation of Sprague Dawley rats led to RVFV infection of the eye. Surprisingly, direct inoculation of the conjunctiva did not result in successful ocular infection. The posterior segment of the eye, including the optic nerve, choroid, ciliary body, and retina, were all positive for RVFV antigen in SC-infected rats, and live virus was isolated from the eyes. Proinflammatory cytokines and increased leukocyte counts were also found in the eyes of infected rats. Additionally, human ocular cell lines were permissive for Lrp1-dependent RVFV infection. This study experimentally defines viral tropism of RVFV in the posterior segment of the rat eye and characterizes virally-mediated ocular inflammation, providing a foundation for evaluation of vaccines and therapeutics to protect against adverse ocular outcomes. IMPORTANCE Rift Valley fever virus (RVFV) infection leads to eye damage in humans in up to 10% of reported cases. Permanent blindness occurs in 50% of individuals with significant retinal scarring. Despite the prevalence and severity of this outcome, very little is known about the mechanisms of pathogenesis. We addressed this gap by developing a rodent model of ocular disease. Subcutaneous infection of Sprague Dawley rats resulted in infection of the uvea, retina, and optic nerve along with the induction of inflammation within the posterior eye. Infection of human ocular cells induced inflammatory responses and required host entry factors for RVFV infection similar to rodents. This work provides evidence of how RVFV infects the eye, and this information can be applied to help mitigate the devastating outcomes of RVF ocular disease through vaccines or treatments.

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2022-03-23 | Therapeutic Applications of Adeno-Associated Virus (AAV) Gene Transfer of HLA-G in the Eye

The purpose of this paper is to review human leukocyte antigen G (HLA-G) in the eye, its role in immune tolerance, and the potential therapeutic use of AAV gene transfer and expression of HLA-G in various ocular tissues. Several studies are reviewed that demonstrate efficacy in animal models of disease, including intracorneal delivery of AAV-HLA-G to treat corneal inflammation and prevent corneal graft rejection, subconjunctival injection of AAV-HLA-G for ocular graft vs. host disease and potentially dry eye disease, and intravitreal injection of AAV-HLA-G to inhibit uveitis. Furthermore, due to the anti-vascular function of HLA-G, AAV-HLA-G may be an effective therapy for posterior ocular diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, and choroidal neovascularization. Therefore, AAV-mediated gene transfer of HLA-G may be an effective treatment for common immune-mediated, inflammatory, and neovascular diseases of the eye.

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2014-11-24 | Gene Delivery of a Viral Anti-Inflammatory Protein to Combat Ocular Inflammation

Inflammation of the retina is a contributing factor in ocular diseases such as uveitis, diabetic retinopathy, and age-related macular degeneration (AMD). The M013 immunomodulatory protein from myxoma virus has been shown to interfere with the proinflammatory signaling pathways involving both the NLRP3 inflammasome and NF-κB. We have developed and characterized an adeno-associated viral (AAV) vector that delivers a secretable and cell-penetrating form of the M013 protein (TatM013). The expressed TatM013 protein was secreted and blocked the endotoxin-induced secretion of interleukin (IL)-1β in monocyte-derived cells and the reactive aldehyde-induced secretion of IL-1β in retinal pigment epithelium cells. The local anti-inflammatory effects of AAV-delivered TatM013 were evaluated in an endotoxin-induced uveitis (EIU) mouse model after intravitreal injection of mice with an AAV2-based vector carrying either TatM013 fused to a secreted green fluorescent protein (GFP) tag (sGFP-TatM013) or GFP. Expression of the sGFP-TatM013 transgene was demonstrated by fluorescence funduscopy in living mice. In EIU, the number of infiltrating cells and the concentration of IL-1β in the vitreous body were significantly lower in the eyes injected with AAV-sGFP-TatM013 compared with the eyes injected with control AAV-GFP. These results suggest that a virus-derived inhibitor of the innate immune response, when delivered via AAV, could be a generalized therapy for various inflammatory diseases of the eye.

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2008-06-26 | Lentiviral-vector-mediated expression of murine IL-1 receptor antagonist or IL-10 reduces the severity of endotoxin-induced uveitis

Uveitis is a sight threatening inflammatory disorder that remains a significant cause of visual loss. We investigated lentiviral gene delivery of interleukin 1 receptor antagonist (IL-1ra) or interleukin (IL)-10 to ameliorate murine endotoxin-induced uveitis (EIU). An human immunodeficiency virus-1-based vector containing the mIL-1ra or mIL-10 cDNA demonstrated high expression of biologically active cytokine. Following administration of Lenti.GFP into the anterior chamber, transgene expression was observed in corneal endothelial cells, trabecular meshwork and iris cells. To treat EIU, mice were injected with Lenti.IL-1ra, Lenti.IL-10 or a combination of these. EIU was induced 14 days after vector administration and mice were culled 12 h following disease induction. Lenti.IL-1ra or Lenti.IL-10-treated eyes showed significantly lower mean inflammatory cell counts in the anterior and posterior chambers compared with controls. The aqueous total protein content was also significantly lower in treated eyes, demonstrating better preservation of the blood-ocular barrier. Furthermore, the treated eyes showed less in vivo fluorescein leakage from inner retinal vessels compared with controls. The combination of both IL-1ra and IL-10 had no additive effect. Thus, lentiviral gene delivery of IL-1ra or IL-10 significantly reduces the severity of experimental uveitis, suggesting that lentiviral-mediated expression of immunomodulatory genes in the anterior chamber offers an opportunity to treat uveitis.

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