Search Results (181)

The cornea is an avascular, immune-privileged tissue critical to maintaining transparency, optimal light refraction, and protection from microbial and immunogenic insults. Corneal neovascularization (CoNV) is a pathological sequela of multiple anterior segment diseases and presents a major cause for reduced visual acuity and overall quality of life. Various aetiologies, including infection (e.g., herpes simplex), inflammation (e.g., infective keratitis), hypoxia (e.g., contact lens overuse), degeneration (e.g., chemical burns), and trauma, disrupt the homeostatic avascular microenvironment, triggering an overactive compensatory response. This response is governed by a complex interplay of pro- and anti-angiogenic factors. This review investigates the potential for these mediators to serve as therapeutic targets. Current therapeutic strategies for CoNV encompass topical corticosteroids, anti-VEGF injections, fine-needle diathermy, and laser modalities including argon, photodynamic therapy and Nd:YAG. Emerging therapies involve steroid-sparing immunosuppressants (including cyclosporine and rapamycin), anti-fibrotic agents and advanced drug delivery systems, including ocular nanosystems and viral vectors, to enhance drug bioavailability. Adjunctive therapy to attenuate the protective corneal epithelium prior to target neovascular plexi are further explored. Gene-based approaches, such as Aganirsen (antisense oligonucleotides) and CRISPR/Cas9-mediated VEGF-A editing, have shown promise in preclinical studies for CoNV regression and remission. Given the multifactorial pathophysiology of CoNV, combination therapies targeting multiple molecular pathways may offer improved visual outcomes. Case studies of CoNV highlight the need for multifaceted approaches tailored to patient demographics and underlying ocular diseases. Future research and clinical trials are essential to elucidate optimal therapeutic strategies and explore combination therapies to ensure better management, improved treatment outcomes, and long-term remission of this visually disabling condition. Full article

The cornea maintains transparency by preserving immune and (lymph)angiogenic privilege through active suppression of inflammation and vascular invasion, a process centrally regulated by limbal epithelial stem cells (LESCs) located at the corneoscleral junction. Beyond renewing the corneal epithelium, LESCs maintain immune and vascular balance via extracellular matrix interactions and paracrine signalling, exerting predominantly anti-inflammatory and anti-(lymph)angiogenic effects in vivo. Disruption of the limbal niche by trauma, UV exposure, or genetic disorders such as aniridia leads to limbal stem cell deficiency (LSCD), chronic inflammation, loss of corneal avascularity, and vision loss. The identification of ABCB5 as a key LESC marker has clarified functional limbal subsets, highlighting ABCB5⁺ epithelial cells as mediators of repair, remodelling, and immune suppression, and positioning them as promising therapeutic targets for treatments that restore both epithelial integrity and corneal immune privilege. Full article

The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies including hemophilia (A and B), Crigler–Najjar syndrome, mucopolysaccharidoses, phenylketonuria, Fabry, Gaucher, Wilson and Pompe diseases. The efficacy and safety of liver-directed gene therapy rely on the use of strong tissue-specific promoters. To date, there are many different liver-specific promoters used in preclinical and clinical studies, including novel completely synthetic promoters. This review provides a comprehensive analysis of the design, engineering and application of liver-specific promoters. Furthermore, we discuss fundamental principles of gene expression regulation in the liver and the physiological and immunological characteristics that make it a suitable target organ for gene therapy delivery. Full article

Alopecia is a multifactorial disorder in which immune, endocrine, metabolic, and microbial systems converge within the follicular microenvironment. In alopecia areata (AA), loss of immune privilege, together with interferon-γ- and interleukin-15-driven activation of the JAK/STAT cascade, promotes cytotoxic infiltration, whereas selective inhibitors, including baricitinib, ritlecitinib, and durvalumab, restore immune balance and permit anagen reentry. In androgenetic alopecia (AGA), excess dihydrotestosterone and androgen receptor signaling increase DKK1 and prostaglandin D2, suppress Wnt and β-catenin activity, and drive follicular miniaturization. Combination approaches utilizing low-dose oral minoxidil, platelet-rich plasma, exosome formulations, and low-level light therapy enhance vascularization, improve mitochondrial function, and reactivate metabolism, collectively supporting sustained regrowth. Elucidation of intracellular axes such as JAK/STAT, Wnt/BMP, AMPK/mTOR, and mitochondrial redox regulation provides a mechanistic basis for rational, multimodal intervention. Advances in stem cell organoids, biomaterial scaffolds, and exosome-based therapeutics extend treatment from suppression toward structural follicle reconstruction. Recognition of microbiome and mitochondria crosstalk underscores the need to maintain microbial homeostasis and redox stability for durable regeneration. This review synthesizes molecular and preclinical advances in AA and AGA, outlining intersecting signaling networks and regenerative interfaces that define a framework for precision and sustained follicular regeneration. Full article

Gene therapy represents a transformative frontier in ophthalmology, offering the potential to address inherited and acquired retinal diseases at their genetic origin rather than through symptomatic management. By introducing exogenous genetic material to restore or modulate gene expression, gene therapy aims to preserve or even restore vision in patients with mutations that disrupt normal retinal function. The eye’s small, compartmentalized structure, relative immune privilege, and direct accessibility through subretinal or intravitreal routes make it an ideal target for localized delivery with minimal systemic exposure. The approval of voretigene neparvovec-rzyl for RPE65-mediated retinal dystrophy marked a pivotal milestone, establishing proof of concept for durable and safe gene replacement therapy. Looking ahead, continued refinements in vector design, CRISPR-based editing strategies, and delivery platforms are expected to expand the therapeutic reach of gene therapy beyond monogenic disorders. With multiple early-phase clinical trials underway for inherited and acquired retinal diseases, the coming decade is poised to bring broader applicability, improved durability, and more accessible gene-based treatments across the spectrum of retinal pathology. Full article

Alopecia areata (AA) is a chronic autoimmune disease characterized by non-scarring hair loss, where pathogenesis is closely linked to the collapse of hair follicle immune privilege and dysregulated T-cell responses. Increasing evidence suggests that gut dysbiosis may contribute to systemic immune alterations relevant to autoimmune disorders, yet its role in AA remains largely unexplored. In this study, we aimed to characterize the gut microbiota composition of AA patients and evaluate its potential as a biomarker for disease discrimination. Fecal samples from patients with AA and healthy controls were analyzed by 16S rRNA sequencing and processed through QIIME2 and MicrobiomeAnalyst platforms. Diversity metrics, differential abundance, and microbial network correlations were assessed, and supervised machine learning models were developed to classify AA versus control profiles. Our results revealed distinct microbial signatures in AA, with enrichment of pro-inflammatory genera such as Methanobrevibacter, Collinsella, and Ruminococcus gnavus, and depletion of immunoregulatory commensals, including Faecalibacterium and Eubacterium eligens group. Network analyses showed more complex microbial interactions in AA, and Random Forest models achieved 92% accuracy in discriminating AA from controls. These findings indicate that gut dysbiosis may play a role in AA pathogenesis, providing potential diagnostic biomarkers and supporting microbiota-targeted interventions as future therapeutic strategies. Full article

Background/Objectives: Alopecia areata (AA) is a common, noncicatricial autoimmune hair loss disorder characterized by relapsing inflammation and breakdown of hair follicle immune privilege. Increasing amounts of evidence suggest that pyroptosis, a lytic and inflammatory form of programmed cell death mediated by gasdermins and inflammasome activation, may play a role in AA pathogenesis. This review aims to synthesize current data on the molecular mechanisms linking inflammasome-driven pyroptosis with AA and to highlight emerging therapeutic opportunities. Methods: A comprehensive literature review was conducted focusing on mechanistic studies, ex vivo human scalp models, murine AA models, and interventional clinical data. A structured system of Levels of Evidence (LoE) and standardized nomenclature for experimental models was applied to ensure transparency in evaluating the role of pyroptosis and treatment strategies in AA. Results: Available evidence indicates that outer root sheath keratinocytes express functional inflammasome components, including NOD-like receptor family, pyrin domain containing 3 (NLRP3), adaptor-apoptosis-associated-speck-like protein (ASC), and caspase-1, and contribute to interleukin (IL)-1β release and pyroptotic cell death. Mitochondrial dysfunction, mediated by regulators such as PTEN and PINK1, amplifies NLRP3 activation and cytokine secretion, linking mitophagy impairment with follicular damage. Animal and human biopsy studies confirm increased inflammasome activity in AA lesions. Therapeutic approaches targeting pyroptosis include Janus kinase (JAK) inhibitors, biologics, Phosphodiesterase 4 (PDE4) inhibitors, mesenchymal stem cell therapy, natural compounds, and inflammasome inhibitors such as MCC950. While some agents demonstrated efficacy in clinical trials, most strategies remain at preclinical or early clinical stages. Conclusions: Pyroptosis represents a critical mechanism driving hair follicle structural and functional disruption and immune dysregulation in AA. By integrating evidence from molecular studies, disease models, and early clinical data, this review underscores the potential of targeting inflammasome-driven pyroptosis as a novel therapeutic strategy. Full article

Alopecia areata (AA) is a complex disease with a multifactorial etiology, in which autoimmune mechanisms play a central role. Increasing evidence suggests that AA may be a systemic condition, potentially affecting organs beyond the skin due to shared pathogenic pathways. One proposed mechanism is the breakdown of immune privilege, a protective state that limits immune activity in specific tissues, such as the hair follicle and the eye. Although research on the relationship between AA and ophthalmic comorbidities remains limited, several studies have reported recurrent ocular abnormalities, whether subclinical or symptomatic, appearing at younger ages than typically observed in the general population. This review aims to summarize current knowledge on the association between AA and ocular involvement, exploring shared pathogenic mechanisms, clinical eye manifestations, and practical considerations for addressing ocular symptoms in dermatological practice. Full article

Retinal detachment (RD) disrupts the eye’s immune-privileged status, causing a local inflammatory response that contributes to adverse clinical outcomes, including proliferative vitreoretinopathy and suboptimal visual recovery. Comprehensive profiling of intraocular immune cells will offer mechanistic insights and support the development of personalized immunomodulatory strategies. Here, we describe a robust and standardized protocol for the collection and high-dimensional analysis of the intraocular immune infiltrate from patients undergoing RD surgery, using state-of-the-art spectral cytometry. Vitreous and retinal tissue samples were obtained during standard surgical procedures, without the need for additional invasive interventions. Our approach integrates two complementary protocols: one that enables selective isolation of immune cells by sorting for CD45⁺ populations, and a second one that applies a 39-color spectral cytometry panel to profile the general landscape of immune subpopulations. The panel can identify up to 62 distinct viable immune subsets per sample, along with their functional status, as it includes expression of 13 functional markers. Hence, we hereby detail sample preparation, staining, and acquisition workflow, as well as the gating strategy and essential steps necessary for reproducible immunophenotyping. Our protocol, which enables high-dimensional immune profiling from minimal biological material, provides a valuable platform for studying ocular inflammation in RD and other retinal diseases. Full article

The gut-brain axis has emerged as a critical pathway influencing central nervous system (CNS) tumor biology through complex microbiome-mediated mechanisms. Understanding these interactions is essential for developing novel therapeutic strategies and biomarkers for CNS tumors. To systematically review and meta-analyze current evidence on gut microbiota interactions with CNS tumors, examining mechanisms, clinical correlations, therapeutic implications, and biomarker potential. We conducted a comprehensive systematic review following PRISMA guidelines, searching PubMed, EMBASE, Google Scholar, and Cochrane Library databases for studies published from 2010–2025. A random-effects meta-analysis of reported statistical outcomes was performed to quantify microbiome alterations using standardized mean differences (Cohen’s d) and diagnostic accuracy measures. Analyses were based on published summary statistics rather than reprocessed raw sequencing data, acknowledging cross-study heterogeneity. From 161 identified records, 12 studies met inclusion criteria (6 clinical studies, n = 387 participants; 6 preclinical studies). Meta-analysis revealed significant Shannon diversity reduction in CNS tumor patients (Cohen’s d = −1.237 [95% CI: −1.614, −0.860; 95% PI: −2.48, −0.12]) with moderate heterogeneity (I² = 60.5%). Evidence demonstrated significant gut microbiome alterations with reduced microbial diversity, increased pathogenic bacteria (Akkermansia muciniphila: 2.23-fold increase, Fusobacterium spp.: 2.04-fold increase), and decreased beneficial bacteria (Bifidobacterium spp.: 47% reduction, Lachnospira spp.: 56% reduction). Diagnostic performance showed fair discrimination (pooled AUC = 0.786 [95% CI: 0.781, 0.791]). Key mechanisms include bidirectional tumor-microbiota interactions through immune system modulation, metabolic pathway alterations involving short-chain fatty acids, and inflammatory response modifications within the altered CNS immune privilege environment. Preliminary evidence suggests gut microbiota alterations in CNS tumor patients, but findings require validation in large, standardized cohorts before clinical application. Current evidence quality is low (GRADE assessment), necessitating substantial additional research. Full article

Heat stress typically suppresses systemic immunity in fish; however, its effects on the brain—an organ traditionally regarded as immune-privileged—remain unclear. In this study, we performed histopathological examination and RNA-seq analysis on the brains of juvenile largemouth bass (Micropterus salmoides) exposed to control (28 °C) and elevated (36.5 °C) water temperatures for 8 weeks. Histological analysis revealed distinct cytoarchitectural and pathological changes in specific brain regions. RNA-seq analysis identified a total of 1240 differentially expressed genes, with 22 heat shock protein genes notably showing significant up-regulation. The immune system-associated genes emerged as the most prominently affected category. Gene set enrichment analysis (GSEA) based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations revealed that up-regulated genes were enriched in immunity-related pathways, including the NOD-like receptor (NLR) signaling pathway, Toll-like receptor (TLR) signaling pathway, and cytosolic DNA-sensing pathway. Additionally, the levels of apoptosis and necroptosis were moderately increased. GSEA based on Gene Ontology (GO) terms indicated that down-regulated genes were primarily associated with cell division. Protein–protein interaction (PPI) and clustering analysis identified 41 core genes in the top three clusters, encompassing those related to nuclear chromosome segregation, ribosome biogenesis, and stress response. The inhibition of genes involved in nuclear chromosome segregation may disrupt cellular homeostasis by significantly impairing microtubule dynamics. In contrast, genes associated with ribosome biogenesis and stress response were up-regulated, which could counteract the adverse effects caused by long-term heat stress. We propose that brain-specific immune activation, particularly via the NLR and TLR signaling pathways, acts as a compensatory strategy to counterbalance heat-induced cell death, thereby revealing a novel neuro-immune adaptation axis. Full article

Cell-based therapeutics are redefining interventions for vision loss by enabling tissue replacement, regeneration, and neuroprotection. This review surveys contemporary cellular strategies in ophthalmology through the lenses of therapeutic effectiveness, translational readiness, and governance. We profile principal sources—embryonic and induced pluripotent stem cells, mesenchymal stromal cells, retinal pigment epithelium, retinal progenitor and limbal stem cells—and enabling platforms including extracellular vesicles, encapsulated cell technology and biomaterial scaffolds. We synthesize clinical evidence across age-related macular degeneration, inherited retinal dystrophies, and corneal injury/limbal stem-cell deficiency, and highlight emerging applications for glaucoma and diabetic retinopathy. Delivery routes (subretinal, intravitreal, anterior segment) and graft formats (single cells, sheets/patches, organoids) are compared using standardized structural and functional endpoints. Persistent barriers include GMP-compliant derivation and release testing; differentiation fidelity, maturation, and potency; genomic stability and tumorigenicity risk; graft survival, synaptic integration, and immune rejection despite ocular immune privilege; the scarcity of validated biomarkers and harmonized outcome measures and ethical, regulatory, and health-economic constraints. Promising trajectories span off-the-shelf allogeneic products, patient-specific iPSC-derived grafts, organoid and 3D-bioprinted tissues, gene-plus-cell combinations, and cell-free extracellular-vesicle therapeutics. Overall, cell-based therapies remain investigational. With adequately powered trials, methodological harmonization, long-term surveillance, scalable xeno-free manufacturing, and equitable access frameworks, they may eventually become standards of care; at present, approvals are limited to specific products/indications and regions, and no cell therapy is the standard of care for retinal disease. Full article

Regulated proteolysis via autophagy is essential for cellular homeostasis, yet the specific role of autophagy-related gene 7 (ATG7) in corneal epithelial maintenance remains unclear. Using a conditional knockout mouse model (Atg7^f/f K14Cre^+/−), we investigated the impact of ATG7 deficiency on corneal epithelial autophagy, morphology, and vascular dynamics. Loss of ATG7 disrupted autophagosome formation, evidenced by increased LC3B expression but reduced LC3B-positive puncta and absence of autophagosomes ultrastructurally. Although gross corneal morphology was preserved, ATG7 deficiency led to thickened epithelium and increased peripheral lymphatic vessel sprouting, indicating a pro-inflammatory and pro-lymphangiogenic microenvironment. Proteomic analysis revealed upregulation of RAB8, TM9S3, and RETR3, suggesting activation of compensatory pathways such as exophagy, reticulophagy, and Golgiphagy. Inflammatory and angiogenic components were downregulated, suggesting a moderate loss of inhibitory capacity based on the lymphatic phenotypes observed. At the same time, while these two compensatory changes occur, other proteins that positively regulate lysosome formation are reduced, resulting in a phenotype linked to deficient autophagy. These findings demonstrate that ATG7-mediated autophagy maintains corneal epithelial homeostasis and immune privilege, with implications for understanding corneal inflammation and lymphangiogenesis in ocular surface diseases. Full article

Hyper-IgE syndrome (HIES) is a rare genetic immunodeficiency characterized by elevated serum IgE levels and associated immune dysregulation, manifesting in recurrent infections, eczema, and skeletal abnormalities. Emerging evidence suggests a link between HIES and audiovestibular dysfunction, potentially mediated by IgE-driven inflammation in the inner ear, which is not immunologically privileged. However, the nature of this association remains poorly understood. This systematic review synthesizes current evidence on the characteristics, pathophysiology, diagnostic approaches, and management of audiovestibular dysfunction in HIES patients. Literature searches across PubMed, Embase, ClinicalKey, Web of Science, and ScienceDirect (up to 6 August 2025) were conducted in accordance with PRISMA guidelines. Key findings indicate that HIES-related audiovestibular issues, including sensorineural hearing loss and vestibular impairment, may arise from IgE-mediated endolymphatic sac inflammation, leading to hydrops and hair cell damage. Diagnostic tools such as audiometry, electrocochleography, and allergen challenge tests show promise, with elevated IgE correlating with abnormal otoacoustic emissions and prolonged auditory brainstem response latencies. Treatment focuses on immunomodulation (e.g., corticosteroids, dupilumab) to mitigate IgE effects, though evidence is limited to case reports. A proposed schematic diagram illustrates pathophysiology, emphasizing IgE’s role in inner ear toxicity. Timely recognition and intervention may prevent progression to permanent hearing loss or vestibular disability, improving quality of life. Future research should explore genetic–immunologic mechanisms and prospective trials for targeted therapies. Trial registration: PROSPERO CRD420251120600. Full article

As essential skin appendages, hair follicles exhibit complex developmental and regenerative processes shaped by the skin microenvironment. Imbalances in skin microenvironmental homeostasis are often accompanied by follicle miniaturization and even hair loss. In studying the mechanisms of hair follicle development, in addition to focusing on the self-regulation of intrinsic signaling within the follicle, it is also crucial to examine the remodeling of the follicular microenvironment triggered by dynamic changes in the skin microenvironment. Herein, we review the individual and combined roles of various cells, tissues, signaling molecules, and metabolic alterations within the skin microenvironment in hair follicle development. Moreover, we summarize the potential applications of the skin microenvironment in treating hair-related diseases, highlight the existing challenges and limitations in the research field, and provide perspectives on future research directions, aiming to elucidate the critical role of the skin microenvironment in regulating hair follicle development. Full article