Search Results (78)

Adeno-associated virus (AAV) vectors face a critical translational challenge in ocular gene therapy due to pre-existing neutralizing antibodies (NAbs) whose seroprevalence limits patient eligibility. Standard NAb detection using non-ocular cell models (Human Embryonic Kidney 293T) may inadequately predict retinal transduction inhibition due to cell type-related variations in receptor usage and immunogenicity. This study established parallel NAb detection platforms utilizing human retinal pigment epithelial (ARPE-19) cells and standard 293T cells to systematically evaluate clinical serum samples against ophthalmologically relevant AAV serotypes (2, 5, 8, 9) via luciferase reporter-based transduction inhibition assays. Comparative analysis demonstrated ARPE-19 exhibited 42–48% higher NAb titers against AAV5/9 compared to 293T cells, with distinct serotype-biased neutralization hierarchies observed between cellular models. Furthermore, female-derived sera exhibited significantly elevated NAbs against particular serotypes in the ARPE-19 system. Critically, inter-serotype cross-neutralization correlation patterns differed substantially between cellular platforms. These findings demonstrate that physiologically relevant retinal cellular models provide essential immunological profiling data, revealing NAb characteristics obscured in standard assays. Consequently, employing retinal cell-based platforms is crucial for optimizing AAV serotype selection, patient stratification, and predicting clinical outcomes in ocular gene therapy. Full article

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of pan-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered by on-target toxicities, particularly ocular and cardiotoxic effects, as well as the induction of pro-survival, compensatory heat shock responses. Together, these and other complications have prompted the development of isoform-selective Hsp90 inhibitors. In this review, we discuss the molecular bases for Hsp90 function and inhibition and emphasize recent advances in isoform-selective targeting. Importantly, we highlight how Hsp90 inhibition can sensitize tumors to cancer immunotherapy by enhancing antigen presentation, reducing immune checkpoint expression, remodeling the tumor microenvironment, and promoting innate immune activation. Special focus is given to Hsp90β-selective inhibitors, which modulate immunoregulatory pathways without eliciting the deleterious effects observed with pan-inhibition. Preclinical and early clinical data support the integration of Hsp90 inhibitors with immune checkpoint blockade and other immunotherapeutic modalities to overcome resistance mechanisms in immunologically cold tumors. Therefore, the continued development of isoform-selective Hsp90 inhibitors offers a promising avenue to potentiate cancer immunotherapy with improved efficacy. Full article

Background and Objectives: Pediatric Sjögren’s syndrome is a rare autoimmune disease with a heterogeneous clinical expression and limited pediatric-specific diagnostic criteria. Ocular involvement often represents an early manifestation, yet it may go unrecognized in children due to poor symptom reporting and the underuse of objective diagnostic tools. This retrospective study evaluated six pediatric patients with Sjögren’s syndrome, integrating systemic and ocular findings with a focus on early immunological and clinical markers. Materials and Methods: All patients underwent ophthalmological assessments, including tear break-up time, Schirmer’s test, and slit-lamp examination. Results: Tear break-up time values consistently indicated tear film instability (mean RE 7.4 ± 2.5 s; LE 7.7 ± 2.3 s), while Schirmer’s test showed greater variability. Slit-lamp examination revealed inhomogeneous tear films in all patients and blepharitis in 66.7%, consistent with Meibomian gland dysfunction. Systemic features included arthralgia, Raynaud’s phenomenon, fatigue, and frequent seropositivity for ANA and anti-SSA/Ro antibodies. Minor salivary gland biopsy confirmed lymphoepithelial sialadenitis in all cases. Conclusions: These findings highlight the importance of combining laboratory and clinical markers with ophthalmological parameters to support an early diagnosis of Sjögren’s syndrome in pediatric patients. Integrating TBUT and slit-lamp evaluation with serological and histopathological data may enhance diagnostic accuracy and guide timely, targeted intervention to prevent long-term complications. Full article

Purpose: To profile tear cytokine changes in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) patients after instillation of daily topical cyclosporine-A 0.1% cationic emulsion. Methods: Participants in a longitudinal study were given cyclosporine eyedrops daily from 3 to 5 weeks before and 3 months, 6 months, and 12 months post-HSCT. The outcomes included tear cytokine concentration assayed by the Proximity Extension Assay O-linked target 96 platform. The patients were divided into two groups: Group 1 (n = 8 conjunctival CD4 cells responding to cyclosporine) and Group 2 (n = 5 conjunctival CD4 cells not suppressed after cyclosporine, where patients were non-compliant with cyclosporine). All participants had a standardized clinical examination, including meibomian gland evaluation and tear breakup times. Results: The levels of 38 cytokines/chemokines showed significant changes (p < 0.05) over time, and in many, the elevation was marked at one year. These include gamma-interferon, CXCL9, CCL3, and CCL4 (all p < 0.0001). For gamma-interferon, there was significant interaction between group and time at 1 year (p = 0.022), where the cytokine was significantly suppressed in Group 1. Four other cytokines showed significant group and time interaction at 1 year: FGF23, FGF5, LIFR, and Enrage (all p < 0.05). All patients had either withdrawal or a reduction in systemic immunomodulation between 6 months and 1 year. We found several cytokines to be associated with changes in tear osmolarity or symptom scores. Conclusions: HSCT induces significant elevation of 38 tear cytokines/chemokines even without the occurrence of ocular graft-versus-host disease when systemic immunosuppression is reduced within the first year. Topical daily cyclosporine eyedrops can reduce some pro-inflammatory tear cytokines. Full article

Pregnancy orchestrates profound neurological, hormonal, and anatomical transformations in the maternal brain, preparing it for caregiving and infant bonding. Neuroimaging reveals structural changes such as gray matter reductions and white matter reorganization during pregnancy, followed by partial recovery postpartum. These adaptations are modulated by fluctuating levels of estradiol, progesterone, prolactin, and oxytocin, which coordinate neuroplasticity and behavioral readiness. At the molecular and cellular levels, pregnancy hormones drive synaptic remodeling, neurogenesis, and glial activity. Together, these changes support maternal motivation, attachment, and responsiveness, highlighting the maternal brain’s dynamic plasticity across gestation and the postpartum period. Also, pregnancy induces profound physiological changes, particularly in vascular, hormonal, and neurologic systems, to support maternal and fetal health. While these adaptations are essential, they can predispose pregnant individuals to various neurologic and ophthalmic pathologies. This review explores how pregnancy-related changes—including hypercoagulability, pituitary enlargement, hormonal fluctuations, and immunological modulation—contribute to conditions such as stroke, idiopathic intracranial hypertension, preeclampsia-associated visual disturbances, and demyelinating disorders like neuromyelitis optica spectrum disorder and multiple sclerosis. Additionally, ocular manifestations of systemic diseases like diabetic retinopathy and thyroid orbitopathy are discussed. Understanding these complex interactions is critical for prompt recognition, accurate diagnosis, and appropriate management of vision-threatening and neurologically significant complications during pregnancy. Nevertheless, many aspects of physiological and pathological changes during and after pregnancy remain unknown and warrant further investigation. Full article

Background: Sjögren’s syndrome (SS) is a multifaceted clinical condition characterized by various features, including ocular dryness (OD), which plays a substantial role in shaping the clinical presentation of the disease and has detrimental effects on quality of life. Recent research has acknowledged the advantages of the Mediterranean diet (MD) for its positive impact on various autoimmune diseases. This study aims to investigate the correlation between the severity of ocular symptoms in individuals with SS and adherence to the MD. Methods: This was a cross-sectional observational study of previously diagnosed SS patients recruited from the histopathological and immunological archives of a university hospital. The data were collected through a telephone questionnaire, including demographic and disease data, the Ocular Surface Disease Index (OSDI) score to evaluate the OD severity, and the Mediterranean Diet Adherence Screener (MEDAS) score to determine adherence to the MD. The primary outcome of the study, the correlation between OSDI and MEDAS scores, was evaluated using Spearman’s correlation coefficient. Results: The study included 114 patients, with a mean age of 51 (±13.4) years and a female proportion of 86%. OD was documented in 80.7% of the patients. The median OSDI and MEDAS scores were 23 (IQR 10–40) and 8 (IQR 5–11), respectively. A strong negative correlation was observed between the MEDAS and the OSDI scores (ρ = −0.73, p < 0.01). Additionally, there was a significant negative relationship between the richness of diet in fatty acids and the OSDI score (ρ = −0.67, p < 0.01). Conclusions: The study results suggest an association between lower OD severity in patients with SS and adherence to the MD, particularly the components related to polyunsaturated fatty acids consumption. This approach may serve as a complementary strategy with multiple health benefits, alongside conventional treatment options. Full article

Autoantibodies have been implicated in the pathogenesis of autoimmune diseases, including autoimmune retinopathies. Our study aimed to identify retinal autoantigens recognized by serum autoantibodies (AAbs) in patients with visual disturbance. We evaluated 2453 serum samples for anti-retinal AAbs from patients with or without cancer and complaints of visual loss. Anti-TULP1 AAbs were more prevalent in the subset of women with breast cancer and vision loss. Epitope mapping was determined by ELISA using peptides covering the conservative carboxy terminal of TULP1, revealing major lineal epitopes within the sequences 334–341 and 480–488. We found no significant difference in the main epitope recognition between sera from patients with or without breast cancer. Although we show a correlation of anti-TULP1 AAbs with breast cancer, we found no TULP1 protein expression in breast cells, making this association unclear. In the retina, anti-TULP1 AAbs can disrupt the transport of proteins to outer segments and be involved in the degeneration of photoreceptors in a similar fashion to the degeneration induced by TULP1 gene mutation. Nevertheless, the strong association of detectable anti-TULP1 AAbs in breast cancer patients with vision problems indicates its potential as a biomarker for cancer-associated autoimmune retinopathy. Full article

In this article, we provide a review of large B-cell lymphomas (LBCLs), comparing the recently published fifth edition of the WHO classification and the International Consensus Classification (ICC) on hematolymphoid tumors. We focus on updates in the classification of LBCL, an heterogeneous group of malignancies with varying clinical behaviors and different pathological and molecular features, providing a comparison between the two classifications. Besides the well-recognized diagnostic role of clinical, morphological and immunohistochemical data, both classifications recognize the ever-growing impact of molecular data in the diagnostic work-up of some entities. The main aim is to offer a guide for clinicians and pathologists on how the new classifications can be applied to LBCL diagnosis in routine practice. In the first part of the paper, we review the following categories: LBLs transformed from indolent B-cell lymphomas, diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), double-hit/triple-hit lymphomas (DH/TH), high-grade large B-cell lymphoma, not otherwise specified (HGBCL, NOS), LBCL with IRF4 rearrangement, Burkitt lymphoma (BL) and HGBCL/LBCL with 11q aberration, focusing on the differences between the two classifications. In the second part of the paper, we provide a practical diagnostic algorithm when facing LBCLs in routine daily practice. Full article

Sarcoidosis is a systemic inflammatory disease with an unknown etiology and a wide range of clinical manifestations. The incidence of sarcoidosis ranges from approximately 1 to 15 cases per 100,000 individuals per year worldwide. The significant variability in clinical presentations and target organs, as well as concomitant diseases, greatly complicates diagnosis. We analyzed articles in PubMed, Scopus, Cochrane Library, and Embase, where databases were searched using the keywords “chronic sarcoidosis”, “diagnosis of sarcoidosis”, “course of sarcoidosis”, “pulmonary sarcoidosis”, “cardiac sarcoidosis”, “skin sarcoidosis”, “neurosarcoidosis”, “ocular sarcoidosis”, and “autoimmune inflammation”. Studies on the course and diagnosis of sarcoidosis with a deep search of ten years were included. In this review, we present an analysis of publications on the course and diagnosis of chronic sarcoidosis, as well as a clinical case. We have noted that the diagnosis of chronic sarcoidosis is particularly difficult due to the lack of specific biomarkers or their combination. The development and introduction of new diagnostic criteria for this disease will contribute to increasing the level of efficiency, not only of the diagnostic complex, but also the prognosis of the development and course of the pathological process. Conclusion: For the most accurate diagnosis and determination of prognosis, the existence of a single immunological or imaging marker with sufficient sensitivity and specificity is necessary. Full article

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, offering significant improvements in patient survival across various malignancies. However, their use is associated with a broad spectrum of immune-related adverse events (irAEs), including those affecting the eye and its surrounding structures, collectively termed ocular irAEs (OirAEs). Although rare, OirAEs (e.g., keratitis, uveitis, retinal vasculitis, etc.) can significantly impact a patient’s quality of life, leading to ocular complications if left untreated. This review provides a comprehensive overview of OirAEs associated with ICIs, including their clinical manifestations, underlying mechanisms, and current management strategies. We delve into the anterior and posterior segment adverse events, highlighting conditions such as dry eye, uveitis, and retinal disorders, as well as neuro-ophthalmic and orbital complications. Furthermore, we discuss the challenges in diagnosing and treating these conditions, particularly given the overlap with other autoimmune and paraneoplastic syndromes. Finally, we identify key knowledge gaps and suggest future research directions aimed at optimizing the management of OirAEs while maintaining the efficacy of cancer therapy. This review underscores the need for increased awareness among clinicians to prevent irreversible ocular damage and enhance patient outcomes. Full article

Peripheral ulcerative keratitis (PUK) is an inflammatory process causing thinning of the cornea, epithelial defect, and inflammatory infiltrates and is caused by several etiologies. This sight-threatening condition can indicate the presence of potentially fatal underlying systemic conditions, and, accordingly, warrants thorough investigation upon clinical presentation and immediate intervention in order to mitigate disease progression. This review aims to provide an update on the current diagnostic and management landscape for PUK, specifically with immunomodulatory methods in cases of noninfectious etiologies. A literature search was conducted to develop a nuanced, evidence-based perspective in which we present our preferred approaches. There are currently a number of viable options, following which a “stepladder” method is typically employed, where treatment methods are escalated as a result of inadequate clinical response to lower-level interventions. This method balances efficacy with the potential side effects of immunomodulatory medications. Ultimately, carefully monitored treatment regimens are needed to mitigate visual impairment in patients with PUK, and efforts must be made to achieve steroid-free remission to avoid the known side effects of long-term corticosteroid use. Full article

Conjunctival melanoma (Co-M) is an aggressive, invasive eye and eyelid cancer. Its global incidence of ~1 in a million is increasing at a rate ratio of ~1.4, but this rises sharply in over 65-year-olds. Although rare, Co-M has a devastating impact on the lives of those who develop it. Co-M is often misdiagnosed or overlooked, leading to vision loss either from the destructive effects of the tumour or side effects of therapy, facial disfigurement from radical surgery, and death from metastases. Due to its rarity, there is limited evidence for diagnosis and management; hence, there is no standardised treatment and not all cases are referred to a specialised ocular oncology centre. Recent progress in cancer immunology and genetics have revolutionised the treatment of cutaneous melanomas, which share some similarities to Co-M. Importantly, a better understanding of Co-M and its precursor lesions is urgently needed to lead to the development of novel targeted and immunotherapies both for local tumour control and disseminated disease. This review aims to provide a comprehensive clinical overview of the current knowledge regarding Co-M, its epidemiology, pathogenesis, presentation, diagnosis and recent changes in the classification of its precursor lesions, management, and recent advances in novel biological therapies for personalised treatment of this disease. Full article

Objectives: In this study, we establish a protocol for evaluating the outcomes of endothelial keratoplasty, including graft survival, rejection, or failure. Additionally, we also evaluate the alloimmune response in graft recipients. Methods: We performed EK using C57BL/6 (allogeneic) and BALB/c (syngeneic) as donors and BALB/c mice as recipients. Slit-lamp examination and optical coherence tomography were performed for clinical evaluations for 16 weeks post-procedure. Criteria for the assessment of corneal opacity were established and the animals were graded weekly. Additionally, we assessed corneal endothelial cell density by harvesting the corneas and staining with zonula occludens-1 (ZO-1). Lastly, lymph nodes were collected, and CD4⁺ T cells were MACS-sorted and co-cultured with syngeneic or allogeneic antigen-presenting cells (APCs) to assess the IFN-γ expression levels by alloreactive Th1 cells (ELISPOT) in response to the direct (donor) or indirect (host) pathways of sensitization. Results: We observed graft failure in four animals, including irreversible corneal opacity, graft detachment, and anterior synechiae in the first four weeks. The remaining animals were graded between 0 and 5 as per the established criteria. The total and graft corneal thickness and endothelial cell density progressively worsened with a higher grade of corneal opacity. The direct allosensitization of Th1 cells was significantly higher in mice with a higher grade of corneal opacity. At 16 weeks follow-up, the grafts remained stable with low opacity scores in syngeneic EK recipients; however, the opacity scores were higher and variable in allogeneic EK recipients. Conclusions: These findings establish a standardized protocol to assess the graft outcomes in a murine model of EK. Furthermore, we delineate the underlying immunological pathway that contributes to the immune-mediated rejection of grafts in this model. Full article

Background: 22q11.2 deletion syndrome (22q11.2DS) is a genetic disorder caused by the deletion of the q11.2 band of chromosome 22. It may affect various systems, including the cardiovascular, immunological, gastrointestinal, endocrine, and neurocognitive systems. Additionally, several ocular manifestations have been described. Results: We report a case of a 34-year-old female diagnosed with 22q11.2DS who presented with visual discomfort and foreign body sensation in both eyes. She had no history of recurrent ocular pain. A comprehensive ophthalmological examination was performed, including anterior segment optical coherence tomography and in vivo confocal microscopy. Overall, the exams revealed bilateral corneal map-like lines, dots, and fingerprint patterns, consistent with a diagnosis of epithelial basement membrane dystrophy (EBMD). In addition to presenting with this novel corneal manifestation for 22q11.2 DS, we review the ocular clinical features of 22q11.2DS in the context of our case. Conclusions: The EBMD may represent a new corneal manifestation associated with 22q11.2 syndrome, although the link between these conditions is unknown. Further research is warranted to investigate potentially shared genetic or molecular pathways to the understanding of the phenotypic variety observed among this rare syndrome. Full article

Diabetes mellitus (DM) is a chronic metabolic disorder marked by hyperglycemia due to defects in insulin secretion, action, or both, with a global prevalence that has tripled in recent decades. This condition poses significant public health challenges, affecting individuals, healthcare systems, and economies worldwide. Among its numerous complications, ocular surface disease (OSD) is a significant concern, yet understanding its pathophysiology, diagnosis, and management remains challenging. This review aims to explore the epidemiology, pathophysiology, clinical manifestations, diagnostic approaches, and management strategies of diabetes-related OSD. The ocular surface, including the cornea, conjunctiva, and associated structures, is vital for maintaining eye health, with the lacrimal functional unit (LFU) playing a crucial role in tear film regulation. In DM, changes in glycosaminoglycan metabolism, collagen synthesis, oxygen consumption, and LFU dysfunction contribute to ocular complications. Persistent hyperglycemia leads to the expression of cytokines, chemokines, and cell adhesion molecules, resulting in neuropathy, tear film abnormalities, and epithelial lesions. Recent advances in molecular research and therapeutic modalities, such as gene and stem cell therapies, show promise for managing diabetic ocular complications. Future research should focus on pathogenetically oriented therapies for diabetic neuropathy and keratopathy, transitioning from animal models to clinical trials to improve patient outcomes. Full article