Investigative ophthalmology & visual science最新文献

{"title":"Prevalence of HSV Genomic Signatures Among Acanthamoeba Hosts and Contaminated Lens Cases: A Molecular and Clinical Study.","authors":"Juan-Carlos Navia, Alexander Alfonso, Darlene Miller, Jorge Maestre-Mesa, Heather Durkee, Paula A Sepulveda-Beltran, Felipe Echeverri-Tribin, Salomon Merikansky, Jaime D Martinez, Harry W Flynn, Eduardo C Alfonso, Jean-Marie Parel, Guillermo Amescua","doi":"10.1167/iovs.66.2.4","DOIUrl":"https://doi.org/10.1167/iovs.66.2.4","url":null,"abstract":"<p><strong>Purpose: </strong>To document the presence of herpes simplex virus (HSV) genomic signatures among Acanthamoeba hosts recovered from patients with Acanthamoeba keratitis (AK) and in contaminated lens cases.</p><p><strong>Methods: </strong>We used a combination of PCR sequencing and shotgun metagenomics to detect and confirm the presence of HSV genomic signatures in Acanthamoeba hosts and lens cases. Clinical outcomes were correlated with the prevalence of host HSV signatures.</p><p><strong>Results: </strong>HSV genomic signatures were detected in 26% (n = 6) of Acanthamoeba hosts recovered from patients with culture confirmed AK. HSV-1 and HSV-2 or both were identified in 33%, 50%, and 17% of isolates, respectively. Fifty-two percent of patients (12/23) were misdiagnosed initially as presenting with HSV keratitis. Patients with HSV-positive Acanthamoeba isolates had a mean best-corrected visual acuity of 1.43 LogMAR at diagnosis and 0.53 LogMAR at follow-up, compared with 1.85 and 0.92 LogMAR, respectively, in HSV-negative cases. Contact lens use was identified as a risk factor in 83% of 18 patients. We detected 46,597 viral signatures in 5 of 14 contaminated lens cases (35.7%). Distribution included 33% bacteriophages, 8.2% giant viruses, 4.1% nonhuman Herpesviridae, and 0.39% human Herpesviridae. Among the 184 human Herpesviridae genomic signatures, HSV types 1 or 2 or both were documented in 5.7%, VZV in 39.7%, HHV7 in 38.6%, HHV6 in 15.0%, and Epstein-Barr virus in 0.5%.</p><p><strong>Conclusions: </strong>This study is the first to identify HSV-positive genomic signatures in clinical AK isolates and/or contact lens cases. Taken together, the high prevalence of HSV genomic signatures in both amebic hosts and lens cases, might signal an unrecognized Acanthamoeba-HSV association and the need for reassessing current management.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"4"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lamp2 Deficiency Enhances Susceptibility to Oxidative Stress-Induced RPE Degeneration.","authors":"Guannan Wu, Shoji Notomi, Ziming Xu, Yosuke Fukuda, Yusuke Maehara, Yan Tao, Huanyu Zhao, Keijiro Ishikawa, Yusuke Murakami, Toshio Hisatomi, Koh-Hei Sonoda","doi":"10.1167/iovs.66.2.2","DOIUrl":"https://doi.org/10.1167/iovs.66.2.2","url":null,"abstract":"<p><strong>Purpose: </strong>Autophagy and lysosomal degradation are vital processes that protect cells from oxidative stress. This study investigated the role of lysosome-associated membrane protein 2 (Lamp2), a lysosomal protein essential for autophagosome maturation and lysosome biogenesis, in maintaining retinal health under oxidative stress.</p><p><strong>Methods: </strong>To induce oxidative stress, young Lamp2 knockout (KO) and wild-type mice received an intravenous injection of a low dose (10 mg/kg) of sodium iodate (NaIO3). We examined retinal histopathology and morphological changes in the RPE. The involvement of resident microglia or infiltrating macrophages was assessed using immunostaining, flow cytometry, and real-time PCR for chemokines and cytokines.</p><p><strong>Results: </strong>After administering a low-dose NaIO3, Lamp2 KO mice showed significant RPE degeneration, whereas wild-type mice had minimal damage. Histological analysis and electron microscopy revealed significant thinning of the outer nuclear layer and loss of RPE epithelial polarity in Lamp2 KO mice. Additionally, there was a significant increase in ionized calcium-binding adaptor molecule 1-positive microglia and macrophages in the outer retina. Early proliferation of CD45lowMHC-IIlow resident microglia was followed by the infiltration of CD45highLy6Chigh monocytes and the engraftment of CD11b+CD45high monocyte-derived macrophages. Transcript levels of monocyte chemoattractant protein 1, macrophage inflammatory protein 1β, Il- 1β, and Il-6 also increased in the retinas of Lamp2 KO mice. Furthermore, pretreatment with the macrophage-depleting agent clodronate prevented NaIO3-induced RPE degeneration and macrophage infiltration in Lamp2 KO mice.</p><p><strong>Conclusions: </strong>Lamp2 deficiency, when combined with oxidative stress, leads to RPE degeneration in vivo. Lysosomal dysfunction also promotes macrophage engraftment and triggers neurotoxic inflammation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"2"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Subtype Identification and Potential Drug Prediction Based on Anoikis-Related Genes Expression in Keratoconus.","authors":"Zhixin Jiang, Boyang Zhang, Shichong Jia, Xiaoyong Yuan","doi":"10.1167/iovs.66.2.3","DOIUrl":"https://doi.org/10.1167/iovs.66.2.3","url":null,"abstract":"<p><strong>Purpose: </strong>Anoikis is a special apoptosis accompanied by the loss of extracellular matrix (ECM) environment and the decomposition of ECM is an important process in the occurrence of keratoconus (KC). This study aims to describe the expression profile of anoikis-related genes (ARGs) in KC samples, identify differentially expressed genes (DEGs), characterize the biological functions and immune characteristics of different molecular subtypes of KC and predict potential drugs based on the construction of a co-expression network.</p><p><strong>Methods: </strong>First, we identified molecular subtypes by optimal clustering K based on the expression profile of ARGs in the KC dataset and analyzed the differences of functional and immune characteristics. Then a weighted gene co-expression network was constructed based on cluster analysis to obtain hub genes and protein-protein interaction network was constructed to analyze hub nodes and predict potential node-targeting drugs.</p><p><strong>Results: </strong>By comparing the expression profile between disease and normal samples, we found that there were significant differences in ARGs such as BCL2, CAV1, and CEACAM5. Consistent cluster analysis identified two definite clusters on the basis of ARGs expression difference. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis showed that DEGs were enriched significantly in pathways like ECM receptor interaction, chemokine signal, notch signal, focal adhesion, and functional sets like proteolysis, anoikis, regulation of natural killer and T-cell proliferation. CIBERSORT calculation showed that there were significant differences between the two subtypes on immune cell infiltration (monocytes and plasma) and immune molecules (CCL11, CCL14, HLA-A, HLA-B, and so on). Then, co-expression network was constructed based on cluster phenotype, 5202 genes were selected as hub genes, and 321 HubDEGs were obtained after intersection with significant DEGs. Seven hub nodes, EIF4G1, KHSRP, PABPC1, POLR2A, PTBP1, RPS19, and SMARCA4, were identified and matched drugs or small molecular compounds. Insulin and dexamethasone were identified as potential target drugs.</p><p><strong>Conclusions: </strong>We revealed the differential expression of ARGs in KC samples, and identified two distinct subtypes that showed significant differences in biological function and immune infiltration. The identification of hub gene nodes elucidated their therapeutic value on predicted potential drugs.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"3"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping Protein Distribution in the Canine Photoreceptor Sensory Cilium and Calyceal Processes by Ultrastructure Expansion Microscopy.","authors":"Kei Takahashi, Raghavi Sudharsan, William A Beltran","doi":"10.1167/iovs.66.2.1","DOIUrl":"https://doi.org/10.1167/iovs.66.2.1","url":null,"abstract":"<p><strong>Purpose: </strong>Photoreceptors are highly polarized sensory neurons, possessing a unique ciliary structure known as the photoreceptor sensory cilium (PSC). Vertebrates have two subtypes of photoreceptors: rods, which are responsible for night vision, and cones, which enable daylight vision and color perception. Despite the identification of functional and morphological differences between these subtypes, ultrastructural analysis of the PSC molecular architecture between rods and cones is still lacking. This study employed ultrastructure expansion microscopy (U-ExM) to characterize the PSC molecular architecture in canine retina.</p><p><strong>Methods: </strong>Canine neuroretinas (5-mm punches) were fixed in paraformaldehyde solution for either short or long durations. Additionally, 20-µm-thick cryosections from frozen archival retinal tissues fixed using the longer protocol were analyzed. A U-ExM protocol previously developed for mouse retina was adapted to these canine tissues with a battery of specific antibodies that label the various compartments of the PSC.</p><p><strong>Results: </strong>We demonstrated that U-ExM is applicable to both non-frozen and cryopreserved retinal tissues processed with standard paraformaldehyde fixation. Using this validated U-ExM protocol, we revealed the molecular localization of numerous ciliopathy-related proteins in canine photoreceptors. Furthermore, we identified significant architectural differences in the PSC, ciliary rootlet, and calyceal processes between canine rods and cones.</p><p><strong>Conclusions: </strong>U-ExM is a powerful tool for studying the PSC molecular architecture using frozen archival retinas that are processed following standard paraformaldehyde fixation and embedding protocols. The findings gained from this study pave the way for a better understanding of alterations in the molecular architecture of the PSC in canine models of retinal ciliopathies.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 2","pages":"1"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Penetrable AAV2 Capsid Variant for Efficient Intravitreal Gene Delivery to the Retina.","authors":"Xiaoyu He, Yidian Fu, Yangfan Xu, Liang Ma, Peiwei Chai, Hanhan Shi, Yizheng Yao, Shengfang Ge, Renbing Jia, Xuyang Wen, Zhi Yang, Xianqun Fan","doi":"10.1167/iovs.66.1.6","DOIUrl":"https://doi.org/10.1167/iovs.66.1.6","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to identify a novel recombinant adeno-associated virus (rAAV) capsid variant that can widely transfect the deep retina through intravitreal injection and to assess their effectiveness and safety in gene delivery.</p><p><strong>Methods: </strong>By adopting the sequences of various cell-penetrating peptides and inserting them into the capsid modification region of AAV2, we generated several novel variants. The green fluorescent protein (GFP)-carrying variants were screened following intravitreal injection. Gene therapy experiments were conducted via intravitreal injection of rd1 mice. We validated the therapeutic effects utilizing the pupillary light reflex and visual cliff test. Assessment of retinal structure and Pde6b gene levels in rd1 mice after gene therapy further was confirmed through transcriptome sequencing to validate the gene therapy efficacy.</p><p><strong>Results: </strong>We observed enhanced transduction and penetration efficiency of the AAV variant AAV2.CPP.21 after intravitreal injection which can target all layers of the retinas. Normal doses of AAV2.CPP.21 administered via intravitreal injection achieved effective gene therapy for retinitis pigmentosa in rd1 mice, with no increased risk of transgenic leakage in peripheral organs.</p><p><strong>Conclusions: </strong>Our study identified another new, safe, and efficient AAV vector for gene therapy via intravitreal injection for retinal diseases. This new vector holds promise for clinical application and improvement of the efficacy of gene therapy for inherited retinal diseases.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 1","pages":"6"},"PeriodicalIF":5.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinal OCT-Derived Texture Features as Potential Biomarkers for Early Diagnosis and Progression of Diabetic Retinopathy.","authors":"Sara Oliveira, Pedro Guimarães, Elisa Julião Campos, Rosa Fernandes, João Martins, Miguel Castelo-Branco, Pedro Serranho, Paulo Matafome, Rui Bernardes, António Francisco Ambrósio","doi":"10.1167/iovs.66.1.7","DOIUrl":"10.1167/iovs.66.1.7","url":null,"abstract":"<p><strong>Purpose: </strong>Diabetic retinopathy (DR) is usually diagnosed many years after diabetes onset. Indeed, an early diagnosis of DR remains a notable challenge, and, thus, developing novel approaches for earlier disease detection is of utmost importance. We aim to explore the potential of texture analysis of optical coherence tomography (OCT) retinal images in detecting retinal changes in streptozotocin (STZ)-induced diabetic animals at \"silent\" disease stages when early retinal molecular and cellular changes that cannot be clinically detectable are already occurring.</p><p><strong>Methods: </strong>Volume OCT scans and electroretinograms were acquired before and 1, 2, and 4 weeks after diabetes induction. Automated OCT image segmentation was performed, followed by retinal thickness and texture analysis. Blood-retinal barrier breakdown, glial reactivity, and neuroinflammation were also assessed.</p><p><strong>Results: </strong>Type 1 diabetes induced significant early changes in several texture metrics. At week 4 of diabetes, autocorrelation, correlation, homogeneity, information measure of correlation II (IMCII), inverse difference moment normalized (IDN), inverse difference normalized (INN), and sum average texture metrics decreased in all retinal layers. Similar effects were observed for correlation, homogeneity, IMCII, IDN, and INN at week 2. Moreover, the values of those seven-texture metrics described above decreased throughout the disease progression. In diabetic animals, subtle retinal thinning and impaired retinal function were detected, as well as an increase in the number of Iba1-positive cells (microglia/macrophages) and a subtle decrease in the tight junction protein immunoreactivity, which did not induce any physiologically relevant effect on the blood-retinal barrier.</p><p><strong>Conclusions: </strong>The effects of diabetes on the retina can be spotted through retinal texture analysis in the early stages of the disease. Changes in retinal texture are concomitant with biological retinal changes, thus unlocking the potential of texture analysis for the early diagnosis of DR. However, this requires to be proven in clinical studies.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 1","pages":"7"},"PeriodicalIF":5.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic Accommodation Responses in Subjects Wearing Myopia Control Spectacles Modifying Peripheral Refraction.","authors":"Zhenghua Lin, Dimitrios Christaras, Raul Duarte-Toledo, Zhikuan Yang, Augusto Arias, Weizhong Lan, Pablo Artal","doi":"10.1167/iovs.66.1.55","DOIUrl":"10.1167/iovs.66.1.55","url":null,"abstract":"<p><strong>Purpose: </strong>Peripheral optics have been suggested to play a role in myopia progression, with accommodation responses also considered a potential contributor. This study aimed to investigate whether modifications in peripheral optics through different spectacle lenses affect accommodation responses.</p><p><strong>Methods: </strong>Dynamic accommodation responses were assessed using a double-pass instrument while switching the target from distance (3 m for 3 seconds) to near (0.22 m/4.5 D for adults, 0.18 m/5.5 D for children, 5 seconds) and then back to distance (3 m for 3 seconds). Three groups were studied. Group 1 included 13 adults (age = 28 ± 4.5 years). Participants wore one of three myopia control lenses (MiYOSMART [Hoya], Stellest [Essilor], or MyoCare [ZEISS]) randomly, along with their habitual glasses. The testing involved both central clear zones and peripheral side-vision zones, with habitual glasses served as reference. Group 2 underwent same procedure, but in children (age = 9.8 ± 1.7 years). Group 3 included 8 adults (age = 27.9 ± 5.3 years) wearing standard glasses partially excised with central holes (diameter = 12 mm). The lens refraction included plano, +3 D defocus, -3 D defocus, and -3 D oblique astigmatism.</p><p><strong>Results: </strong>The accommodative lag was less than 0.5 D for all eyes under near stimulation. No significant differences in the amplitude of accommodation responses were observed among the myopia control lenses or the partially excised glasses.</p><p><strong>Conclusions: </strong>No effect on accommodation responses was found in subjects wearing different types of myopia control lenses. This finding indicates that the induced changes in the ocular peripheral optics do not have an impact on accommodation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 1","pages":"55"},"PeriodicalIF":5.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preferential Sites of Retinal Capillary Occlusion in Sickle Cell Disease.","authors":"Oscar Otero-Marquez, Affan Haq, Luis Muncharaz Duran, Jordan Bellis, Sarah McCuskee, Sofia Ahsanuddin, Richard B Rosen, Jeffrey Glassberg, Toco Y P Chui","doi":"10.1167/iovs.66.1.57","DOIUrl":"10.1167/iovs.66.1.57","url":null,"abstract":"<p><strong>Purpose: </strong>To assess the preferential sites of retinal capillary occlusion at the parafovea in patients with sickle cell disease (SCD) using optical coherence tomography angiography (OCT-A).</p><p><strong>Methods: </strong>OCT-A scans from 107 patients with SCD and 51 race-matched unaffected controls were obtained using a commercial spectral domain-OCT system. At least eight sequential 3 × 3 mm scans centered at the fovea were acquired and averaged for image analysis. In each participant, foveal avascular zone (FAZ) metrics, perivascular, and quadrant-based capillary densities were measured on the averaged full vascular retinal OCT-A slab. Intermittent capillary perfusion at the FAZ border was also identified using sequential registered OCT-A scans.</p><p><strong>Results: </strong>Perivascular and quadrant-based capillary densities were significantly lower in SCD groups (Kruskal-Wallis tests; P < 0.001) with preferential sites of capillary nonperfusion occurring along periarteriolar aspect of the vascular bed and at the temporal aspect of the fovea. FAZ perimeter and acircularity index were significantly higher in SCD groups (Kruskal-Wallis tests; P ≤ 0.05). However, no significant differences in FAZ area between unaffected control and SCD groups were observed (Kruskal-Wallis test; P = 0.08). The number of capillary segments with intermittent perfusion was higher in the SCD groups.</p><p><strong>Conclusions: </strong>Our findings suggest that the periarteriolar aspect of the vascular bed is the preferential site of retinal capillary occlusion in patients with SCD with more involvement of the temporal aspect of the parafovea.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 1","pages":"57"},"PeriodicalIF":5.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S100A8/A9 Promotes Dendritic Cell-Mediated Th17 Cell Response in Sjögren's Dry Eye Disease by Regulating the Acod1/STAT3 Pathway.","authors":"Yankai Wei, Mei Sun, Xinyu Zhang, Chengyuan Zhang, Chao Yang, Hong Nian, Bei Du, Ruihua Wei","doi":"10.1167/iovs.66.1.35","DOIUrl":"https://doi.org/10.1167/iovs.66.1.35","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the role of S100A8/A9 in the pathogenesis of Sjögren's dry eye disease (SjDED) and explore its potential mechanism of action.</p><p><strong>Methods: </strong>S100A8/A9 expression was determined by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Tear secretion, corneal fluorescein staining, and hematoxylin and eosin staining were used to evaluate the effect of paquinimod, a S100A8/A9 inhibitor, on dry eye disease in nonobese diabetic (NOD) mice. Immune cell infiltration and percentage were assessed by immunofluorescence and flow cytometry. Proinflammatory cytokine levels were examined by qRT-PCR or ELISA. The mechanism of action was analyzed using western blot, immunofluorescence, and chromatin immunoprecipitation.</p><p><strong>Results: </strong>S100A8/A9 was upregulated in peripheral blood mononuclear cells of patients with SjDED and lacrimal glands (LGs) of SjDED mice. The upregulation of S100A8/A9 was correlated with the dry eye severity and inflammatory infiltration levels in LGs. Administration of paquinimod ameliorated clinical and histopathological phenotypes of SjDED mice and reduced the proportion of Th17 cells in LGs, lymph nodes, and spleens. Further experiments revealed that S100A8/A9 did not directly affect Th17 generation and function but upregulated the expression of major histocompatibility complex Ⅱ (MHC Ⅱ) and Th17-polarizing cytokines in dendritic cells (DCs) to augment Th17 cell response. Mechanistically, S100A8/A9 induced the expression of Acod1 and thereby promoted the activation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3), resulting in increased Il23a transcription. STAT3 activator reversed the therapeutic effect of paquinimod on SjDED mice.</p><p><strong>Conclusions: </strong>S100A8/A9 activated the Acod1/STAT3 pathway to promote DC-driven Th17 cell responses in SjDED. The S100A8/A9/Acod1/STAT3 pathway may represent a promising therapeutic target for SjDED.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 1","pages":"35"},"PeriodicalIF":5.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-Inflammatory Effects of Clarstatin, a Shared-Epitope-Antagonistic Cyclic Peptide, on Experimental Autoimmune Uveitis in Mice.","authors":"Shira Merzbach, Adi Schumacher-Klinger, Michal Klazas, Amnon Hoffman, Philip Lazarovici, Chaim Gilon, Gabriel Nussbaum, Radgonde Amer","doi":"10.1167/iovs.66.1.13","DOIUrl":"https://doi.org/10.1167/iovs.66.1.13","url":null,"abstract":"<p><strong>Purpose: </strong>Polymorphism and mutations of human leukocyte antigens (HLAs) and calreticulin are risk factors for uveitis. Here, we sought to determine the therapeutic effects of Clarstatin, a cyclic peptide antagonist of the HLA shared-epitope-calreticulin interaction, in experimental autoimmune uveitis (EAU) models.</p><p><strong>Methods: </strong>Mice were injected with Clarstatin intraperitoneally and its effect was compared to that of corticosteroid. EAU was evaluated clinically and histologically. Ocular infiltration of CD45+ hematopoietic cells and splenocyte CD4+ expression were determined using immunofluorescence and flow cytometry (fluorescence-activated cell sorting [FACS]). ELISA was used to measure the ocular level of the proinflammatory cytokines.</p><p><strong>Results: </strong>Clarstatin significantly ameliorated the severity of EAU in the C57BL/6J mild and the B10.RIII severe mice models. There was a significant dose and time-dependent decrease, in the range of 30% to 80%, in the clinical score (P < 0.05), histological score (P < 0.05), and number of retinal and spleen CD45+ cells (P < 0.05 and P < 0.001, respectively), a comparable effect to corticosteroid. Clarstatin reduced the intraocular levels of interleukin 6 (IL-6; P < 0.05) and monocyte chemoattractant protein-1 (MCP-1; P < 0.01) by 41% and 59%, respectively.</p><p><strong>Conclusions: </strong>Systemic delivery of Clarstatin significantly improved mild and severe EAU. Its potential anti-inflammatory therapeutic effects represent a novel mode of treatment in ocular inflammation. It may also be a relevant treatment modality in systemic autoimmune conditions in which calreticulin plays a role in their pathogenesis.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"66 1","pages":"13"},"PeriodicalIF":5.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}