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Purpose: Inflammation is involved in the pathogenesis of diabetes, however the impact of diabetes on organ-specific autoimmune diseases remains unexplored. Experimental autoimmune uveoretinitis (EAU) is a widely accepted animal model of human endogenous uveitis. In this study, we investigated the effects of diabetic conditions on the development of EAU using a mouse diabetes model., Methods: EAU was induced in wild-type C57BL/6 (WT) mice and Ins2 Akita (Akita) mice with spontaneous diabetes by immunization with IRBP peptide. Clinical and histopathological examinations, and analysis of T cell activation state were conducted. In addition, alternations in the composition of immune cell types and gene expression profiles of relevant immune functions were identified using single-cell RNA sequencing., Results: The development of EAU was significantly attenuated in immunized Akita (Akita-EAU) mice compared with immunized WT (WT-EAU) mice, although T cells were fully activated in Akita-EAU mice, and the differentiation into Th17 cells and regulatory T (Treg) cells was promoted. However, Th1 cell differentiation was inhibited in Akita-EAU mice, and single-cell analysis indicated that gene expression associated AP-1 signaling pathway (JUN, FOS, and FOSB) was downregulated not only in Th1 cells but also in Th17, and Treg cells in Akita-EAU mice at the onset of EAU., Conclusions: In diabetic mice, EAU was significantly attenuated. This was related to selective inhibition of Th1 cell differentiation and downregulated AP-1 signaling pathway in both Th1 and Th17 cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Takeuchi, Nishio, Someya, Sato, Yoshimura, Ito and Harimoto.)

The distribution of age at diagnosis in ocular sarcoidosis has shifted towards the older age groups in developed countries. In systemic sarcoidosis, age-related differences in the clinical presentation, which reflect the therapeutic strategies, was reported. We retrospectively compared 100 consecutive patients from April 2010 to March 2016 who were initially diagnosed with ocular sarcoidosis by International Workshop on Ocular Sarcoidosis criteria. They were classified into elder (>65 years: 50 patients) and younger (≤65 years: 50 patients) groups by the age at diagnosis of uveitis associated with sarcoidosis. All patients received ophthalmic examination to assess the presence of seven intraocular signs and 4 laboratory parameters. Significantly fewer ocular signs (2.8 ± 1.5 and 3.6 ± 1.5; P = 0.0034) and abnormal laboratory results (1.5 ± 1.2 and 2.0 ± 1.2; P = 0.023) were detected in the elder group than in the younger group; statistical differences were found between the groups regarding the frequencies of mutton-fat keratic precipitates (40% and 64%; P = 0.012), vitreous opacities (60% and 78%; P = 0.0059), bilateral inflammation (64% and 80%; P = 0.012), and bilateral hilar lymphadenopathy between the groups (52% and 78%; P < 0.001). Multiple linear regression analysis showed negative correlations between age and number of detected ocular signs (r = -0.36, P < 0.001) and laboratory results (r = -0.20, P = 0.023). The characteristic ocular signs and abnormal laboratory results had a lower frequency in the elder patients compared with the younger patients. Probable or possible ocular sarcoidosis by the international criteria should increase with increased life expectancy in developed countries., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To examine antigen-stimulated cytokine production by Behçet disease patients (BD) before and after infliximab infusion., Methods: PBMCs were obtained before and after infliximab infusion in BD patients with or without recurrent uveitis during at least 1 year of infliximab therapy, and from healthy subjects. PBMCs were cultured with IRBP, and Th-related cytokines in cultures were measured., Results: Levels of IL-4, IL-6, IL-10 IL-17A, IL-17F, IL-31, IFN-γ, and TNFα were higher in BD before infliximab infusion than in healthy subjects, and these levels were the highest in BD with recurrent uveitis. After infliximab infusion, these cytokine levels were reduced to a greater extent in BD without recurrent uveitis than in BD with recurrence., Conclusions: Th-related cytokines produced by IRBP-stimulated PBMCs were elevated in BD, and infliximab infusion suppressed these cytokines to a greater extent in BD without recurrent uveitis than in those with recurrence.

Purpose: High-mobility group box-1 (HMGB1) is a nonhistone DNA-binding nuclear protein released from necrotic cells, which is also secreted by activated leukocytes and acts as a primary proinflammatory cytokine. In this study, we compared vitreous HMGB1 levels in ocular sarcoidosis with those in noninflammatory vitreoretinal diseases and evaluated its association with Th cell-related and proinflammatory cytokines., Methods: The study group consisted of 24 patients with ocular sarcoidosis. The control group consisted of 27 patients with proliferative diabetic retinopathy (PDR) and 24 with idiopathic epiretinal membrane (ERM). Vitreous fluid samples were obtained at the beginning of vitrectomy. Vitreous levels of HMGB1 and IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα were measured., Results: High-mobility group box-1 was detected in the vitreous of 23 of 24 patients (95.8%) with ocular sarcoidosis. Mean vitreous level of HMGB1 was the highest in the sarcoidosis group, followed by the PDR and ERM groups, with significant differences between the three groups. In the sarcoidosis group, vitreous levels of IL-6, IL-10, IL-31, IFN-γ, sCD40L, and TNFα were significantly higher than those in the idiopathic ERM group, and IFN-γ and sCD40L were significantly higher than those in the PDR group. Vitreous HMGB-1 level correlated significantly with IL-10, IFN-γ, and sCD40L levels but not with IL-6, IL-17, IL-31, or TNFα levels., Conclusions: The vitreous level of HMGB1 is elevated in ocular sarcoidosis and is associated with vitreous levels of Th1- and regulatory T-related cytokines, but not with proinflammatory or Th17-related cytokines.

Purpose: To investigate helper T (Th) cell-related cytokines elevated in the vitreous of endogenous uveitis (EU), and to compare these with those of acute retinal necrosis (ARN)., Methods: Vitreous fluids were obtained from 23 eyes of EU patients, 4 eyes of ARN patients, and 14 eyes of patients with epiretinal membrane (ERM) who had had vitrectomy surgery. The vitreous levels of interleukin (IL)-1, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, interferon (IFN)-γ, soluble CD40 ligand (sCD40L) and tumor necrosis factor (TNF)-α were measured., Results: The vitreous cytokine levels of IL-6, IL-10, IL-31, IFN-γ and TNF-α in the EU patients were significantly higher than in the ERM patients. On the other hand, the levels of IL-1β, IL-6, IL-10, IL-31, IFN-γ, sCD40L and TNF-α were significantly higher in the ARN patients than in the EU patients, while those of IL-4, IL-17A and IL-22 were higher in the EU patients than in the ARN patients although they were not significant., Conclusions: It is suggested that Th1-, Th2- and Th17 cells are related to the development of EU, and Th1- and regulatory T cells to that of ARN, and that the severity of ocular inflammation may be associated with the activity of Th1 cells.

Aims: To evaluate the prevalence and aetiology of intraocular hypertension (OHT) in granulomatous and non-granulomatous uveitis, Methods: Medical records of 304 consecutive patients (484 eyes) with uveitis who visited the National Defense Medical Collage Hospital between April 2010 and March 2013 were reviewed retrospectively. OHT irrelevant to glaucomatous changes in optic disc or visual field was investigated., Results: OHT was found in 123 eyes (25.4%) of 93 uveitic patients (30.6%); 92% of the eyes had open-angle OHT, 45.6% of which was steroid-induced. The prevalence of OHT was 100% (8/8) in Posner-Schlossman syndrome, 50.0% (10/20) in varicella zoster virus-associated iridocyclitis, 45% (9/20) in scleritis, 34.1% (15/44) in Vogt-Koyanagi-Harada disease, 32.1% (18/56) in Behçet's disease (BD), 23.1% (6/26) in acute anterior uveitis, and 20.2% (19/94) in sarcoidosis. Pupillary block was observed only in non-granulomatous uveitis, but not in granulomatous uveitis. Seventy percent of OHT in granulomatous uveitis cases was inflammation-induced, while 76.7% in non-granulomatous uveitis cases was steroid-induced., Conclusions: OHT in non-granulomatous uveitis was mainly steroid-induced open-angle OHT with some cases of angle-closure OHT caused by pupillary block, while that in granulomatous uveitis was mostly inflammation-induced open-angle OHT with no pupillary block-related angle-closure OHT., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: To evaluate the efficacy of spectral domain optical coherence tomography (SD-OCT) in monitoring the development of mouse experimental autoimmune uveoretinitis (EAU) as an animal model of endogenous uveitis, and to develop an OCT-based grading system for EAU severity., Methods: C57BL/6 mice were immunised with human interphotoreceptor retinoid-binding protein (amino acid sequence 1-20) peptide and complete Freund's adjuvant to induce EAU. The development of EAU was monitored by SD-OCT serially throughout the disease course, and the images were graded from 1 to 4 and compared with the clinical and histopathological grades., Results: SD-OCT images depicted retinal lamella structures including the inner segment/outer segment (IS/OS) line in normal mice. Retinal structural changes were observed on SD-OCT images in mice that developed EAU clinically scored as grade 1 or higher, which precisely corresponded to the pathological findings. The SD-OCT images of EAU were graded as follows: grade 1, a few infiltrating cells in the vitreous and retina; grade 2, increased vitreous cells, retinal vasculitis, and granulomatous lesion; grade 3, cell infiltration into the whole retina, disappearance of IS/OS line, and destruction of the retinal layer structure; and grade 4, disappearance of the outer retina. The SD-OCT grade of EAU based on these criteria correlated significantly with both the clinical grade (R(2)=0.282, p<0.005) and histopathological grade (R(2)=0.846, p<0.0001)., Conclusions: SD-OCT is useful for evaluating the development and severity of mouse EAU. The SD-OCT scoring system we developed accurately reflects clinical and histopathological changes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)