Optical Coherence Tomographic Features and Prognostic Values of Macular Edema in Vogt-Koyanagi-Harada Disease.

Purpose: To determine optical coherence tomographic (OCT) features of macular edema (ME) and identify potential prognostic values for ME and visual outcomes in Vogt-Koyanagi-Harada disease (VKH). Methods: In the retrospective case series, a total of 1,377 VKH patients who were seen in a tertiary uveitis center between September 2011 and January 2018 were reviewed on their demographics, visual acuity, ocular and extraocular manifestations, modes of treatment, and OCT examinations. Of these patients, 79 (5.7%) having ME were included for analysis of OCT features. Four patients were missed without ME resolution, and the remaining 75 patients who either had ME resolved or were followed up for 2 years were included for analysis of disease outcomes. Results: Of the 115 affected eyes in these 79 patients, 100 (87.0%) had cystoid ME (CME), accounting for the most common OCT feature of VKH-related ME. Disruption of the inner-segment/outer-segment junction (IS/OS) band seen in 33 (28.7%) affected eyes of 24 (30.4%) patients was found as a risk factor for the development of persistent ME [10 of 62 (16.1%) vs. 13 of 13 (100%); P < 0.001] and a poor visual outcome (1.16 ± 0.42 vs. 1.17 ± 0.46 in logMAR unit; P = 0.89). CME patients with a concurrent choroidal neovascular membrane often had a disrupted IS/OS band, thus becoming refractory cases. A 6-month well-controlled intraocular inflammation following standard treatment regimens was found to associate with complete resolution of the refractory edema [4 of 5 (80%) vs. 2 of 13 (15%); P = 0.02]. Conclusions: Intraretinal cystoid changes are most commonly seen in the edematous macula of VKH patients. Disruption of the IS/OS band is a useful risk sign for poor ME and visual outcomes in VKH-related ME, and a long-term well-controlled intraocular inflammation may be critical for the resolution of refractory cases.

The Rs12569232 SNP Association with Vogt-Koyanagi-Harada Disease and Behcet's Disease is Probably Mediated by Regulation of Linc00467 Expression.

Purpose: To investigate whether the rs12569232 SNP association with Vogt-Koyanagi-Harada disease and Behcet's disease is mediated by regulation of Linc00467 expression.Methods: The expression of linc00467 was detected by real-time PCR. Adenovirus carrying the linc00467 was transduced into CD4+T cells and the effect on cell viability was measured by the CCK-8 test. Human proteome microarray and starBase 2.0 were used to identify the binding proteins of linc00467 and RNA Immunoprecipitation (RIP) was used to confirm the identity of bound proteins.Results: The rs12569232 was associated with the expression of linc00467. The expression of linc00467 was up-regulated in PBMCs and CD4+T cells from VKH disease and BD patients. Over-expression of linc00467 increased cell viability of CD4+T cells. HUR was the common binding protein identified by the two methods and confirmed by RIP.Conclusions: The rs12569232 association with VKH disease and BD may be mediated via regulating the expression of linc00467.

The haplotypes of various TNF related genes associated with scleritis in Chinese Han.

BACKGROUND: Several studies have stated that TNF-α participates in the pathogenesis of scleritis, but also in several systemic autoimmune diseases and vasculitis, of which some are associated with scleritis. Earlier GWAS and SNP studies have confirmed that multiple SNPs of TNF related genes are associated with many immune-mediated disorders. The purpose of this study was to examine the association of TNF related gene polymorphisms with scleritis in Chinese Han. A case-control study was carried out in 556 non-infectious scleritis cases and 742 normal controls. A total of 28 single-nucleotide polymorphisms (SNPs) were genotyped by the iPLEXGold genotyping assay. RESULTS: No significant correlations were seen between the individual SNPs in the TNF related genes and scleritis. Haplotype analysis showed a significantly decreased frequency of a TNFAIP3 TGT haplotype (order of SNPs: rs9494885, rs3799491, rs2230926) (Pc = 0.021, OR = 0.717, 95% CI = 0.563-0.913) and a significantly increased frequency of a TNFSF4 GT haplotype (order of SNPs: rs3850641, rs704840) (Pc = 0.004, OR = 1.691, 95% CI = 1.205-2.372) and TNFSF15 CCC haplotype (order of SNPs: rs6478106, rs3810936, rs7865494) (Pc = 0.012, OR = 1.662, 95% CI = 1.168-2.363) in patients with scleritis as compared with healthy volunteers. CONCLUSIONS: This study reveals that a TGT haplotype in TNFAIP3 may be a protective factor for the development of scleritis and that a GT haplotype in TNFSF4 and a CCC haplotype in TNFSF15 may be risk factors for scleritis in Chinese Han.

Weak association of a TNFRSF1A polymorphism with Behcet's disease in Chinese Han.

The purpose of this study was to investigate whether single nucleotide polymorphisms (SNPs) of the tumor necrosis factor receptor superfamily (TNFRSF) and their ligand (TNFSF) gene are associated with susceptibility to Behcet's Disease (BD) in Chinese Han. A two-phase case-control study was performed in 1055 BD patients and 1829 healthy controls. A total of 27 SNPs was tested using MassARRAY iPLEX® technology. Data were analyzed using a Chi-square (χ2) test and Fisher's exact calibration test. The Bonferroni correction was applied for multiple testing. A statistically significant higher frequency of the A allele and a lower frequency of the G allele of rs1800692 was found in BD (Pc = 0.013, OR = 1.233, 95% CI = 1.103-1.379: Pc = 0.013, OR = 0.811, 95% CI = 0.725-0.907, respectively). Our findings indicate that TNFRSF1A might confer genetic susceptibility to BD in a Chinese Han population.

Altered gut microbiome composition in patients with Vogt-Koyanagi-Harada disease.

BACKGROUND: Vogt-Koyanagi-Harada (VKH) disease is a multisystemic autoimmune disorder characterized by granulomatous panuveitis. Gut microbiome has been considered to play a role in the pathogenesis of this disease but whether the alternation of gut microbiome was involved is unclear. This study was set up to identify abnormalities of gut microbiome composition in VKH disease. RESULTS: Depleted butyrate-producing bacteria, lactate-producing bacteria and methanogens as well as enriched Gram-negative bacteria were identified in the active VKH patients, as well as in VKH patients of Mix enterotype and Bacteroides enterotype. Changes of gut microbiome in the VKH patients were partially restored after an immunosuppressive treatment. The disease susceptibility genotype HLA-DRA was associated with Bacteroides sp.2.1.33B, Paraprevotella clara, Alistipes finegoldii and Eubacterium eligens. A microbial marker profile including 40 disease-associated species was established to differentiate patients from controls. Another microbial marker profile including 37 species was found to be associated with the response to treatment. An animal experiment showed that transfer of gut microbiome from VKH patients could significantly exacerbate disease activity clinically and pathologically in the recipient mice. CONCLUSION: Our results revealed a distinct gut microbiome signature in VKH patients and showed an exacerbating effect of this gut microbiome on experimental autoimmune uveitis (EAU). We also developed two microbial marker profiles in differentiating VKH patients from healthy controls as well as predicting the effectiveness of treatment.

Uveitis genetics.

Uveitis is usually considered as a vision-threatening multiple system intraocular inflammatory disease. Among uveitis, Vogt-Koyanagi-Harada (VKH) disease and Behcet's disease (BD) are common non-infectious uveitis entities. Although the exact pathogenesis of uveitis is not yet clear, it is acknowledged that the combination of a certain genetic or epigenetic factors with an imbalance in the regulation of the immune response leads to the development of this disease. HLA genes show a strong association with both VKH disease (HLA-DR4, DRB1/DQA1) and BD (HLA-B51) in multiple ethnic populations. Candidate association studies based on a pathogenesis hypothesis laid the foundation for genetic research of uveitis and identified a large number of genes associated with VKH disease or BD including SUMO4, MCP-1, and CTLA4. Genome-wide association study (GWAS) provided a powerful tool for genome-wide level analysis to explore the genetic predisposition for uveitis and revealed several genes to be associated with uveitis including IL23R/C1orf141, STAT4 and ADO/ZNF365/EGR2. Another variant type, the so called copy number variants (CNV), in IL17F, IL23A and C4A also showed an association with uveitis. Additionally, epigenetic factors such as DNA methylation and ncRNAs play important roles in the development of uveitis. The application of new technologies such as whole exome sequencing and whole genome sequencing and other epigenetic modifications such as N6-methyl-adenosine (m6A) modification of mRNAs will be helpful to discover new pathogenic risk genes for uveitis. The understanding of the genetic and epigenetic mechanisms in uveitis may provide a foundation to find novel targets and to develop new strategies in the treatment of uveitis in the near future.

Aqueous cytokine levels in four common uveitis entities.

To investigate aqueous cytokine profiles in acute anterior uveitis (AAU), Fuchs' syndrome, Vogt-Koyanagi-Harada (VKH) disease and Behcet's disease (BD), we assayed the concentrations of 17 cytokines by multiplex immunoassay in aqueous humor (AqH) collected during cataract surgery from 24 AAU, 29 Fuchs' syndrome, 29 VKH disease, 30 BD and 30 senile cataract control patients. Aqueous cytokine levels were compared between the five groups and analysed by logistic regression. Cytokine levels were then compared between uveitis patients who underwent cataract surgery within 3 months and those who underwent this surgery more than 3 months after complete control of intraocular inflammation. The results showed that aqueous levels of interferon (IFN)-γ, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1ß and tumour necrosis factor (TNF)-α levels in AqH from patients with Fuchs' syndrome were significantly higher than those in the other four groups. Using multivariate analysis, MIP-1ß was found to be significantly associated with Fuchs' syndrome. There was no difference in aqueous cytokine levels between cases having cataract surgery within 3 months compared to those after 3 months of complete control of their intraocular inflammation. The current study shows that Chinese patients with Fuchs' syndrome appear to have a specific cytokine profile. MIP-1ß is an important chemokine in the intraocular environment of Fuchs' syndrome. Aqueous cytokine profiles support the performance of cataract surgery in uveitis within 3 months after intraocular inflammation control.

Association of apoptosis genes in PDCD1 but not PDCD1LG2, FAS, and FASLG with pediatric idiopathic uveitis in Han Chinese.

BACKGROUND: Previous studies have shown that aberrant T lymphocyte apoptosis is involved in the pathogenesis of uveitis. Genetic variants of apoptotic pathway-related factors (including PDCD1, PDCD1LG2, FAS, and FASLG) may affect apoptosis and in turn predict susceptibility to autoimmune disease. This has not yet been studied in pediatric idiopathic uveitis (PIU) and juvenile idiopathic arthritis (JIA)-associated uveitis and was therefore the subject of the study presented here. METHODS: Fourteen single-nucleotide polymorphisms (SNPs) of several apoptosis-related pathway genes were analyzed in 1238 PIU patients, 128 JIA-associated uveitis patients and 1114 healthy controls using the iPLEX Gold Assay and MassARRAY platform. RESULTS: A lower frequency of the PDCD1/rs6710479 CC genotype in PIU patients was found when compared to controls (Pc = 3.42 × 10-3). A higher frequency of the PDCD1/rs7421861 A allele (Pc = 4.85 × 10-3) was observed in PIU patients as compared with controls. Stratification analysis showed a positive association of band keratopathy with the PDCD1/rs7565639 CT genotype (Pc = 1.05 × 10-2) and a negative association of this parameter with the PDCD1/rs7565639 C allele (Pc = 3.76 × 10-2). CONCLUSIONS: This study revealed that rs6710479 and rs7421861 in the PDCD1 gene confer susceptibility to PIU in Han Chinese. A stratified analysis showed that PDCD1/rs7565639 is associated with band keratopathy in PIU patients.

Replication of Genome-Wide Association Analysis Identifies New Susceptibility Loci at Long Noncoding RNA Regions for Vogt-Koyanagi-Harada Disease.

Purpose: This study was aimed at investigating the association of long noncoding RNA (lncRNA)-related single nucleotide polymorphisms (SNPs) with Vogt-Koyanagi-Harada (VKH) disease. Methods: LncRNA-related SNPs were selected by multi-omics analysis. Genotyping, expression of lncRNA and mRNA, cell proliferation, and cytokine production were tested by MassARRAY System, real-time PCR, CCK8, and ELISA. Results: A significant association with VKH was found for lnc-TOR3A-1:1/rs3829794, which is located in a non-HLA region (CC genotype: Bonferroni corrected P values [PC] = 2.98 × 10-8, odds ratio [OR] = 0.62; TT genotype: PC = 1.64 × 10-8, OR = 1.57; C allele: PC = 1.39 × 10-12, OR = 0.71). Additionally, an association was found for four lncRNA SNPs located in the HLA region. Functional experiments in rs3829794 genotyped individuals showed decreased ABL2 (ABL proto-oncogene 2, nonreceptor tyrosine kinase) expression, decreased proliferation of anti-CD3 plus anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs), and an increased production of IL-10 in CC carriers compared to TT carriers (P = 0.0073, P = 0.0011, and P = 0.002, respectively). Conclusions: Our study identified five new loci associated with VKH susceptibility and identified a functional variant (lnc-TOR3A-1:1/rs3829794) that confers risk for VKH, which is possibly mediated by modulating gene expression, proliferation of lymphocytes, and regulation of anti-inflammatory cytokine production.

Outcomes of therapeutic keratoplasty for severe infectious keratitis in Chongqing, a 16-year experience.

PURPOSE: This study aimed to evaluate the outcomes of therapeutic keratoplasty for severe infectious keratitis in Chongqing (Southwest China). PATIENTS AND METHODS: The records of 561 eyes that underwent therapeutic keratoplasty for refractory microbial keratitis from 2001 to 2016 were analyzed in this retrospective study. Data included demographic information, microbiological investigations, associated factors, graft size, preoperative status, postoperative complications, and final anatomical outcomes. RESULTS: Trauma was the most common cause (267, 47.6%) for corneal ulcers leading to therapeutic keratoplasty. The etiological diagnosis included bacterial keratitis (80 eyes, 14.3%), fungal keratitis (317 eyes, 56.5%), acanthamoeba keratitis (3 eyes, 0.5%), and mixed bacteria/fungal infection (15 eyes, 2.7%). Anatomical success was achieved for 492 eyes (87.7%), with bacterial keratitis having a better outcome than fungal and mixed infections. Diabetes and preoperative time ≥30 days were significantly associated with anatomical failure in the multivariate logistic regression (P=0.028 and P=0.022, respectively). Patients with hypopyon, corneal perforation, surgical delay, and/or large graft size had a higher incidence of postoperative complications (reinfection, cataract, glaucoma, hyphema, or graft rejection) (P<0.05). CONCLUSION: Therapeutic keratoplasty was an effective procedure in managing refractory infectious keratitis. Prompt and appropriate surgery would result in fewer complications and better outcomes.

Macular Abnormalities in Vogt-Koyanagi-Harada Disease.

Purpose: To investigate the prevalence of macular abnormalities in Chinese Vogt-Koyanagi-Harada (VKH) patients.Methods: Clinical characteristics, therapeutic effectiveness and visual outcome were reviewed and analyzed.Results: The most common macular abnormality was macular edema (ME), followed by macular choroidal neovascularization (CNV). Macular abnormalities were associated with recurrent episodes, disease course and visual acuity ≤20/50 at first visit. The prevalence of macular abnormalities in patients who were not treated according to our regular treatment regimen with corticosteroids combined with immunosuppressive agents and who were followed-up for at least one year (13.1%) was significantly higher than in patients receiving the regular treatment (5.7%). Visual improvement was found in 66.7% of eyes with macular abnormalities after regular treatment.Conclusion: Macular abnormalities were associated with recurrent uveitis, course of disease and lower visual acuity at first visit. Regular treatment could prevent the development of macular abnormalities and improved visual outcome in most patients.

Comparison of Clinical Features and Visual Outcome between Sympathetic Ophthalmia and Vogt-Koyanagi-Harada Disease in Chinese Patients.

PURPOSE: To characterize the clinical features of sympathetic ophthalmia (SO) and compare SO and Vogt-Koyanagi-Harada (VKH) disease in Chinese patients. DESIGN: Retrospective case series. PARTICIPANTS: A total of 131 consecutive SO and 500 VKH disease patients randomly selected from among those referred to our uveitis center from April 2008 through June 2018. METHODS: History, extraocular and ocular findings, best-corrected visual acuity (BCVA), auxiliary examination findings, complications, and therapeutic effects were analyzed retrospectively in SO and VKH disease patients. MAIN OUTCOME MEASURES: Visual outcome, extraocular and ocular findings, and therapeutic effects. RESULTS: Sympathetic ophthalmia manifested as posterior uveitis (68.8%) within 2 weeks and equal involvement of anterior and posterior segment (44.4%), respectively, was observed between 2 weeks and 2 months after disease onset. Two months after disease onset, SO patients showed sunset glow fundus (51.2%) and granulomatous anterior uveitis (27.3%). Vogt-Koyanagi-Harada disease patients mainly showed posterior uveitis (100%), anterior segment involvement (92.4%) associated with posterior uveitis (84.9%), and granulomatous anterior uveitis (97.4%) accompanying sunset glow fundus (91.5%) in the 3 periods mentioned above. The frequencies of extraocular manifestations were lower in SO patients (24.4%) as compared with VKH disease patients (84.8%; P < 0.001). Best-corrected visual acuity of SO patients improved from 0.68±0.86 logarithm of the minimum angle of resolution (logMAR) to 0.47±0.78 logMAR (P = 0.01), and BCVA of VKH disease patients improved from 0.67±0.79 logMAR to 0.24±0.53 logMAR (P < 0.001) at 12 months of follow-up. A worse BCVA was noted in SO patients compared with VKH disease patients after treatment (P = 0.003). Kaplan-Meier survival analysis showed that the risk of loss of useful vision in SO patients was significantly higher than that of VKH disease patients (P < 0.001). CONCLUSIONS: Chinese SO and VKH disease patients have a different evolutionary process. The frequency of extraocular manifestations in SO patients is much lower as compared with VKH disease patients. Visual outcome is worse in SO as compared with VKH disease.

Long-Term Efficacy and Safety of Interferon Alpha-2a in the Treatment of Chinese Patients with Behçet's Uveitis Not Responding to Conventional Therapy.

PURPOSE: To investigate the long-term efficacy and safety of interferon alpha-2a (IFNα-2a) in Chinese patients with Behçet's uveitis (BU) refractory to conventional therapy. METHODS: In a prospective observational cohort study, 127 patients were treated with an initial dosage of 3 million units per day in the first three months, followed by gradual tapering of the dose. RESULTS: After 3 months of treatment, IFNα-2a was shown to be effective in 115 cases (91%). At the end of the 1-year follow-up, the frequency of ocular relapses decreased to 1.59 ± 1.68 per year (ranging 0-6) (p < 0.001), as compared to 5.09 ± 2.51 per year (ranging 3-15). Moreover, the frequency of oral ulcer relapses also decreased to 2.49 ± 1.84 per year (ranging 0-6) (p < 0.001), as compared to 8.20 ± 3.72 per year (ranging 2-10). Visual improvement or stability was observed in 32 patients (59%) in these 54 patients. During a mean follow-up of 11 months (range 3-33), the mean final VA (logMAR) had progressed from 1.0 logMAR to 0.8 logMAR in all treated patients. CONCLUSIONS: Long-term low dose of IFNα-2a is useful in treating Chinese BU patients who do not respond adequately to conventional therapy.

Disabled-2 (DAB2) Overexpression Inhibits Monocyte-Derived Dendritic Cells' Function in Vogt-Koyanagi-Harada Disease.

Purpose: Recent studies reported that the tumor suppressor disabled-2 (DAB2) is a negative regulator of immune function. In this study, we investigated the role of DAB2 in monocyte-derived dendritic cells (DCs) from Vogt-Koyanagi-Harada disease (VKH) patients. Methods: The mRNA and protein levels of DAB2 were quantified by quantitative real-time PCR and Western blot. The Sequenom MassARRAY system was used to detect the promoter methylation level. An adenovirus carrying the DAB2 gene was transduced into immature DCs, isolated, and induced from active VKH patients. The surface markers of DCs, the frequency of T helper (Th) type 1 (Th1) and Th17 cells in CD4+T cells, which were cocultured with DCs, were tested by flow cytometry. ELISA was used to analyze the inflammatory cytokines produced by DC and CD4+T cell cocultures. Results: The mRNA and protein expression levels of DAB2 in DCs obtained from active VKH patients were decreased, while the DAB2 promoter methylation level was marginally increased when compared with inactive VKH patients and normal controls. The expression of CD86 on DCs was significantly downregulated by DAB2 overexpression. The DC-related inflammatory factors IL-6 and TNF-α were also decreased. The frequency of Th1 and Th17 cells and their related cytokines were reduced significantly after coculture with DAB2 overexpressing DCs. DAB2 overexpression did not affect autophagy in DCs from VKH patients. Conclusions: These results suggest that the decreased expression of DAB2 in DCs plays a role in the pathogenesis of VKH disease. DAB2 overexpression inhibits DC function, but this is not mediated via autophagy.

Outcome and Prognostic Factors of Phacoemulsification Cataract Surgery in Vogt-Koyanagi-Harada Uveitis.

PURPOSE: To investigate visual outcome and prognostic factors following cataract surgery in patients with Vogt-Koyanagi-Harada (VKH) disease. DESIGN: Retrospective, interventional case series. METHODS: The history, clinical characteristics, best-corrected visual acuity (BCVA), full-field electroretinogram (ERG), intraocular inflammation, complications, and extraocular manifestations were analyzed retrospectively. RESULTS: One hundred and forty-eight male (214 eyes) and 138 female (194 eyes) VKH patients with complicated cataract were included. Surgery was performed on 352 eyes after complete control of intraocular inflammation for at least 3 months. In another set of 56 eyes, surgery was done 1 month after intraocular inflammation control. There was no difference in postoperative complications or BCVA between these 2 groups. The main complications after surgery were hyphema, ocular hypertension, and moderate anterior chamber reaction. Average preoperative visual acuity was 0.08. At last visit, BCVA was improved in 405 eyes (99.3%). The preoperative BCVA, treatment delay after disease onset, preoperative intraocular hypertension, and iris synechiae were associated with final visual outcome. Other parameters such as postoperative inflammation, IOL type, and presence of extraocular VKH features did not affect final BCVA. Poor visual acuity was caused by optic nerve atrophy, choroidoretinal neovascularization, and subretinal fibrosis. Poor postoperative BCVA was associated with an abnormal preoperative ERG profile. CONCLUSIONS: Phacoemulsification and IOL implantation in VKH patients can be safely and successfully performed in quiet eyes even after 1 month following the last signs of inflammation. Visual prognosis was associated with preoperative BCVA, treatment delay after disease onset, preoperative intraocular hypertension, iris synechiae, and presence of preoperative ERG abnormalities.

Aryl Hydrocarbon Receptor Regulates Apoptosis and Inflammation in a Murine Model of Experimental Autoimmune Uveitis.

Uveitis is characterized as a common cause of blindness worldwide. Aryl hydrocarbon receptor (AhR), a ligand-activated nuclear receptor, has been implicated to play a role in human uveitis, although the exact mechanisms remain poorly understood. The purpose of this study was to enhance our knowledge concerning the role of AhR during intraocular inflammation. We immunized wild-type and AhR-knockout C57BL/6J mice with IRBP651-670 to induce experimental autoimmune uveitis (EAU). Disease severity was evaluated with both clinical and histopathological grading. Blood-retinal barrier (BRB) integrity was tested by Evans blue and tight junction proteins qualifications. Apoptosis was measured using TdT-mediated dUTP nick end labeling staining. Macrophage/microglia activation and polarization were studied by immunofluorescence and Western blot. Following EAU induction, AhR-/- mice had more severe clinical and histopathological manifestations of uveitis than AhR+/+ mice. Increased vascular permeability and apoptotic cells were observed in AhR-/- EAU mice when compared with AhR+/+ EAU mice. In addition, AhR-/- EAU mice showed evidence of a significantly increased macrophage/microglia cells and a stronger polarization from the M2 to the M1 phenotype as compared to AhR+/+ EAU mice. The levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ß were increased in AhR-/- EAU mice, which was associated with the activation of NF-κB and signal transducers and activators of transcription (STAT) pathways. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an agonist of AhR, caused a significant decrease in the clinical and histopathological manifestations, preserved BRB integrity, reduced apoptotic cells, inhibited macrophage/microglia activation, and shifted their polarization from M1 toward M2. Moreover, decreased expression of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1ß and inhibition of NF-κB and STAT pathways were found in EAU mice following TCDD treatment. In conclusion, AhR activation with TCDD exhibits an immunomodulatory effect by reducing BRB breakdown, inhibiting retinal cell apoptosis, and reducing pro-inflammatory cytokine expression during EAU. The underlying mechanism may involve the modulation of macrophages/microglia polarization and the downregulation of NF-κB and STAT pathways.

Association of genetic variations in PTPN2 and CD122 with ocular Behcet's disease.

BACKGROUND: Protein tyrosine phosphatases (PTPs) play critical roles in human autoimmunity. Previous studies found that PTPN2 may be the key regulatory factor in the T-cell-mediated immune response. PTPN2 regulates the Janus kinase/signal transducers and activators of transcription pathway by inhibiting signalling via the interleukin (IL)-2 receptor (CD122). An association between genetic variations in PTPN2 and CD122 with ocular Behcet's disease (BD) has not yet been addressed and was therefore the purpose of this study. METHODS: A two-stage case-control study was performed in 906 patients with ocular BD and 2178 healthy controls. Genotyping analysis of 11 single nucleotide polymorphisms was carried out. The expression of PTPN2 in peripheral blood mononuclear cells (PBMCs) was quantified by real-time PCR and cytokine production was measured by ELISA. RESULTS: The frequency of the GG genotype of PTPN2-rs7234029 was significantly lower in patients with ocular BD (p=1.94×10-5, pc=8.34×10-4, OR=0.466). Stratification according to gender showed that rs7234029 was significantly associated with BD in men. A stratified analysis according to the main clinical features showed that rs7234029 was significantly associated with genital ulcers, skin lesions and a positive pathergy test. No association could be detected between BD and CD122 gene polymorphisms. Functional studies showed that rs7234029 GG genotype carriers had a higher PNPT2 mRNA expression level than those which carrying the AA or AG genotype, and a decreased secretion of IL-17 and tumour necrosis factor-alpha was seen by PBMCs from GG carriers. No significant difference could be detected concerning IL-1ß or IL-6 production by stimulated PBMCs between the different genotype groups. CONCLUSIONS: This study shows that a PTPN2-rs7234029 polymorphism is associated with ocular BD and is strongly influenced by gender. In addition, our results suggest that the genetic association with PTPN2 may involve the regulation of PTPN2 mRNA expression and cytokine secretion.

The Choroidal Vascularity Index Decreases and Choroidal Thickness Increases in Vogt-Koyanagi-Harada Disease Patients During a Recurrent Anterior Uveitis Attack.

PURPOSE: To measure changes in the choroidal vascularity index (CVI) in chronic Vogt-Koyanagi-Harada (VKH) disease during a recurrent anterior uveitis attack. METHODS: Forty VKH patients and 40 normal controls were included in this study. Choroidal images were recorded before and during a recurrent anterior uveitis attack, as well as after appropriate treatment. CVI was measured by the binarization technique using ImageJ software (Bethesda, MD). RESULTS: The CVI was 0.75 ± 0.09 in quiescent VKH patients, which was significantly higher compared to healthy controls (0.70 ± 0.05, p ＜ 0.0001). The CVI significantly decreased to 0.72 ± 0.09 when granulomatous anterior uveitis appeared in these patients. However, it returned to 0.75 ± 0.08 after uveitis resolved. CONCLUSIONS: A significant decrease of the CVI occurred during recurrent anterior uveitis in chronic VKH. CVI may provide a novel parameter to guide the treatment of VKH disease.

Novel treatment regimen of Vogt-Koyanagi-Harada disease with a reduced dose of corticosteroids combined with immunosuppressive agents.

PURPOSE: To investigate the effectiveness, visual outcome, and prognostic factors of Vogt-Koyanagi-Harada (VKH) disease treatment with a reduced dose of corticosteroids combined with immunosuppressive agents. METHODS: The clinical characteristics, auxiliary examinations, treatment result, visual outcome, and prognostic factors in VKH patients were analyzed. RESULTS: A total of 998 VKH patients were divided into posterior uveitis group (Group1), anterior uveal involvement group (Group 2), and recurrent granulomatous anterior uveitis group (Group 3). Reduced doses of corticosteroids combined with immunosuppressive agents were used for 1-1.5 years. Uveitis was controlled in 100%, 100%, and 96.8% of these three groups, respectively. Visual improvement and stability was observed in 98.1%, 96.5%, and 88.3%, respectively. Treatment after disease onset, visual acuity at first visit, and 1 month after treatment was positively associated with BCVA at last visit (p < 0.05). CONCLUSION: A reduced dose of corticosteroids combined with immunosuppressive agents effectively controlled the intraocular inflammation and improved visual acuity in most Chinese VKH patients.

Ocular Behcet's disease is associated with aberrant methylation of interferon regulatory factor 8 (IRF8) in monocyte-derived dendritic cells.

Aberrant methylation of interferon regulatory factor 8 (IRF8) has been noted in various tumors. IRF8 has also been reported to be involved in many autoimmune diseases, including Behcet's disease (BD). However, the methylation status of IRF8 in BD has not been reported. To address this issue, we investigated whether the degree of methylation of IRF8 in dendritic cells (DCs) plays a role in the development of BD. We found a lower mRNA expression and a higher methylation level of IRF8 in active ocular BD patients as compared to normal subjects and inactive patients. Treatment with a demethylation agent, 5-Aza-2'-deoxycytidine (DAC) resulted in an increase of mRNA expression and a reduction of the IRF8 methylation level. It also down-regulated the expression of the co-stimulatory molecules CD86, CD80, CD40, and reduced the production of IL-6, IL-1ß, IL-23 and IL-12. An inhibition of Th1/Th17 responses was observed as evidenced by a decreased production of IFN-γ, IL-17, and a reduction of IFN-γ/IL-17- producing CD4+ T cells following treatment with DAC. This study shows that active ocular BD patients have an aberrant IRF8 methylation status. These findings suggest that epigenetic control of IRF8 expression may offer a future target in the treatment of ocular BD.