OR11H1 Missense Variant Confers the Susceptibility to Vogt-Koyanagi-Harada Disease by Mediating Gadd45g Expression.

Vogt-Koyanagi-Harada (VKH) disease is a severe autoimmune disease. Herein, whole-exome sequencing (WES) study are performed on 2,573 controls and 229 VKH patients with follow-up next-generation sequencing (NGS) in a collection of 2,380 controls and 2,278 VKH patients. A rare c.188T>C (p Val63Ala) variant in the olfactory receptor 11H1 (OR11H1) gene is found to be significantly associated with VKH disease (rs71235604, Pcombined = 7.83 × 10-30 , odds ratio = 3.12). Functional study showes that OR11H1-A63 significantly increased inflammatory factors production and exacerbated barrier function damage. Further studies using RNA-sequencing find that OR11H1-A63 markedly increased growth arrest and DNA-damage-inducible gamma (GADD45G) expression. Moreover, OR11H1-A63 activates the MAPK and NF-κB pathways, and accelerates inflammatory cascades. In addition, inhibiting GADD45G alleviates inflammatory factor secretion, likely due to the regulatory effect of GADD45G on the MAPK and NF-κB pathways. Collectively, this study suggests that the OR11H1-A63 missense mutation may increase susceptibility to VKH disease in a GADD45G-dependent manner.

4-Octyl Itaconate Inhibits Proinflammatory Cytokine Production in Behcet's Uveitis and Experimental Autoimmune Uveitis.

4-octyl itaconate (4-OI) is an anti-inflammatory metabolite that activates the nuclear-factor-E2-related factor 2 (NRF2) signaling. In the current work, we investigated whether 4-OI could affect the production of proinflammatory cytokines in Behcet's uveitis (BU) and experimental autoimmune uveitis (EAU). Peripheral blood mononuclear cells (PBMCs) of active BU patients and healthy individuals with in vitro 4-OI treatment were performed to assess the influence of 4-OI on the proinflammatory cytokine production. EAU was induced and used for investigating the influence of 4-OI on the proinflammatory cytokine production in vivo. The flow cytometry, qPCR, and ELISA were performed to detect proinflammatory cytokine expression. NRF2 signaling activation was evaluated by qPCR and western blotting (WB). Splenic lymphocyte transcriptome was performed by RNA sequencing. The NRF2 expression by BU patients-derived PBMCs was lower than that by healthy individuals. After treatment with 4-OI, the proportion of Th17 cells, along with the expression of proinflammatory cytokines (IL-17, TNF-α, MCP-1, and IL-6) by PBMCs, were downregulated, and anti-inflammatory cytokine (IL-10) expression was upregulated, although IFN-γ expression was unaffected. The EAU severity was ameliorated by 4-OI in association with a lower splenic Th1/Th17 cell proportion and increased nuclear NRF2 expression. Additionally, 4-OI downregulated a set of 248 genes, which were enriched in pathways of positive regulation of immune responses. The present study shows an inhibitory effect of 4-OI on the proinflammatory cytokine production in active BU patients and EAU mice, possibly mediated through activating NRF2 signaling. These findings suggest that 4-OI could act as a potential therapeutic drug for the treatment and prevention of BU in the future study.

Association of Long Non-coding RNA C1RL-AS1 and PTPN6 Gene Polymorphisms with Ocular Behcet's Disease in Han Chinese.

PURPOSE: To explore the association of the polymorphisms in PTPN6 and LncRNA C1RL-AS1 genes with ocular BD in Han Chinese patients. METHODS: Correlation study was performed using the iPLEX system on a cohort of ocular BD patients andcontrols. The genotyping of 7 SNPs for LncRNA C1RL-AS1 and PTPN6 genes in ocular BD patients was performed using the iPLEX Gold genotype. RESULTS: The frequencies of rs4013722 AG genotype/A allele in LncRNA C1RL-AS1 were significantly decreased in BD patients, and the frequency of GG genotype was significantly increased in BD patients. The rs4013722 was associated with ocular BD in male patients, but not in female patients. The AG and GG genotype of rs4013722 were associated with skin lesions in male patients. The gene polymorphisms of PTPN6 were not associated with BD patients. CONCLUSIONS: The LncRNA C1RL-AS1/rs4013722 polymorphism conferred susceptibility to ocular BD in Han Chinese patients, which was influenced by sex.Abbreviations: LncRNA: Long Non-coding RNA; BD: Behcet's disease; SNP: single nucleotide polymorphism; PBMCs: peripheral blood mononuclear cells; PTPs: Protein tyrosine phosphatases; PTPN6: protein tyrosine phosphatase non-receptor 6; GWAS: genome-wide association study; HWE: Hardy-Weinberg equilibrium; LD: linkage disequilibrium; OR: odds ratio; CI: confidence interval; eQTL: expression quantitative trait loci; IBD: inflammatory bowel disease; RA: rheumatoid arthritis; Padj: Bonferroni corrected P value; NS: non-significant.

A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing.

Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1ß, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease.

Association Between HLA Polymorphisms and Sympathetic Ophthalmia in Han Chinese.

PURPOSE: Sympathetic ophthalmia (SO) is considered as an autoimmune disease with unclear mechanisms. This study investigated the relationship between HLA polymorphisms and SO. METHODS: HLA typing was performed using the LABType reverse SSO DNA typing method. The allele and haplotype frequencies were assessed using the PyPop software. Statistical significance of genotype distributions between 116 patients and 84 healthy individuals (control) was determined using Fisher's exact test or Pearson's chi-squared test. RESULTS: The SO group had a higher frequency of HLA-DRB1 * 04:05, HLA-DQB1 * 04:01, DRB1 * 04:05-DQB1 * 04:01 haplotype as compared to the control group (Pc < 0.001 for all). CONCLUSION: This study revealed that DRB1 * 04:05 and DQB1 * 04:01 alleles, as well as DRB1 * 04:05-DQB1 * 04:01 haplotye could be potential risk factors for SO.

Association of ZC3HAV1 single nucleotide polymorphisms with the susceptibility of Vogt-Koyanagi-Harada Disease.

BACKGROUND: Polymorphisms of genes related to the immune response have been reported to confer susceptibility to Vogt-Koyanagi-Harada (VKH) disease. This study was carried out to determine whether zinc finger CCCH-type containing antiviral 1 (ZC3HAV1) and tripartite motif-containing protein 25 (TRIM25) genetic polymorphisms are associated with this disease. METHODS: A total of 766 VKH patients and 909 healthy individuals were enrolled in this two-stage case-control study. Thirty-one tag single nucleotide polymorphisms (SNPs) of ZC3HAV1 and TRIM25 were genotyped by MassARRAY System and iPLEX Gold Genotyping Assay. Allele and genotype frequencies were analyzed by the χ2 test or Fisher's exact test. Cochran-Mantel-Haenszel test was used to assess the pooled odds ratio (OR) in the combined study. A stratified analysis was performed in terms of the major clinical features of VKH disease. RESULTS: We found a statistically significant increased frequency of the minor A allele of ZC3HAV1 rs7779972 (P = 1.50 × 10- 4, pooled OR = 1.332, 95%CI = 1.149-1.545) in VKH disease as compared with controls by using the Cochran-Mantel-Haenszel test. The GG genotype of rs7779972 showed a protective association with VKH disease (P = 1.88 × 10- 3, OR = 0.733, 95%CI = 0.602-0.892). There was no difference regarding the frequency of the remaining SNPs between VKH cases and controls (all P > 2.08 × 10- 3). The stratified analysis showed no significant association of rs7779972 with the major clinical characteristics of VKH disease. CONCLUSION: Our study indicated that the ZC3HAV1 variant rs7779972 might confer susceptibility to VKH disease in Han Chinese.

TET2-mediated upregulation of 5-hydroxymethylcytosine in LRRC39 promoter promotes Th1 response in association with downregulated Treg response in Vogt-Koyanagi-Harada disease.

DNA 5-Hydroxymethylcytosine (5-hmC), an oxidative reaction mediated by the ten-eleven translocation (TET) family, has been reported to play an essential role in the progression of auto-inflammatory and autoimmune diseases. By far, little is known about the effect of DNA 5-hmC and the TET family on the development of Vogt-Koyanagi-Harada (VKH) disease. In this study, we discovered that the global DNA 5-hmC level and the TET activity were elevated in association with the up-regulated expression of TET2 at both mRNA and protein levels in CD4+T cells from active VKH patients compared to healthy controls. Integrated analysis of DNA 5-hmC pattern and transcription profile of CD4+ T cells revealed that 6 candidate target genes were involved in the development of VKH disease. The promoter 5-hmC and mRNA levels of leucine rich repeat containing 39 (LRRC39) were verified to be elevated in active VKH patients. Functional experiments showed that TET2 could up-regulate LRRC39 mRNA expression by increasing the promoter 5-hmC level of LRRC39 in CD4+ T cells from active VKH patients. Up-regulated LRRC39 expression could increase the frequencies of IFN-γ+ and IL-17+ CD4+ T cells as well as the secretions of IFN-γ and IL-17 in association with the decreased frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and the reduced production of IL-10. Additionally, restoration of LRRC39 rescued TET2-silencing-mediated reduced frequency of IFN-γ+ CD4+ T cells and increased frequency of CD4+CD25+FOXP3+ Treg cells. Collectively, our study reveals a novel axis, the TET2-5-hmC-LRRC39-Th1/Treg responses axis, in the pathogenesis of VKH and provides a potential target for further investigation into the epigenetic therapy of this disease.

Genetic association of PRKCD and CARD9 polymorphisms with Vogt-Koyanagi-Harada disease in the Chinese Han population.

BACKGROUND: Protein kinase C delta (PRKCD) and caspase recruitment domain family member 9 (CARD9) are genes involved in B and T cell activation, and cytokine production, which are vital mechanisms underlying autoimmune disease development. This study aimed to explore the association of the PRKCD and CARD9 genes with Vogt-Koyanagi-Harada disease (VKH) disease. The case-control study was performed to in 912 patients with VKH and 878 normal controls. MassARRAY system, SHEsis online platform, real-time PCR, and enzyme-linked immunosorbent assay were used to detect genotyping, haplotyping, mRNA expression, and cytokine levels, respectively. RESULTS: We found that rs74437127 C allele of PRKCD, rs3812555 CC genotype, and C allele of CARD9 were associated with increased susceptibility of VKH (Pc = 0.020, OR = 1.624; Pc = 2.04 × 10-5, OR = 1.810; Pc = 2.76 × 10-5, OR = 1.698, respectively). However, the rs74437127 T allele, and rs3812555 TC genotype and T allele were linked with decreased susceptibility to VKH (Pc = 0.020, OR = 0.616; Pc = 7.85 × 10-5, OR = 0.559; Pc = 2.76 × 10-5, OR = 0.589, respectively). PRKCD ATG and CARD9 GCTTA haplotypes decreased susceptibility to VKH (Pc = 3.11 × 10-3, OR = 0.594; Pc = 5.00 × 10-3, OR = 0.639, respectively). Functional studies on rs3812555 genotyped individuals revealed that CC carriers had significantly higher CARD9 mRNA expression and tumour necrosis factor-α production than TC/TT carriers (P = 1.00 × 10-4; P = 2.00 × 10-3, respectively). CONCLUSIONS: We found an association between PRKCD rs74437127 and CARD9 rs3812555 polymorphisms and VKH susceptibility and revealed that the increased susceptibility of rs3812555 for VKH may be mediated by regulating CARD9 gene expression and the production of pro-inflammatory cytokines, such as TNF-α.

Causal association of juvenile idiopathic arthritis-associated uveitis with depression and anxiety: a bidirectional Mendelian randomization study.

PURPOSE: The objective of this article was to examine the potential effect of juvenile idiopathic arthritis-associated uveitis (JIAU) on the risk of major depressive and anxiety disorders through Mendelian randomization (MR) study. METHODS: Genetic instrumental variables from the largest available genome-wide association study for JIAU, major depressive disorder, and anxiety disorder were applied. A set of complementary MR approaches including inverse-variance weighted (IVW) were carried out to verify the estimate association and assess horizontal pleiotropy. RESULTS: Our results indicated that genetically driven JIAU did not causally produce changes in major depressive or anxiety disorders (IVW: OR = 1.001, 95% CI = 0.997-1.006, P = 0.581; IVW: OR = 1.006, 95% CI = 0.980-1.033, P = 0.649, respectively). In addition, the risk of JIAU could not be influenced by genetically predicted major depressive or anxiety disorders (IVW: OR = 1.132, 95% CI = 0.914-1.404, P = 0.256; IVW: OR = 1.019, 95% CI = 0.548-1.896, P = 0.953, respectively). Besides, several sensitivity analyses indicated that our MR results were robust and no horizontal pleiotropy was observed (P > 0.05). CONCLUSIONS: Our MR study does not reveal sufficient evidence to support the causal association of JIAU with the development of major depressive or anxiety disorders in both directions. Further large studies are warranted to validate the undetermined relationship between JIAU and the risk of major depressive or anxiety disorders.

Succinic acid exacerbates experimental autoimmune uveitis by stimulating neutrophil extracellular traps formation via SUCNR1 receptor.

AIMS: To investigate the effect of succinic acid on the development of experimental autoimmune uveitis (EAU) and the underlying mechanism. METHODS: Succinic acid was administrated intraperitoneally to evaluate its effects on immune response and EAU in mice. Intraocular inflammation was evaluated by histopathological scoring. Frequencies of Th1/Th17 cells were measured by flow cytometry. Concentrations of IFN-γ/IL-17A, neutrophil elastase (NE) and myeloperoxidase (MPO) were determined by enzyme-linked immunosorbent test. Infiltration of neutrophils and generation of neutrophil extracellular traps (NETs) within the eye were assessed by immumofluorescence. NETs formation in extracellular matrix was visualised by laser scanning confocal microscopy. Succinate receptor (SUCNR1) antagonist was used to investigate its effect on the generation of NETs. RESULTS: Intraperitoneal injection of succinic acid exacerbated EAU severity as evidenced by severe histological changes in association with elevated frequencies of splenic Th1/Th17 cells, and upregulated levels of IFN-γ/IL-17A and NETs in plasma. In vitro experiments showed that succinic acid could promote the generation of NETs by neutrophils as shown by increased expression of NE and MPO.NETs could increase the frequencies of Th1/Th17 cells in CD4+ T cells and their expression of IFN-γ/IL-17A. In the experiment of receptor antagonism, the upregulatory effect of succinic acid on NETs could be significantly blocked by SUCNR1 antagonist. CONCLUSIONS: Succinic acid could worsen EAU induced by IRBP in mice. This effect was possibly mediated by its upregulation on NETs generation and frequencies of Th1/Th17 cells in affiliation with increased production of IFN-γ/IL-17A through succinic acid-SUCNR1 axis.

Association of CDK6 gene polymorphisms with Behcet's disease in a Han Chinese population.

Cyclin-dependent kinases 4/6 (CDK4/6) and D1-type cyclins (CCND1) can regulate the pro-inflammatory functions of various cytokines during the inflammatory response. This study investigated the association between CDK4/6-CCND1 variants and susceptibility in patients with Behcet's disease (BD). This case-control study enrolled 542 patients with BD and 754 healthy controls. Fourteen tagged single nucleotide polymorphisms (tag SNPs) of the CDK4/6-CCND1 gene were genotyped using the Sequenom MassARRAY system and iPLEX® Pro assay. The results indicated that the frequency of the CDK6 rs2282983 TT genotype was higher in the BD group than the control group (Pc = 0.040, OR = 1.408, 95% CI = 1.124-1.765), and CDK6 rs2282983 CT and rs42034 AG were negatively associated with BD (Pc = 3.647 × 10-4, OR = 0.598, 95% CI = 0.471-0.758; Pc = 0.039, OR = 0.626, 95% CI = 0.459-0.852, respectively). Furthermore, statistical analysis showed that CDK6 rs2282983 TT and CT genotypes were significantly associated with skin lesions in patients with BD (Pc = 0.042, OR = 1.436, 95% CI = 1.130-1.824; Pc = 0.001, OR = 0.594, 95% CI = 0.461-0.764, respectively). This study suggests that the CDK6 loci rs2282983 and rs42034 might confer genetic susceptibility to BD in a Han Chinese population, which could provide new insights into the pathogenesis of BD.

SNP rs7130280 in lncRNA NONHSAT159216.1 confers susceptibility to Behçet's disease uveitis in a Chinese Han population.

OBJECTIVE: Long noncoding RNA (lncRNA) plays a crucial role in the process of immune-mediated diseases. However, the defined involvement of lncRNA on Behçet's disease (BD) is not well known. The aim of this study was to investigate the effects of lncRNA-related single nucleotide polymorphisms (SNPs) on BD susceptibility in Chinese populations. METHODS: A two-stage case-control association study was conducted in a cohort of 1152 BD individuals and 1152 healthy controls. Genotyping was performed by a MassARRAY System. Quantified expression of the lncRNA-miRNA-mRNA molecular axis was detected by real-time PCR and western blot. The cell proliferation was measured by CCK-8 assay. RESULTS: Two-stage association analysis showed a significantly decreased frequency of A allele of SNP rs7130280 in BD patients compared with healthy controls [OR 0.72 (95% CI 0.64, 0.81), Pc = 1.15 × 10-6]. Functionally, SNP rs7130280 could influence the secondary structure and relative expression of NONHSAT159216.1 in human THP-1/U937 macrophages and in peripheral blood mononuclear cells from healthy volunteers. In vitro, overexpression of the rs7130280 A allele also suppressed cell proliferation. Mechanistically, rs7130280 A allele could inhibit the expression of miR-6778-5p, thus enhancing its downstream molecular RPS6KA4/IL10 in a competing endogenous RNA sponge manner. CONCLUSION: Our findings suggest that NONHSAT159216.1 rs7130280 G>A might be associated with a low risk of BD and participates in a potential lncRNA-miRNA-mRNA regulatory network.

Protective Masks Utilizing Nonendangered Components.

At the beginning of the COVID-19 pandemic when traditional N95 respirators were in short supply in the United States, there was a need for alternative products that did not rely on traditional avenues of sourcing and manufacturing. The purpose of this research was to develop and test alternatives to N95 respirators that could be produced locally without specialized materials and processes. Through an interdisciplinary team of experts, new mask designs that use repurposed filtration media and commercially available components were developed and tested for filtration and fit against current N95 standards. Filtration efficiency test results showed that the filtration media can be used for high-quality facemasks and quantitative fit testing demonstrated that the new mask designs could be viable alternatives to traditional N95 facemasks when those masks are in short supply. Manufacturing viability was tested utilizing a workforce to create 6000 masks over 10 days. The ability to quickly produce masks at scale using a workforce without specialized skills demonstrated the feasibility of the mask designs and manufacturing approach to address shortages of critical healthcare equipment, mitigate risk for healthcare and essential workers, and minimize the transmission and spread of disease.

Detection of Airborne Nanoparticles through Enhanced Light Scattering Images.

A new method is proposed in this paper to detect airborne nanoparticles, detecting the light scattering caused by both the particle and the surrounding molecules, which can surpass the limitations of conventional laser optical methods while maintaining simplicity and cost-effectiveness. This method is derived from a mathematical analysis that describes the particle light scattering phenomenon more exactly by including the influence of light scattered from surrounding gas molecules. The analysis shows that it is often too much of a simplification to consider only light scattering from the detected nanoparticle, because light scattering from the surrounding gas molecules, whether visible or invisible to the sensor, is important for nanoparticle detection. An image detection approach utilizing the light scattering from surrounding air molecules is described for the detection of airborne nanoparticles. Tests using monodisperse nanoparticles confirm that airborne particles of around 50 nm in size can even be detected using a low-cost testing device. This shows further that even when using a simple image processing code, captured particle light scattering images can be converted digitally into instantaneous particle counts or concentrations. The factors limiting conventional pulse detection are further discussed. This new method utilizes a simple static light scattering (SLS) approach to enable the development of new devices with better detection capabilities, paving the way for the further development of nanoparticle detection technology.

Genetically predicted fasting blood glucose level plays a causal role in intraocular pressure: A Mendelian randomisation study.

BACKGROUND: This study aimed to examine possible causal associations between various components of metabolic syndrome and glaucoma-related phenotypes. METHODS: A two-sample Mendelian randomisation study was conducted with the models of inverse-variance weighted (IVW), maximum likelihood, weighted median and MR-Egger regression. We accessed data from publicly available genome-wide association studies for individual parameters of metabolic syndrome as the exposures and the data for glaucoma and its endophenotypes as the outcomes. RESULTS: Among 11 exposures and 6 outcomes examined in this Mendelian randomisation study, only fasting blood glucose level showed evidence of a causal influence on intraocular pressure. Results analysed by the IVW model suggested that each one-SD increase in genetically predicted fasting blood glucose level was significantly associated with 0.80 SD elevation in intraocular pressure (ß: 0.80, 95% CI: 0.38-1.22, p: 2.12e-4). The maximum likelihood model (ß: 0.82, 95% CI: 0.39-1.25, p: 1.616e-4) also supported a significant causal effect. The weighted median model (ß: 0.78, 95% CI: 0.17-1.39, p: 0.012) showed a nominally significant effect whereas the MR-Egger model (ß: 0.63, 95% CI: -0.32-1.59, p: 0.212) showed a consistent direction of effect but was not statistically significant. Several sensitivity analyses indicated no evidence of directional horizontal pleiotropy that would bias the result. CONCLUSIONS: This Mendelian randomisation study provides evidence for a causal role for genetically determined higher fasting blood glucose level in the development of increased intraocular pressure. This finding could be considered in the monitoring and control of intraocular pressure and may be instrumental in prevention strategies for ocular hypertension.

Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study.

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD). METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1. RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1. CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Development of revised diagnostic criteria for Fuchs' uveitis syndrome in a Chinese population.

BACKGROUND/AIMS: Fuchs' uveitis syndrome (FUS) is one of the frequently misdiagnosed uveitis entities, which is partly due to the absence of internationally recognised diagnostic criteria. This study was performed to develop and evaluate a set of revised diagnostic criteria for FUS. METHODS: The clinical data of Chinese patients with FUS and patients with non-FUS were collected and analysed from a tertiary referral centre between April 2008 and December 2020. A total of 593 patients with FUS and 625 patients with non-FUS from northern China were enrolled for the development of diagnostic criteria for FUS. Three hundred and seventy-seven patients with FUS and 503 patients with non-FUS from southern China were used to validate the criteria. Clinical symptoms and ocular signs were collected from all patients with FUS and patients with non-FUS. Multivariate two-step cluster analysis, logistic regression and decision tree algorithms in combination with the clinical judgement of uveitis experts were used to revise diagnostic criteria for FUS. RESULTS: Three essential findings including diffuse iris depigmentation, absence of posterior synechiae, mild inflammation in the anterior chamber at presentation and five associated findings including mostly unilateral involvement, cataract, vitreous opacities, absence of acute symptoms and characteristic iris nodules were used in the development of FUS diagnostic criteria. All essential findings were required for the diagnosis of FUS, and the diagnosis was further strengthened by the presence of associated findings. CONCLUSION: Revised diagnostic criteria for FUS were developed and validated by analysing data from Chinese patients and showed a high sensitivity (96.55%) and specificity (97.42%).

Meta-Analysis of miRNA Variants Associated with Susceptibility to Autoimmune Disease.

PURPOSE: Various studies have shown an association between miRNA polymorphisms and susceptibility to autoimmune disease (AD); however, the results are inconclusive. To evaluate whether miRNA polymorphisms account for a significant risk of AD, a total of 87 articles, including 39431 patients and 56708 controls, were identified to estimate their association with 12 AD subtypes. METHODS: Several electronic databases were searched to analyze population-based studies on the relationship between miRNA variants and AD risk. Fixed effects or random effect models were used in the meta-analysis for the risk assessment. RESULTS: In our meta-analysis, miR-146a rs2910164/rs57095329 conferred a marginally elevated risk for AD (allele model, OR = 1.08, 95% CI: 1.01-1.15, P = 0.019; allele model, OR = 1.09, 95 CI: 1.05-1.15, P < 0.001, respectively). Furthermore, miR-196a2 rs11614913 was also associated with AD risk (allele model, OR = 0.92, 95% CI: 0.88-0.97, P = 0.001) as well as miR-499 rs3746444 (allele model, OR = 1.16, 95% CI: 1.03-1.29, P = 0.011). In addition, associations were observed between miR-149 rs2292832/miR-27a rs895819 and AD susceptibility in the overall population (allele model, OR = 1.15, 95% CI: 1.06-1.24, P < 0.001; allele model, OR = 1.11, 95% CI:1.01-1.22, P = 0.043, respectively). CONCLUSIONS: Evidence from our systematic review suggests that miR-146a, miR-196a2, miR-499, miR-149, and miR-27a polymorphisms are associated with susceptibility to AD.

Gut microbiota-mediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling.

Gut microbiota-mediated secondary bile acids (BAs) play an important role in energy balance and host metabolism via G protein-coupled receptors and/or nuclear receptors. Emerging evidence suggests that BAs are important for maintaining innate immune responses via these receptors. However, the effect of BAs on autoimmune uveitis is still unknown. Here, we demonstrate decreased microbiota-related secondary BA concentration in feces and serum of animals with experimental autoimmune uveitis (EAU). Restoration of the gut BAs pool attenuates severity of EAU in association with inhibition of nuclear factor κB (NF-κB)-related pro-inflammatory cytokines in dendritic cells (DCs). TGR5 deficiency partially reverses the inhibitory effect of deoxycholic acid (DCA) on DCs. TGR5 signaling also inhibits NF-κB activation via the cyclic AMP (cAMP)-protein kinase A (PKA) pathway in DCs. Additionally, both DCA and TGR5 agonists inhibit human monocyte-derived DC activation. Taken together, our results suggest that BA metabolism plays an important role in adaptive immune responses and might be a therapeutic target in autoimmune uveitis.

Changes in the Gut Microbiome Contribute to the Development of Behcet's Disease via Adjuvant Effects.

Behcet's disease (BD) is associated with considerable gut microbiome changes. However, it still remains unknown how the composition of the gut microbiome exactly affects the development of this disease. In this study, transplantation of stool samples from patients with active ocular BD to mice via oral gavage was performed. This resulted in decreases of three short chain fatty acids (SCFAs) including butyric acid, propionic acid and valeric acid in the feces of the BD-recipient group. Intestinal barrier integrity of mice receiving BD feces was damaged as shown by a decreased expression of tight junction proteins and was associated with the release of Lipopolysaccharides (LPS) in the circulation. The mice also showed a higher frequency of splenic neutrophils as well as an enrichment of genes associated with innate immune responses in the neutrophils and CD4 + T cells as identified by single cell RNA sequencing. Analysis of neutrophils and T cells functions in these mice showed an enhanced mesenteric lymph node and splenic Th1 and Th17 cell differentiation in association with activation of neutrophils. Transplantation of BD feces to mice and subsequent induction of experimental uveitis (EAU) or encephalomyelitis (EAE) led to an exacerbation of disease in both models, suggesting a microbial adjuvant effect. These findings suggest that the gut microbiome may regulate an autoimmune response via adjuvant effects including increased gut permeability and enhancement of innate immunity.