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Background/aimsFuchs’ 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.MethodsThe 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.ResultsThree 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.ConclusionRevised 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%).

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.

Zhangluxi Liu, Jing Xu, Hongxi Li, Jia Shu, Guannan Su, Chunjiang Zhou, Peizeng Yang The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, People’s Republic of ChinaCorrespondence: Peizeng Yang, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People’s Republic of China, Tel/Fax +86-23-89012851, Email peizengycmu@126.comBackground: Effector T cells, especially T helper 1 (Th1) cells and T helper 17 (Th17) cells, are involved in the pathogenesis of many autoimmune diseases such as uveitis. Under hyperactive immune conditions, these effector T cells pathologically maintain a high expression level of programmed cell death protein 1 (PD-1) receptors and distinctively engage aerobic glycolysis via cellular energy metabolism mediated by pyruvate kinase M2 (PKM2). Therefore, we proposed that the synergy of metabolic inhibition and receptor guidance might target and down-regulate these hyperactive effector T cells to achieve anti-immune effects.Methods: PD-1 antibody and TEPP-46 were integrated by polyethylene glycol (PEG) modified poly (lactic-co-glycolic acid) (PLGA) as a nanoplatform (TPP). Characteristics of TPP were basically detected. The biosafety of TPP was evaluated in vitro and in vivo. The targeting effect of TPP was detected by laser scanning confocal microscopy and flow cytometry (FCM). Interleukin-2 (IL-2)/interleukin-17A (IL-17A)/interferon-gamma (IFN-γ) producing cells were detected by FCM. Experimental autoimmune uveoretinitis (EAU) was induced in C57BL/6J mice as the inflammatory model.Results: TPP had homogeneous distribution, good stability in vitro, and high biosafety in vitro and in vivo. Encapsulated TEPP-46 showed a sustained release profile with burst, steady and slow release periods. Early activation and proliferation of effector T cells was inhibited by TPP treatment in vitro. Th1 and Th17 cells were suppressed by TPP in vitro and in vivo. EAU was alleviated in mice by systemic administration of TPP.Conclusion: The novel nanoplatform TPP could suppress Th1 and Th17 cells and exhibited an anti-inflammatory effect on EAU, providing an alternative approach to ameliorate autoimmune diseases mediated by these cells.Graphical Abstract: Keywords: anti-inflammation, experimental autoimmune uveitis, sustained release, aerobic glycolysis, biomaterial, Th1 and Th17 cells

SummaryA better understanding of wheat functional genomics could facilitate the targeted breeding for agronomic traits improvement and environmental adaptation. With the release of reference genomes and extensive re-sequencing data of wheat and relatives, wheat functional genomics enters a new era. However, limited transformation efficiency in wheat hampers in-depth gene functional study and genetic manipulation for breeding. Here, we generated an EMS mutagenesis library of KN9204, a widely grown elite wheat variety in northern China, with available reference genome, transcriptome, and epigenome of various tissues. The library harbors enormous developmental diversity covering important tissues and transition stages. Exome capture sequencing of 2,090 mutant lines, with probes designed by KN9204 genome, revealed that 98.79% of coding genes have mutations and 1,383 EMS-type SNPs per line averagely. Novel allelic variations for important agronomic trait-related genes, such asRht-D1, Q, TaTB1, andWFZP, were identified. We tested 100 lines with severe mutations in 80 NAC TFs under drought and salinity stresses, and found 13 lines with altered sensitivity. Three lines were further analyzed for the regulation insight of NAC TFs in stress response by combing transcriptome and available chromatin accessibility data. Hundreds of direct targets of NAC with altered transcriptional pattern in mutant lines under salt or drought stress induction were identified, includingSNAC1, DREB2B, CML16andZFP182, knowing factors in abiotic stresses response. Thus, we have generated and indexed KN9204 EMS mutant library which would facilitate functional genomics study and provide resources for genetic manipulation in wheat.

The role of adaptive immunity in myocardial recovery post myocardial infarction (MI), particularly the immune response by B lymphocytes, remains elusive. Bone marrow immune microenvironment in response to MI is remotely regulated by the hypothalamic pituitary adrenal (HPA) axis. We utilized the cardioprotective actions of SGLT2 inhibitor to identify and characterize bone marrow B cell subsets that respond to myocardial injury. Initially, we preformed ligation of left anterior descendant (LAD) coronary artery in male C57BL/6J mice to monitor the dynamic changes of immune cells across tissues. Mechanistic insights from mouse models demonstrated arrest of bone marrow B cell maturation and function 24 h post MI. A secondary MI model (twice MIs) in mice was established for the first time to evaluate the dosage-dependent cardioprotection of empagliflozin (EMPA). Single-cell RNA-Seq further demonstrated that EMPA restored bone marrow naïve B cell (B220

Purpose Pediatric idiopathic uveitis typically shows anterior segment involvement. Whether retinal vasculitis is an important manifestation of this disease remains unknown and was therefore the subject of this study. Methods This study was performed involving patients with pediatric idiopathic uveitis. Fundus fluorescein angiography was used to assess the presence of retinal vasculitis. Results A total of 1,867 patients with pediatric uveitis were seen between December 2008 and January 2018, of whom 1,364 had undergone fundus fluorescein angiography examination. Idiopathic uveitis was the most common entity, accounting for 81.2%. Among these patients with idiopathic uveitis, 79.6% had retinal vasculitis in at least one eye. After 1-year treatment with oral prednisone mostly combined with cyclosporine, 76.3% patients in the retinal vasculitis group achieved control of their ocular inflammation, which was significantly lower as compared with 85.1% in those without (P = 0.008). Retinal vasculitis was an independent predictor for a lower probability of inflammation control after 1-year treatment. Visual function (best-corrected visual acuity > 20/25 in the better seeing eye) was worse in the retinal vasculitis group than in the control group after 5 years. Conclusion Almost 80% of patients with pediatric idiopathic uveitis show manifestations of retinal vasculitis, which is associated with a lower probability of inflammation control resulting in a worse visual prognosis.

ImportanceImproper host response to COVID-19 vaccines could trigger immune-mediated adverse events. The question remains whether COVID-19 vaccination should be postponed until complete remission in patients with uveitis, a preexisting immune-related condition.ObjectiveTo compare recommendations for early and deferred COVID-19 vaccination with respect to uveitis outcomes.Design, Setting, and ParticipantsThis open-label, randomized clinical trial at a large, specialized teaching center for uveitis care in China enrolled unvaccinated patients with inactive uveitis between August 10, 2021, and February 22, 2022, with follow-up to June 6, 2022.InterventionsParticipants were randomly assigned to receive recommendation for early or deferred COVID-19 vaccination after complete remission of uveitis. Non–messenger RNA (non-mRNA) COVID-19 vaccines were available in China during the trial.Main Outcomes and MeasuresThe primary outcome was the time to symptomatic uveitis worsening during 3 months of follow-up. Secondary outcomes included uveitis activity and best-corrected visual acuity at 3 months.ResultsOf the 543 participants (304 women [56.0%]; median age, 35 [IQR, 26-49] years), 262 were recommended for early vaccination and 281 for deferred vaccination. By month 3, 109 patients (41.6%) in the early group had been vaccinated compared with 14 (5.0%) in the deferred recommendation group. In the intention-to-treat population, the time to symptomatic uveitis worsening was shorter in the early group than in the deferred group (hazard ratio, 1.68 [95% CI, 1.09-2.59]; P = .01 by log-rank test). Changes in anterior chamber cells, vitreous haze, and best-corrected visual acuity from baseline to month 3 appeared similar in the 2 groups in the evaluable population after the month 3 in-person visit.Conclusions and RelevanceIn this randomized clinical trial of patients with inactive uveitis, recommendation for early non-mRNA COVID-19 vaccination resulted in a higher incidence of self-reported symptomatic uveitis worsening with possible reporting bias compared with recommendation for deferred vaccination, but no adverse effects were observed in disease and visual prognosis at 3 months. These findings would be useful to guide the individual timing choices of non-mRNA COVID-19 vaccination in this clinically vulnerable population.Trial RegistrationChinese Clinical Trial Registry: ChiCTR2100049467

Background Leaf senescence comprises numerous cooperative events, integrates environmental signals with age-dependent developmental cues, and coordinates the multifaceted deterioration and source-to-sink allocation of nutrients. In crops, leaf senescence has long been regarded as an essential developmental stage for productivity and quality, whereas functional characterization of candidate genes involved in the regulation of leaf senescence has, thus far, been limited in wheat. Results In this study, we analyzed the expression profiles of 97 WRKY transcription factors (TFs) throughout the progression of leaf senescence in wheat and subsequently isolated a potential regulator of leaf senescence, TaWRKY42-B, for further functional investigation. By phenotypic and physiological analyses in TaWRKY42-B-overexpressing Arabidopsis plants and TaWRKY42-B-silenced wheat plants, we confirmed the positive role of TaWRKY42-B in the initiation of developmental and dark-induced leaf senescence. Furthermore, our results revealed that TaWRKY42-B promotes leaf senescence mainly by interacting with a JA biosynthesis gene, AtLOX3, and its ortholog, TaLOX3, which consequently contributes to the accumulation of JA content. In the present study, we also demonstrated that TaWRKY42-B was functionally conserved with AtWRKY53 in the initiation of age-dependent leaf senescence. Conclusion Our results revealed a novel positive regulator of leaf senescence, TaWRKY42-B, which mediates JA-related leaf senescence via activation of JA biosynthesis and has the potential to be a target gene for molecular breeding in wheat.

Summary Vogt–Koyanagi–Harada (VKH) disease is an autoimmune disease leading to visual impairment. Its pathogenic mechanisms remain poorly understood. Our purpose was to investigate the distinctive protein and metabolic profiles of sweat in patients with VKH disease. In the present study, proteomics and metabolomics analysis was performed on 60 sweat samples (30 VKH patients and 30 normal controls) using liquid chromatography tandem mass spectrometry. Parallel reaction monitoring (PRM) analysis was used to validate the results of our omics analysis. In total, we were able to detect 716 proteins and 175 metabolites. Among them, 116 proteins (99 decreased and 17 increased) were observed to be significantly different in VKH patients when compared to controls. Twenty-one differentially expressed metabolites were identified in VKH patients, of which 18 included choline, L-tryptophan, betaine and L-serine were reduced, while the rest were increased. Our multi-omics strategy reveals an important role for the amino acid metabolic pathway in the pathogenesis of VKH disease. Significant differences in proteins and metabolites were identified in the sweat of VKH patients and, to some extent, an aberrant amino acid metabolism pathway may be a pathogenic factor in the pathogenesis of VKH disease.

Using the Community Earth System Model (CESM) version 1.2, this study investigates the changes in secondary inorganic aerosols (SIOAs) over the Northern Hemisphere from 1850 to 2007, regional contributions, and consequences on surface air temperature. Results show that SIOAs changes can be divided into two stages. At the first stage (1850–1980), European and North American SIOAs concentrations increase, with a cooling effect especially over Europe and Eastern Siberia. At the second stage (1980–2007), SIOAs concentrations over Europe and North America are reduced with a warming effect in the mid-high latitudes, whereas SIOAs increase over East Asia and South Asia leading to a cooling effect there. The temperature changes over the emission source regions are mainly driven by radiative forcing. Horizontal transfer of heat leads to a temperature response in the Siberian region.

Aberrant lipid metabolism plays a role in inflammation and progression of autoimmune diseases but the definite mechanism remains unclear. In this study we investigate lipidomic profiles in Behçet's disease (BD) and the role of triglyceride (TAG) in the pathogenesis of autoimmune uveitis. Lipidomics revealed a distinct lipid metabolite profile including increased TAG metabolites in plasma of active BD patients. TAG could stimulate the proliferation, IL-17 and IFN-γ expression by CD4

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.

Source data for figures and tables in 'Sulfate emissions from consumption by high and low income countries produce comparable climate impacts' published in Nature Geoscience.

Regional consumption activities supported by domestic production and international trade have led to substantial amounts of aerosols worldwide, yet the resulting impacts on the global climate system remains unknown. Here we quantify for the first time the climate response to aerosols associated with consumption by developing and developed countries, by integrating a most current-generation fully coupled Earth system model, a recent multi-regional input-output table and an updated emission inventory used for climate change assessment. We find that although consumption associated sulfur dioxide emissions of developed countries are only 60% of those of developing countries, they lead to comparable impacts on the global mean surface air temperature (-0.20±0.09 versus -0.18±0.11 K; with 2 standard deviations) and precipitation (-0.017±0.017 versus -0.019±0.019 mm/day). This is because the emissions of developed countries and resulting forcing are more evenly distributed zonally and located at higher latitudes than the emissions of developing countries. Emissions of both developing and developed countries strongly cool the Northern Hemisphere and cause southward movement of the Intertropical Convergence Zone, while emissions of developing countries have stronger temperature and precipitation impacts over the tropical monsoon regions of China and India. This work serves as the first step of a comprehensive assessment of consumption associated climate impacts in support of global concerted action towards sustainable consumption and stabilized climate.

The deep blue sky is an indicator of a lower concentration of aerosols and a cloudless sky. With increasing human emissions, a trend towards days with fewer deep blue skies might indicate a decline in a good living environment for humans. This study investigates the long-term changes of the deep blue sky in China from 1980 to 2018. Due to a lack of direct measurements, we use atmospheric visibility and low cloud cover to classify blue sky days into three grades: light blue day, medium blue day, and deep blue day. Climatologically, annual deep blue days increase from southeast China to northwest China, with the maximum number in Xinjiang and eastern Inner Mongolia and the minimum number in western Qinghai and southern Hebei. From 1980 to 2018, annual deep blue days show a prominent decreasing trend in most of China, with area-mean annual deep blue days decreasing by −0.48 days per year (d/y) in China, and the variation becomes more obvious after 2013. The maximum decreasing trend is observed in eastern China. The most prominent decreases of deep blue days are seen in winter. Both air pollution and the change in meteorological conditions contribute to the decrease of wintertime deep blue days in China. Specifically, the decrease in surface wind speed hinders the cleaning of air by winds, the increase in surface air temperature, and decrease in relative humidity is favorable for low cloud increase, and the increasing emission of pollution reduces atmospheric visibility. Supplementary Information The online version contains supplementary material available at 10.1007/s00704-021-03898-1.

Fuchs’ uveitis syndrome (FUS) is one of the most under- or misdiagnosed uveitis entities. Many undiagnosed FUS patients are unnecessarily overtreated with anti-inflammatory drugs, which may lead to serious complications. To offer assistance for ophthalmologists in the screening and diagnosis of FUS, we developed seven deep convolutional neural networks (DCNNs) to detect FUS using slit-lamp images. We also proposed a new optimized model with a mixed “attention” module to improve test accuracy. In the same independent set, we compared the performance between these DCNNs and ophthalmologists in detecting FUS. Seven different network models, including Xception, Resnet50, SE-Resnet50, ResNext50, SE-ResNext50, ST-ResNext50, and SET-ResNext50, were used to predict FUS automatically with the area under the receiver operating characteristic curves (AUCs) that ranged from 0.951 to 0.977. Our proposed SET-ResNext50 model (accuracy = 0.930; Precision = 0.918; Recall = 0.923; F1 measure = 0.920) with an AUC of 0.977 consistently outperformed the other networks and outperformed general ophthalmologists by a large margin. Heat-map visualizations of the SET-ResNext50 were provided to identify the target areas in the slit-lamp images. In conclusion, we confirmed that a trained classification method based on DCNNs achieved high effectiveness in distinguishing FUS from other forms of anterior uveitis. The performance of the DCNNs was better than that of general ophthalmologists and could be of value in the diagnosis of FUS.

BackgroundIdiopathic paediatric uveitis (IPU) and juvenile idiopathic arthritis associated uveitis (JIA-U) are the two most common entities in paediatric uveitis. This study addressed the possible association of IPU and JIA-U with genes that had been shown earlier to be associated with juvenile idiopathic arthritis.MethodsWe carried out a case-control association study involving 286 IPU, 134 JIA-U patients and 743 healthy individuals. A total of 84 candidate single nucleotide polymorphisms (SNPs) in 60 genes were selected for this study. The MassARRAY platform and iPLEX Gold Genotyping Assay was used to genotype 83 candidate SNPs and the remaining SNP (rs27293) was analysed using the TaqMan SNP Genotyping Assay.ResultsNo evidence was found for an association of the candidate polymorphisms tested with IPU. Six SNPs (PRM1/rs11074967, JAZF1/rs73300638, IRF5/rs2004640, MEFV/rs224217, PSMA3/rs2348071 and PTPN2/rs7234029) showed an association with JIA-U (p−2).ConclusionOur findings showed associations of six SNPs (PRM1/rs11074967, JAZF1/rs73300638, IRF5/rs2004640, MEFV/rs224217, PSMA3/rs2348071 and PTPN2/rs7234029) with JIA-U. No association was detected between the 84 tested SNPs and IPU.

Whether ambient temperature influences immune responses leading to uveitis is unknown. We thus tested whether ambient temperature affects the symptoms of experimental autoimmune uveitis (EAU) in mice and investigated possible mechanisms. C57BL/6 mice were kept at a normal (22 degrees C) or high temperature (30 degrees C) housing conditions for 2 weeks and were then immunized with human interphotoreceptor retinoid-binding protein (IRBP651-670) peptide to induce EAU. Histological changes were monitored to evaluate the severity of uveitis. Frequency of Th1 cells and Th17 cells was measured by flow cytometry (FCM). The expression of IFN-gamma and IL-17A mRNA was measured by real-time qPCR. The generation of neutrophil extracellular traps (NETs) was quantified by enzyme-linked immunosorbent assay (ELISA). Differential metabolites in the plasma of the mice kept in the aforementioned two ambient temperatures were measured via ultra-high-performance liquid chromatography triple quadrupole mass spectrometry quadrupole time of flight mass spectrometry (UHPLC-QQQ/MS). The differential metabolites identified were used to evaluate their effects on differentiation of Th1 and Th17 cells and generation of NETs in vitro. The results showed that EAU mice kept at high temperature experienced a more severe histopathological manifestation of uveitis than mice kept at a normal temperature. A significantly increased frequency of Th1 and Th17 cells in association with an upregulated expression of IFN-gamma and IL-17A mRNA was observed in the splenic lymphocytes and retinas of EAU mice in high temperature. The expression of NETs as evidenced by myeloperoxidase (MPO) and neutrophil elastase (NE), was significantly elevated in serum and supernatants of neutrophils from EAU mice kept at high temperature compared to the normal temperature group. The metabolites in the plasma from EAU mice, fumaric acid and succinic acid, were markedly increased in the high temperature group and could induce the generation of NETs via the NADPH oxidase-dependent pathway, but did not influence the frequency of Th1 and Th17 cells. Our findings suggest that an increased ambient temperature is a risk factor for the development of uveitis. This is associated with the induction of Th1 and Th17 cells as well as the generation of NETs which could be mediated by the NADPH oxidase-dependent pathway.

AimsTo investigate the effect of succinic acid on the development of experimental autoimmune uveitis (EAU) and the underlying mechanism.MethodsSuccinic 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.ResultsIntraperitoneal 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.ConclusionsSuccinic 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.

Combination of corticosteroids (CS) with cyclosporin A (CsA) is widely used in the treatment of autoimmune diseases, autoinflammatory diseases and transplantation rejection. However, some patients fail to respond or develop resistance to the combination regimen. In Vogt-Koyanagi-Harada (VKH) disease model, we performed RNA sequencing (RNA-seq) based transcriptomics, isobaric tags for relative and absolute quantification (iTRAQ) based proteomics and assays in vitro to screen and validate potential resistant molecules. We found that a total of 1697 differentially expressed genes (DEGs) and 21 differentially expressed proteins (DEPs) in CD4(+) T cells between CsA & CS-resistant and -sensitive VKH patients. Ribosomal Protein S4, Y-Linked 1 (RPS4Y1) was verified to regulate the resistance of CD4(+) T cells from male VKH patients to CsA & CS. Importantly, we showed that chlorambucil (CLB) could reverse the resistance by RPS4Y1 suppression. Taken together, we identify RPS4Y1 as an important CsA & CS resistance gene in VKH disease. Researchers should consider validating the resistant effect of RPS4Y1 in other autoimmune diseases or organ transplantation.

Vogt-Koyanagi-Harada (VKH) disease is a common type of uveitis in China, but the diagnosis criteria of VKH disease is controversial. The aim of this study was to investigate potential diagnostic plasma biomarkers for VKH disease. A case-control study including 55 VKH patients (28 active patients and 27 inactive VKH patients) and 30 healthy controls in a tertiary referral center was performed. The metabolic phenotype of VKH patients showed a significant difference compared to healthy controls. Fifteen differentially expressed metabolites (DEMs) were identified between active VKH patients and healthy controls and nine DEMs were found between inactive VKH patients and healthy controls after controlling variable importance in the projection (VIP) value > 1 and false discovery rate (FDR) < 0.05. D-mannose, stearic acid and L-lysine were shown to be potential diagnostic biomarkers which can discriminate active VKH patients from healthy controls with a diagnostic performance with AUC = 0.965, 0.936 and 0.910 respectively in independent diagnosis and an AUC = 0.999 when combined. Sarcosine was recognized as an independent potential biomarker which could distinguish inactive VKH patients from healthy controls. This study reveals a significant difference of plasma metabolic phenotype and identifies diagnostic biomarkers for VKH disease. Changes in the metabolic profile may provide clues towards the pathophysiology of VKH disease.

Leaf senescence is a complex and precise regulatory process that is correlated with numerous internal and environmental factors. Leaf senescence is tightly related to the redistribution of nutrients, which significantly affects productivity and quality, especially in crops. Evidence shows that the mediation of transcriptional regulation by WRKY transcription factors is vital for the fine-tuning of leaf senescence. However, the underlying mechanisms of the involvement of WRKY in leaf senescence are still unclear in wheat. Using RNA sequencing data, we isolated a novel WRKY transcription factor, TaWRKY40-D, which localizes in the nucleus and is basically induced by the progression of leaf senescence. TaWRKY40-D is a promoter of natural and dark-induced leaf senescence in transgenic Arabidopsis thaliana and wheat. We also demonstrated a positive response of TaWRKY40-D in wheat upon jasmonic acid (JA) and abscisic acid (ABA) treatment. Consistent with this, the detached leaves of TaWRKY40-D VIGS (virus-induced gene silencing) wheat plants showed a stay-green phenotype, while TaWRKY40-D overexpressing Arabidopsis plants showed premature leaf senescence after JA and ABA treatment. Moreover, our results revealed that TaWRKY40-D positively regulates leaf senescence, possibly by altering the biosynthesis and signalling of JA and ABA pathway genes. Together, our results suggest a new regulator of JA- and ABA-related leaf senescence, as well as a new candidate gene that can be used for molecular breeding in wheat.

Background: Berberine (BBR) was reported to have immunoregulatory and anti-inflammatory properties. In this study, we investigated whether BBR could exert its effects on the development of experimental autoimmune uveitis (EAU), and if so, what was the underlying mechanism?Methods: EAU was induced in B1 OR.III mice by immunization with IRBP 161-180, followed by 100 mg/kg/d BBR intragastric administration. Disease severity was assessed by evaluation of clinical and histopathological scores. Blood-retinal barrier (BRB) breakdown was tested by Evans blue. Effector and regulatory T (Treg) cell balance was evaluated by quantitative real-time PCR and flow cytometry. Spleen transcriptome was characterized by RNA sequencing (RNA-seq). Gut microbiota composition was investigated by 16S rRNA analysis.Results: BBR treatment significantly blocked EAU as shown by the decrease of the clinical and histological scores, as well as the inhibition of BRB breakdown. The frequency of splenic Th1 and Th17 cells was decreased, whereas Treg cells were increased in the BBR-treated group. RNA-seq of the spleen revealed 476 differentially expressed genes (DEGs) between the EAU and EAU-BBR group. GO functional classification, as well as KEGG analysis demonstrated that BBR treatment markedly influences genes belonging to chromatin remodeling and immune-related pathways. Intervention with BBR modified the gut microbiome in EAU mice, increasing the number of bacteria with immunomodulatory capacity. Depletion of gut microbiota affected the efficacy of BBR on EAU. Moreover, the altered bacterial strains showed a significant correlation with the expression of histones.Conclusions: BBR inhibited IRBP induced EAU, which was associated with a significant change in the spleen transcriptome and intestinal microbial composition.

Background/aimsThis study was performed to examine the prevalence, risk factors and treatment outcome of OHT/glaucoma in Chinese patients with Vogt-Koyanagi-Harada (VKH).MethodsRetrospective non-interventional case series were conducted on a total of 2281 patients with VKH referred from April 2008 to April 2019. Of these cases, 1457 had a minimum follow-up period of 3 months and were included for this study. Medical records were reviewed for demographic, ocular and treatment data.ResultsAmong 2914 eyes of 1457 patients with VKH, 695 (23.9%) eyes of 425 patients (29.2%) developed OHT/glaucoma. The risk factors of OHT/glaucoma included initial BCVA of 20/200 or worse (OR=4.826), final best-corrected visual acuity (BCVA) of 20/50–20/100 (OR=5.341) and final BCVA of 20/200 or worse (OR=4.235), the interval between uveitis attack and referral time interval being 2 months or more (OR=3.318), more than three recurrent episodes (OR=4.177) and posterior synechiae (OR=1.785). The main possible mechanisms of OHT/glaucoma were inflammatory factor-induced open-angle OHT/glaucoma in 277 eyes (39.9%) and pupillary block arising from complete posterior synechiae in 201 eyes (28.9%). In these 695 eyes with OHT/glaucoma, normalised intraocular pressure (IOP) was achieved in 389 eyes (56.0%) following medical treatment. In the remaining 306 eyes, various surgical interventions were performed and a normalised IOP could be achieved in 249 eyes (81.4%).ConclusionOHT/glaucoma is a common complication in Chinese patients with VKH. Risk factors of OHT/glaucoma included worse acuity at first and final visits, the longer interval between uveitis attack and referral, more recurrent episodes and posterior synechiae.

Purpose: To study the role of palmitoleic acid (PA) in the pathogenesis of acute anterior uveitis (AAU).Methods: PA levels in feces from AAU patients were measured by gas chromatography coupled with a mass spectrometer (GC-MS) and compared with samples obtained from healthy individuals. Enzyme linked immunosorbent assay (ELISA) and flow cytometry (FCM) were used to assess the effect of PA on dendritic cells (DCs) and CD4(+)T cells obtained from mice, AAU patients and healthy individuals. C57BL/6 mice were fed with PA or vehicle and experimental autoimmune uveitis (EAU) was induced with a human retinal IRBP651-670 peptide. Disease severity of EAU was evaluated by clinical manifestation and histology. Differentiation of splenic Type 1 helper T cells (Th1) and Th17 cells was evaluated by FCM. Tandem mass tag (TMT)-based proteomics analysis was used to identify differentially expressed proteins following incubation of DCs with PA.Results: The fecal concentration of PA was increased in AAU patients as compared with healthy individuals. In vitro, PA promoted apoptosis of DCs and inhibited the secretion of TNF-alpha from mouse bone-marrow-derived dendritic cells (BMDCs) as well as in DCs from AAU patients and healthy individuals. It only decreased DCs surface marker expression and IL-12p70 secretion in BMDCs and healthy individuals DCs but not in AAU patient DCs. PA-treated BMDCs inhibited Th cell differentiation from mouse naive CD4(+)T cells and IL-17 and IFN-gamma secretion in co-culture supernatants. PA also inhibited the differentiation of Th cells and secretion of IFN-gamma and IL-17 in CD4(+)T cells from mice, AAU patients and healthy individuals. In vivo, PA-treated EAU mice showed milder clinical and histopathological intraocular manifestations as compared with the control group. PA feeding inhibited differentiation of splenic Th17 cells, whereas Thl cells were not affected. Up to 30 upregulated and 77 downregulated proteins were identified when comparing PA-treated DCs with controls.Conclusion: An increased expression of fecal PA was observed in AAU patients. PA was shown to have immunoregulatory effects on DCs and CD4(+)T cells and attenuated disease severity in EAU mice.

BackgroundAn Immunochip study recently identified the association of a number of new genetic loci with Behcet’s disease (BD).ObjectiveTo confirm the association between new genetic loci reported in an Immunochip study and BD in a Han Chinese population.MethodsA two-stage association study was carried out in 1238 patients with BD and 1458 healthy controls. Twenty-two candidate single nucleotide polymorphisms (SNPs) were selected for genotyping by iPLEXGold genotyping or TaqMan SNP assays and a meta-analysis was performed for significantly associated markers.ResultsThe results showed that four SNPs (LACC1/rs9316059, CEBPB-PTPN1/rs913678, ADO-EGR2/rs224127 and RIPK2/rs10094579) were associated with BD in an allelic association test (rs9316059 T allele: pc=4.95×10−8, OR=0.687; rs913678 C allele: pc=3.01×10−4, OR=1.297; rs224127 A allele: pc=3.77×10−4, OR=1.274; rs10094579 A allele: pc=6.93×10−4, OR=1.302). For four SNPs tested by meta-analysis, the association with BD was strengthened and all exceeded genome-wide significance (rs9316059: p=2.96×10−16; rs913678: p=2.09×10−16; rs224127: p=5.28×10−13; rs10094579: p=9.21×10−11).ConclusionsOur findings confirmed the association of four loci (LACC1, CEBPB-PTPN1, ADO-EGR2 and RIPK2) in Chinese Han patients with BD.

PURPOSE: To investigate the dynamic changes of full field electroretinography (ffERG) and its relationship with structural changes in Vogt-Koyanagi-Harada (VKH) disease. DESIGN: Interventional case series. METHODS: A total of 42 VKH patients (84 eyes) and 45 normal controls (90 eyes) were included in this study. All of the patients showed active uveitis and were referred to us within 2 months after disease onset. Dynamic changes of retinal function were evaluated by ffERG before treatment and 2, 6, and 12 months after treatment with systemic corticosteroids and cyclosporine. The relationship between ffERG data with structural changes as disclosed by B-scan ultrasonography, fundus fluorescein angiography (FFA), indocyanine green angiography, and optical coherence tomography were also evaluated. RESULTS: All investigated VKH patients showed a significantly decreased visual acuity and retinal structural changes before treatment. These changes significantly improved at 2 months and no abnormalities were apparent at 6 months following treatment. Full-field ERG showed significantly decreased amplitudes and prolonged implicit times for all dark-adapted (DA) and light-adapted ffERG responses before treatment. All these parameters, except the a-wave amplitude in the DA response, were improved at 2 months and returned to the normal level at 12 months. CONCLUSION: Our findings show that ffERG is a more sensitive method to detect improvement of visual function in VKH following treatment when compared to corrected distance visual acuity and the various imaging techniques to detect structural abnormalities in VKH. (C) 2018 Elsevier Inc. All rights reserved.

BackgroundProtein 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.MethodsA 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.ResultsThe 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-1β or IL-6 production by stimulated PBMCs between the different genotype groups.ConclusionsThis 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.