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UNASSIGNED: Non-infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet\'s disease (BD) and Vogt-Koyanagi-Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD can show similar clinical manifestations, but the underlying immunopathogenesis remains unclear.
UNASSIGNED: To understand immune landscapes in inflammatory eye tissues, we performed single-cell RNA paired with T cell receptor (TCR) sequencing of immune cell infiltrates in aqueous humour from six patients with BD (N = 3) and VKHD (N = 3) uveitis patients.
UNASSIGNED: Although T cells strongly infiltrated in both types of autoimmune uveitis, myeloid cells only significantly presented in BD uveitis but not in VKHD uveitis. Conversely, VKHD uveitis but not BD uveitis showed an overwhelming dominance by CD4+ T cells (> 80%) within the T cell population due to expansion of CD4+ T cell clusters with effector memory (Tem) phenotypes. Correspondingly, VKHD uveitis demonstrated a selective expansion of CD4+ T cell clones which were enriched in pro-inflammatory Granzyme H+ CD4+ Tem cluster and showed TCR and Th1 pathway activation. In contrast, BD uveitis showed a preferential expansion of CD8+ T cell clones in pro-inflammatory Granzyme H+ CD8+ Tem cluster, and pathway activation for cytoskeleton remodelling, cellular adhesion and cytotoxicity.
UNASSIGNED: Single-cell analyses of ocular tissues reveal distinct landscapes of immune cell infiltration and T-cell clonal expansions between VKHD and BD uveitis. Preferential involvements of pro-inflammatory CD4+ Th1 cells in VKHD and cytotoxic CD8+ T cells in BD suggest a difference in disease immunopathogenesis and can guide precision disease management.

Uveitis is the most common form of ocular lesions in Behcet\'s disease, severely affecting visual function. Molecular pathological changes of ocular lesions in patients with Behcet\'s uveitis (BU) are largely unknown. In this study, we performed the first comprehensive transcriptomic profiling of iris specimens from BU patients and healthy donors to provide an insight into intraocular immunopathogenesis. The mRNA sequencing identified 1633 differentially expressed genes (DEGs) between the BU group and healthy controls. GO functional enrichment analysis on DEGs showed that T cell activation was the most significantly enriched biological process. KEGG analysis of DEGs also revealed several prominently enriched T cell-related pathways, including the T cell receptor signaling pathway, Th17 cell differentiation, and Th1 and Th2 cell differentiation. The lymphocyte-specific protein tyrosine kinase (LCK) was identified as the key hub gene in the protein interaction network of DEGs. Western blot analysis further showed increased expression of active LCK in the BU group, suggesting activation of LCK signaling. Using publicly accessible single-cell RNA-sequencing data of the healthy iris, LCK was found to be expressed in clusters of activated T cells but not in other iris cell clusters, suggesting an overt association between LCK upregulation and T cell-mediated immune dysregulation. Additionally, 16 drugs were predicted to be potential inhibitors of LCK. Overall, these findings not only highlighted the central role of T cell-mediated immunity and previously unreported LCK signaling in intraocular immunopathogenesis but also revealed the potential value of LCK as a new therapeutic target for BU patients.

The present study was designed to explore the interrelationship between single nucleotide polymorphisms (SNP) of the tumor necrosis factor superfamily (TNFSF) and its respective receptor superfamily (TNFRSF) genes and Behcet\'s disease (BD) and Vogt-Koyanagi-Harada syndrome (VKH) in Han Chinese. The study sample included 796 patients with BD, 792 patients with VKH syndrome, and 1604 healthy controls. The genotyping of 35 SNPs was performed by MassARRAY platform (Sequenom), iPLEX Gold Assay, PCR-restriction fragment length polymorphism assay and TaqMan SNP assay. The mRNA expression levels of TNFSF4, TNFSF8 and TNFSF15 were analyzed by real-time PCR. The IL-6 and TNF-α expression levels were measured by ELISA. The A allele and AA genotype frequencies of TNFSF4/rs1234313 were significantly increased, and the GG genotype frequency of rs1234313 was decreased in subjects with BD. Significantly lower frequencies of the C allele and the CC genotype and higher frequencies of the TT and CT genotypes of TNFSF15/rs4246905 were observed in BD patients. A decreased frequency of the A allele of TNFSF8/rs7028891 was observed in BD patients. The expression of TNFSF15 in CT carriers was significantly higher than that in CC/TT individuals. Increased IL-6 expression and TNF-α production were found in the TNFSF15 CT carriers compared with the CC/TT genotype carriers. No significant differences were observed between the VKH patients and controls. This study indicates that TNFSF4, TNFSF15 and TNFSF8 may participate in the susceptibility to BD among Han Chinese.

Previous studies have identified that disturbed apoptosis was involved in the pathogenesis of Behçet disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome. This study aims to investigate whether copy number variations of apoptosis-related genes, including FAS, CASPASE8, CASPASE3, and BCL2, are associated with BD and VKH syndrome in Han Chinese. A two-stage association study was performed in 1,014 BD patients, 1,051 VKH syndrome patients, and 2,076 healthy controls. TaqMan(®) Copy Number Assays and real-time PCR were performed. The first-stage study showed that increased frequency of high FAS copy number (>2) was found in BD (P = 1.05 × 10(-3) ) and VKH syndrome (P = 2.56 × 10(-3) ). Replication and combined study confirmed the association of high copy number (>2) of FAS with BD (P = 3.35 × 10(-8) ) and VKH syndrome (P = 9.77 × 10(-8) ). A significant upregulated mRNA expression of FAS was observed in anti-CD3/CD28 antibodies-stimulated CD4(+) T cells from individuals carrying a high gene copy number (>2) as compared to normal diploid 2 copy number carriers (P = 0.004). Moreover, the mRNA expression of FAS both in active patients with BD and VKH syndrome was significantly higher than that in controls (P = 0.001 and P = 0.007, respectively). Our findings suggest that a high copy number of FAS gene confers risk for BD and VKH syndrome.