Clinical and Transcriptional Profiles Reveal the Treatment Effect of Adalimumab in Patients with Initial-Onset and Recurrent Vogt-Koyanagi-Harada Disease.

PURPOSE: We aimed to evaluate adalimumab efficacy in patients with initial-onset or recurrent Vogt-Koyanagi-Harada (VKH) syndrome. METHODS: A retrospective clinical study was performed to examine the therapeutic effect of adalimumab in 22 VKH patients,16 with initial-onset and six with recurrent VKH. Another 22 patients with initial-onset VKH who did not receive adalimumab were included as controls. The main observational parameters included the central macular thickness (CMT), subfoveal choroidal thickness (SCT), best-corrected visual acuity (BCVA), anterior chamber cell grade (ACC), glucocorticoid dose (GCD), and the development of sunset glow fundus. MRNA sequencing was used to profile the tumor necrosis factor (TNF)-α pathway in peripheral blood mononuclear cells obtained from nine patients with initial-onset VKH disease, six patients with recurrent VKH, and eight healthy controls. RESULTS: In the initial-onset group, adalimumab therapy significantly improved the BCVA, CMT, SCT, and ACC. Furthermore, adalimumab significantly decreased GCD in patients with initial-onset. In patients with recurrent VKH, the SCT significantly improved after adalimumab treatment, but no significant changes in BCVA, CMT, and ACC were observed. All six patients experienced relapse during follow-up. The TNF-α pathway exhibited a significant increase in initial-onset VKH when compared with that in both healthy controls and recurrent patients. Conversely, it was suppressed in recurrent VKH when compared with that in the initial-onset or healthy control groups. CONCLUSIONS: In patients with initial-onset VKH, adalimumab effectively reduces glucocorticoid dependence. However, adalimumab may not be effective for preventing relapse or providing long-term inflammation relief in patients with recurrent VKH.

New-onset or relapse of uveitis after rapid spreading of COVID-19 infection in China and risk factor analysis for relapse.

BACKGROUND: The aim of this study was to report the clinical profile of new-onset and relapse of uveitis following rapid spreading of coronavirus disease 2019 (COVID-19) infection due to change of anti-COVID-19 policies in China and investigate potential risk factors for inflammation relapse. METHODS: In this retrospective case-control study, patients with new-onset or a history of uveitis between December 23, 2022, and February 28, 2023, were included to assess the influence of COVID-19 infection on uveitis. Detailed information on demographic data, clinical characteristics, treatment measures, treatment response, and ocular inflammatory status before and after COVID-19 infection was collected. RESULTS: This study included 349 patients with a history of uveitis. The uveitis relapse rate was higher (28.8%, n = 288) in those with COVID-19 infection than in patients without COVID-19 infection (14.8%, n = 61) (P = 0.024). Among the relapse cases, 50.8% experienced a relapse of anterior uveitis, while 49.2% had a relapse of uveitis involving the posterior segment. Multivariable regression analysis indicated a positive correlation between disease duration and uveitis relapse, while the last relapse exceeding one year before COVID-19 infection and the use of methotrexate during COVID-19 infection were negatively correlated with relapse of uveitis. Thirteen patients who developed new-onset uveitis following COVID-19 infection were included; among them, three (23.1%) had anterior uveitis and 10 (76.9%) had uveitis affecting the posterior segment. Regarding cases involving the posterior segment, four patients (30.8%) were diagnosed with Vogt-Koyanagi-Harada disease. CONCLUSIONS: COVID-19 infection increases the rate of uveitis relapse. Long disease duration is a risk factor, while time since the last relapse more than 1 year and methotrexate use are protective factors against uveitis relapse.

Plasma-Derived Small Extracellular Vesicles From VKH Patients Suppress T Cell Proliferation Via MicroRNA-410-3p Modulation of CXCL5 Axis.

Purpose: Circulating exosomes regulate immune responses and induce immune tolerance in immune-mediated diseases. This study aimed to investigate the role of circulating small extracellular vesicles (sEVs) derived from patients with Vogt-Koyanagi-Harada (VKH) syndrome, in T-cell responses. Methods: The sEVs were isolated from the plasma of healthy controls, patients with VKH, and other uveitis patients. The effects of autologous and allogeneic sEVs on the proliferation of circulating CD4+ T cells were evaluated. Microarray analysis of sEVs was performed to determine their differential miRNA expression profiles. The target genes of the candidate miRNA were predicted and verified. The role of both the candidate miRNA and target genes in T-cell proliferation was tested. Results: Plasma-derived sEVs from patients with VKH inhibited the proliferation of autologous CD4+ T cells. Among all the miRNAs that might be associated with inflammatory activity, we found that miR-410-3p had the largest number of T-cell proliferation target genes. MiR-410-3p mimics inhibited the proliferation of Jurkat cells and CD4+ T cells. C-X-C motif chemokine ligand 5 (CXCL5) was confirmed to be a potential target gene of miR-410-3p, and siRNA-mediated CXCL5 knockdown inhibited cell proliferation. Conclusions: Circulating sEVs exert an inhibitory effect on autologous CD4+ T cells mediated by miR-410-3p by targeting CXCL5, supporting the possibility of using autogenic sEVs to inhibit ocular inflammation.

Different MicroRNA profiles in Peripheral Blood mononuclear cells from patients with initial-onset and recurrent vogt-Koyanagi-Harada Disease.

BACKGROUND: Vogt-Koyanagi-Harada (VKH) disease is a common type of uveitis that leads to blindness. The clinical manifestations and treatment solutions are different between initial-onset and recurrent VKH. Therefore, identifying the microRNA (miRNA) profiles from initial-onset and recurrent VKH patients may shed light on the molecular mechanisms underlying the pathogenesis of VKH disease. METHODS AND RESULTS: RNAs isolated from peripheral blood mononuclear cells (PBMCs) from patients with initial-onset VKH, recurrent VKH, and healthy individuals were subjected to high-throughput miRNA sequencing. Pairwise analysis of miRNA sequencing data between groups was conducted to identify differentially expressed miRNAs (DEMs), which were verified using real-time quantitative polymerase chain reaction. After receiver operating characteristic analyses, we found that hsa-miR-4664-3p, hsa-miR-7704, hsa-miR-4504, and hsa-miR-206 may serve as biomarkers of different VKH stages. DEMs were classified into three groups based on their differential expression: DEMs in initial-onset stage, DEMs in recurrent stage, and DEMs common between both VKH stages (shared DEMs). Pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes identified the mitogen-activated protein kinase, tumor necrosis factor, and mechanistic target of rapamycin kinase pathways as significantly enriched among the target genes of recurrent stage and shared DEMs. Furthermore, we mapped a network of competing endogenous RNAs for hsa-miR-206, which we used to identify putative targets for VKH treatment. CONCLUSION: Hsa-miR-4664-3p, hsa-miR-7704, hsa-miR-4504, and hsa-miR-206 may serve as biomarkers for different stages of VKH. Additionally, our competing endogenous RNA network of hsa-miR-206 provides a new direction for VKH treatment.

Overexpressing Kallistatin Aggravates Experimental Autoimmune Uveitis Through Promoting Th17 Differentiation.

Kallistatin or kallikrein-binding protein (KBP) has been reported to regulate angiogenesis, inflammation and tumor progression. Autoimmune uveitis is a common, sight-threatening inflammatory intraocular disease. However, the roles of kallistatin in autoimmunity and autoreactive T cells are poorly investigated. Compared to non-uveitis controls, we found that plasma levels of kallistatin were significantly upregulated in patients with Vogt-Koyanagi-Harada (VKH) disease, one of the non-infectious uveitis. Using an experimental autoimmune uveitis (EAU) model induced by human interphotoreceptor retinoid-binding protein peptide 651-670 (hIRBP651-670), we examined the effects of kallistatin on the pathogenesis of autoimmune diseases. Compared to wild type (WT) mice, kallistatin transgenic (KS) mice developed severe uveitis with dominant Th17 infiltrates in the eye. In addition, the proliferative antigen-specific T cells isolated from KS EAU mice produced increased levels of IL-17A, but not IFN-γ or IL-10 cytokines. Moreover, splenic CD4+ T cells from naïve KS mice expressed higher levels of Il17a mRNA compared to WT naïve mice. Under Th17 polarization conditions, KS mice exhibited enhanced differentiation of naïve CD4+ T cells into Th17 cells compared to WT controls. Together, our results indicate that kallistatin promotes Th17 differentiation and is a key regulator of aggravating autoinflammation in EAU. Targeting kallistatin might be a potential to treat autoimmune disease.

Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis.

Increasing evidence has suggested that T helper 17 (Th17) cells play a central role in the pathogenesis of ocular immune disease. The association between pathogenic Th17 cells and the development of uveitis has been confirmed in experimental and clinical studies. Several cytokines affect the initiation and stabilization of the differentiation of Th17 cells. Therefore, understanding the mechanism of related cytokines in the differentiation of Th17 cells is important for exploring the pathogenesis and the potential therapeutic targets of uveitis. This article briefly describes the structures, mechanisms, and targeted drugs of cytokines-including interleukin (IL)-6, transforming growth factor-ß1 (TGF-ß1), IL-1ß, IL-23, IL-27, IL-35, IL-2, IL-4, IL-21, and interferon (IFN)-γ-which have an important influence on the differentiation of Th17 cells and discusses their potential as therapeutic targets for treating autoimmune uveitis.

Lipoxin A4 promotes autophagy and inhibits overactivation of macrophage inflammasome activity induced by Pg LPS.

OBJECTIVE: To explore the role of lipoxin A4 (LXA4) on inflammasome and inflammatory activity in macrophages activated by Porphyromonas gingivalis lipopolysaccharide (PgLPS) one of the major causative agents of chronic periodontitis. METHODS: The mouse macrophage cell line RAW264.7 was used to produce an activated inflammation model. Markers of inflammasome and inflammatory activity and autophagy were assessed by ELISA, reverse transcription polymerase chain reaction (RT-PCR), and Western blot assay. RESULTS: Markers of inflammasome activity, inflammation and autophagy increased with Pg LPS concentration. They also increased with increasing exposure to Pg LPS up to 12h but decreased at 24h. However, markers of autophagy increased. Phosphorylated NF-κBp65 decreased with LXA4, which was similar to results obtained with the autophagy inducer, rapamycin. CONCLUSIONS: LXA4 promoted autophagy and inhibited activation of inflammasomes and inflammation markers in macrophage inflammation induced by PgLPS and this action was linked to the phosphorylation of NF-κB.