Pathogenesis Of Vogt-Koyanagi-Harada Disease Research Articles

Bibliometric analysis of the Vogt‒Koyanagi‒Harada disease literature

PurposeAs an autoimmune disease, Vogt‒Koyanagi‒Harada disease (VKHD) is a main type of uveitis in many countries and regions, significantly impacting patient vision. At present, information regarding VKHD is still limited, and further research is needed. We conducted a bibliometric analysis to characterize the overall status, current trends, and current focus of VKHD research.MethodLiterature published from 1975 to 2022 was obtained from the Web of Science core collection and analysed with the R-language packages Bibliometrix, VOSviewer, and CiteSpace software.ResultsA total of 1050 papers on VKHD were retrieved from 261 journals, and 16,084 references were obtained from the papers in the original search. The average annual number of published articles was approximately 21.9, and the number of publications rapidly increased after 2004. The journal Ocular Immunology and Inflammation published the most papers on VKHD, while the American Journal of Ophthalmology has the highest citation frequency. The leading countries were Japan, China (PRC), and the United States of America (USA). Yang PZ from Chongqing Medical University was the most prolific and cited author. The most frequently cited study discussed revision of VKHD diagnostic criteria. An analysis of the highest frequency keywords showed that most research focused on the treatment, diagnosis, and pathogenesis of VKHD and its relationship with other related diseases. At present, the most urgent research direction is in the relationship between COVID-19 or COVID-19 vaccines and VKHD and the corresponding mechanisms underlying it.ConclusionUtilizing dynamic and visualization tools, bibliometrics provides a clear depiction of the research history, development trends, and research hotspots in VKHD It serves as a valuable tool for identifying research gaps and areas that necessitate further exploration. Our study revealed potential directions for future VKHD research, including investigating specific molecular mechanisms underlying the disease, exploring the clinical utility of optical coherence tomography angiography and other diagnostic techniques, and conducting clinical research on novel therapeutic drugs.

IPSC-based model of Vogt-Koyanagi-Harada disease for phenotype recapitulation and drug screening

Vogt-Koyanagi-Harada (VKH) disease, a major blinding eye disease, is characterized by an autoimmune response against melanocytes in multiple organs throughout the body. Currently, the aetiology and pathogenesis of VKH disease are unclear, and the treatment strategy needs to be further optimized. The retinal pigment epithelium (RPE), a monolayer of pigmented cells of the fundus, is essential for maintaining normal visual function and is involved in both the acute and chronic stages of VKH disease. Therefore, the functions of the RPE may play a critical role in the aetiology and treatment of VKH disease. Herein, we established a human induced pluripotent stem cell (hiPSC) RPE model of VKH disease by reprogramming peripheral blood mononuclear cells (PBMCs) into iPSCs and then differentiating them into RPE cells. Patient-derived RPE cells exhibited barrier disruption, impaired phagocytosis, and depigmentation compared with those from normal controls, which was consistent with the features of VKH disease. Furthermore, a small molecular compound targeting EGR2 was found to rescue the barrier and phagocytic functions of the hiPSC-RPE cells through high-throughput virtual screening and functional studies, suggesting a promising strategy for the treatment of VKH disease.

Analyses of circRNA and mRNA Profiles in Vogt-Koyanagi-Harada Disease.

Recent studies revealed that circular RNAs (circRNAs) are important in numerous biological process and involved in autoimmune diseases. However, their role in Vogt–Koyanagi–Harada (VKH) disease, a classical autoimmune disease, is not yet known. This research aimed to study the expression profile of mRNAs, microRNAs (miRNAs) and circRNAs and investigate the influence of circRNAs on the pathogenesis of VKH disease. We identified circRNAs, miRNAs, and mRNAs expression profiles in CD4+ T cells between 4 VKH patients and 3 healthy controls using the whole-transcriptome sequencing (RNA-seq) technique. We discovered that a total of 5088 mRNAs, 451 circRNAs and 433 miRNAs were differently expressed. The GO and KEGG pathway enrichment analyses were performed for significantly differentially expressed circRNAs and mRNAs. GSEA was conducted for all mRNAs. The functional enrichment suggested that the inflammatory response, the adaptive immune response, NF-kappa B signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation and T cell receptor signaling pathway were associated with VKH disease. In addition, based on the immune-related genes we screened, the circRNA-miRNA-mRNA ceRNA network was analyzed and constructed. Ten differently expressed mRNAs (LAT, ZAP70, ITK, ICOS, RASGRP1, PAG1, PLCG1, PRKCQ, LCK, CARD11) and 5 differently expressed circRNAs (hsa_circ_0033144, hsa_circ_0000233, hsa_circ_0000396, hsa_circ_0001924, hsa_circ_0001320) were selected to be validated by Real-time qPCR (RT-qPCR). The results of RT-qPCR turned out to be consistent with RNA-seq data. Further analysis showed that hsa_circ_0001320 and hsa_circ_0001924 may serve as crucial candidate marker genes of VKH disease. These results reveal that circRNAs may have a crucial immunomodulatory function in the pathophysiological process of VKH disease.

Increased Expression of Indoleamine 2,3-Dioxygenase (IDO) in Vogt-Koyanagi-Harada (VKH) Disease May Lead to a Shift of T Cell Responses Toward a Treg Population.

Previous studies have pointed out that indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme initiating tryptophan metabolism, plays a role in the regulation of the immune system. This project was designed to investigate the potential role of IDO in monocyte-derived dendritic cells (moDCs) obtained from active Vogt-Koyanagi-Harada (VKH) disease patients. In this study, we found that the IDO mRNA expression and enzyme activity were increased in active VKH patients as compared with healthy controls and patients in remission. To investigate the role of IDO in immune regulation, an effective inhibitor 1-methyl-L-tryptophan (1-MT) was used to suppress its activity in DCs. The results showed that inhibition of IDO with 1-MT significantly decreased the expression of DC marker CD86. IDO inhibition did not affect the cytokine production of IL-6, IL-1β, TNF-α, IL-10, and TGF-β in DCs. Downregulation of IDO in DCs also led to the reduction of regulatory T (Treg) cells and an increased CD4+ T cell proliferation. Treatment with 1-MT did not affect the phosphorylation of the MAPK pathway in DCs. In general, our study suggests that IDO may play an important role in the pathogenesis of VKH disease by regulating DC and CD4+ T cell function. Tryptophan deficiency and kynurenine accumulation may account for the complicated effects of IDO. Further research is needed to study the precise tryptophan metabolites that may limit immune responses in VKH disease.

Integrated omics analysis of sweat reveals an aberrant amino acid metabolism pathway in Vogt-Koyanagi-Harada disease.

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 (30VKH patients and 30normal 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 716proteins and 175metabolites. Among them, 116proteins (99decreased and 17increased) 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.

Decreased Expression of TGR5 in Vogt-Koyanagi-Harada (VKH) Disease

ABSTRACTPurpose: To investigate the role of G-protein-coupled bile acid receptor-1, Gpbar1 (TGR5) in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease.Methods: The mRNA level of TGR5, iNOS, Arg1, CD16, and CD206 in macrophages was assayed by real-time PCR. ELISA was used to detect the production of cytokines in cell culture supernatants. The frequencies of CD4+IFN-γ+ and CD4+ IL-17+ T cells were tested by flow cytometry.Results: A decreased expression of TGR5 in M1 macrophages was observed in active VKH patients as compared with normal controls. TGR5 stimulation of M1 macrophages with INT-777 caused a shift of the inflammatory M1 toward the anti-inflammatory M2 macrophage subtype. TGR5 activation of macrophages co-cultured with CD4+ T cells inhibited Th1 and Th17 polarization, as well as the release of IFN-γ and IL-17 in the culture supernatant.Conclusion: Our results show that a decreased TGR5 expression might contribute to the pathogenesis of VKH disease.

Decreased interleukin(IL)-35 Expression is Associated with Active Intraocular Inflammation in Vogt-Koyanagi-Harada (VKH) Disease

ABSTRACTPurpose: Recent studies have reported that IL-35 has a protective effect in autoimmune disease. In this study, we explored the role of IL-35 in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease.Methods: The IL-35/EBI3 and IL-35/P35 mRNA level was assayed by Real-Time PCR. The level of IL-35 in serum was detected by ELISA. PBMCs and monocyte-derived DCs were cultured with or without IL-35 and the concentration of IL-17, IL-10, IFN-γ, IL-6, TNF-α, and IL-1β in supernatants was tested by ELISA.Results: The serum level of IL-35 is reduced in active VKH patients. The mRNA expression of the two subunits IL-35/EBI3 and IL-35/P35 in PBMCs from patients with active VKH was also decreased. IL-35 significantly inhibited IFN-γ and IL-17 expression and induced IL-10 production by PBMCs and inhibited IL-6 production by monocyte-derived DCs.Conclusion: The current study suggests that a decreased IL-35 expression may be involved in the pathogenesis of VKH disease.

TLR3 and TLR4 But not TLR2 are Involved in Vogt-Koyanagi- Harada Disease by Triggering Proinflammatory Cytokines Production Through Promoting the Production of Mitochondrial Reactive Oxygen Species.

Vogt-Koyanagi-Harada (VKH) disease is considered to be an autoimmune disease possibly triggered by an abnormal response to infection. Activation of TLRs signaling pathways by microbial products can drive inflammatory responses and adaptive immunity. In the present study, we investigated the role of TLRs in the pathogenesis of VKH disease. We showed that the expression of TLR3 and TLR4, but not TLR2, was significantly increased in monocyte-derived macrophages (MDMs) from VKH patients with active uveitis compared to controls. VKH patients with active uveitis showed an elevated level of IL-1β, IL-6, IL-8, TNF-α and reactive oxygen species (ROS) in MDMs. IL-1β, IL-6, IL-8 and TNF-α production could be significantly upregulated and downregulated by a ROS activator or inhibitor, respectively. Downregulation of the NLRP3 inflammasome significantly inhibited the production of IL-1β but not IL-6, IL-8 and TNF-α. The phosphorylation levels of p38 and ERK1/2 were significantly higher in MDMs from active VKH patients compared to controls. Inhibition of p38 or ERK1/2 significantly decreased IL-1β, IL-6, IL-8 and TNF-α expression. These results suggest that the increased expression of TLR3/4 in MDMs may be involved in the pathogenesis of VKH disease by the induction of inflammatory cytokines which is mediated by enhanced production of ROS.

Increased IL-7 Expression in Vogt-Koyanagi-Harada Disease

IL-7/IL-7R has been found to be involved in the pathogenesis of several autoimmune diseases. This study was designed to investigate the potential role of IL-7/IL-7R in the pathogenesis of Vogt Koyanagi-Harada (VKH), an organ-specific autoimmune disease. IL-7 was measured with an enzyme-linked immunosorbent assay (ELISA) in serum obtained from patients with active or inactive VKH and from healthy individuals. The expression of IL-7R was measured by flow cytometry (FCM). Cell proliferation was determined after exposure of peripheral blood mononuclear cells (PBMCs) and CD4(+) T cells to recombinant IL-7. The levels of IL-17 and IFN-γ levels were detected by ELISA after these cells were cocultured with recombinant IL-7. The influence of recombinant IL-7 on the expansion of Th1 and Th17 cells was evaluated by using FCM. IL-7 was significantly increased in the serum of patients with active VKH compared with those with inactive VKH (P < 0.001) and normal controls (P < 0.001). However, there was no difference between VKH patients and normal controls in the expression of IL-7Rα on CD4(+) T cells. Recombinant IL-7 induced significant cell proliferation and secretion of IL-17 and IFN-γ by PBMCs and CD4(+) T cells. It furthermore promoted the expansion of both Th1 and Th17 cells. The findings suggest that IL-7 is involved in the pathogenesis of VKH disease.

Vogt-Koyanagi-Harada disease occurring during pegylated interferon-α2b and ribavirin combination therapy for chronic hepatitis C

Vogt-Koyanagi-Harada (VKH) disease is a multisystem syndrome characterized by ocular (uveitis and retinal detachment), neurological (headache, tinnitus, and meningitis), and integumentary (vitiligo, alopecia, and poliosis) involvement. Although the pathogenesis of VKH disease is not well understood, an autoimmune T-cell response to a melanocyte-associated antigen is considered to be a cause of VKH disease. The complex immunological response to interferon and ribavirin may induce or exacerbate the autoimmune condition; however, VKH disease is a very rare complication associated with interferon therapy in chronic hepatitis C. We report a case of VKH disease occurring during pegylated interferon-α2b and ribavirin combination therapy for chronic hepatitis C.

Ocular and Systemic Autoimmunity after Successful Tumor-Infiltrating Lymphocyte Immunotherapy for Recurrent, Metastatic Melanoma

To describe the ophthalmic and systemic autoimmune findings after successful adoptive cell transfer of ex vivo expanded, autologous tumor-reactive tumor-infiltrating lymphocytes (TIL) for metastatic melanoma. Retrospective, interventional case report. A 35-year-old man who underwent immunotherapy for metastatic melanoma with adoptive cell transfer of tumor-reactive TIL. A 35-year-old man with metastatic melanoma was treated with TIL plus interleukin-2 (IL-2) therapy after a lymphodepleting regimen of cyclophosphamide and fludarabine for metastatic melanoma, which led to a complete and durable remission. Bilateral panuveitis, hearing loss, vitiligo, poliosis, and alopecia developed in the patient, requiring local ophthalmic immunosuppressive therapy. The clinical course, diagnostic testing, and therapeutic interventions over a 2-year period are reviewed. Visual acuity, anterior chamber and vitreous inflammation, optical coherence tomography findings, serial electro-oculograms (EOGs), microperimetry (MP-1) testing, flow cytometric analysis of cells derived from the aqueous humor, and aqueous humor cytokine profiles were evaluated. After melanoma immunotherapy, complete tumor regression was achieved at 5 months after treatment with a durable, ongoing, complete remission at 24 months. Early in the treatment course, a high fever, a diffuse rash, hearing loss, and bilateral anterior uveitis developed acutely in the patient. Late autoimmune sequelae included the development of alopecia, vitiligo, poliosis, and bilateral panuveitis with diffuse retinal pigment epithelium (RPE) hypopigmentation, reminiscent of Vogt-Koyanagi-Harada (VKH) syndrome. Bilateral cystoid macular edema also developed that was responsive to acetazolamide. Serial EOGs showed alterations in RPE standing potentials in dark conditions, and MP-1 testing revealed diminished foveal and perifoveal sensitivity. An aqueous humor aspirate revealed a high concentration of melanoma tumor antigen-reactive T cells compared with that of peripheral blood samples, as well as a proinflammatory aqueous cytokine profile. At the time of cataract surgery 22 months after immunotherapy, a repeat aqueous humor sample showed the disappearance of the previously seen melanoma differentiation antigen-reactive lymphocytes, but the proinflammatory cytokine profile persisted. Ocular and systemic autoimmune sequelae resembling VKH may develop after successful melanoma immunotherapy. This report provides insight into the pathogenesis of VKH disease. The patient's clinical course illustrates the fine balance between tumor-specific immunity and loss of self-tolerance. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Update on uveomeningoencephalitides

Uveomeningoencephalitides, commonly known as Vogt-Koyanagi-Harada (VKH) disease, are characterized by chronic bilateral granulomatous panuveitis involving the central nervous, auditory and integumentary systems. Visual prognosis is generally favourable, but outcomes in patients with VKH disease may vary. Also, the treatment of choice differs in different parts of the world. This review addresses the literature on the possible pathogenesis, diagnosis and treatment of this disorder. Atypical presentations of VKH disease, as well as those associated with interferon-alpha therapy, have been reported. Most reports suggest an association with autoimmunity. The diagnostic criteria were revised by the International Workshop on VKH in 1999, allowing for the presence of different ocular findings in the early and late stages of the disease. New techniques have also been developed to aid in the rapid diagnosis of VKH disease and evaluation of treatment. Different routes of administration of corticosteroid and adjuvant therapy were tried, with positive results. Although the pathogenesis of VKH disease is uncertain and antigen-specific treatment strategies have not yet been developed, reports increasingly suggest an autoimmune nature for uveomeningoencephalitides. Currently, systemic corticosteroid therapy remains the standard initial treatment. Different routes of administration are used to reduce the frequency of side effects of systemic corticosteroids, and there are various adjuvant therapies. With the aid of modern equipment, early diagnosis and prompt and appropriate treatment, resulting in better visual outcomes, can be anticipated. A large-scale, multinational, prospective study is warranted to determine the optimal initial therapy.

Helper T-cell subsets in uveitis.

Helper T-cell subsets in uveitis.