Increased serum level of interleukin-33 in Vogt-Koyanagi-Harada correlates with disease activity.

OBJECTIVES: To measure the serum level of IL-33 in patients with Vogt-Koyanagi-Harada disease (VKH) and Behçet's uveitis (BU) in the Chinese Han population and investigate its associations with disease activity and clinical parameters. METHODS: Serum was collected from 41 VKH patients (16 active and 25 inactive patients), 60 BU patients (24 active and 36 inactive patients), and 36 healthy controls. The serum level of IL-33 was measured using the enzyme-linked immunosorbent assay (ELISA) method. Demographic features, clinical manifestations, and intraocular inflammation activity scores (anterior chamber cells score, anterior chamber flare score, and vitreal haze score) were recorded. RESULTS: The serum level of IL-33 significantly increased in all VKH patients, active VKH patients, and inactive VKH patients, as compared to healthy controls (p < 0.001, p < 0.001, and p = 0.002, respectively), and was higher in the active VKH than in the inactive VKH patients (p = 0.049). The serum level of IL-33 positively correlated with the anterior chamber cells score, vitreal haze score, and the annualized number of relapses in VKH patients (Rho = 0.359, p = 0.021; Rho = 0.344, p = 0.028; Rho = 0.537, p < 0.001, respectively). Serum IL-33 level was significantly associated with the annualized number of relapses in patients with BU (Rho = 0.361, p = 0.005). CONCLUSION: Serum IL-33 level is significantly increased in VKH patients in the Chinese Han population. IL-33 level is in positive correlation with the activity and relapses of VKH. Increased IL-33 might contribute to the pathogenesis of VKH and serve as a potential biomarker for VKH disease.

Identification of Ribosomal Protein S4, Y-Linked 1 as a cyclosporin A plus corticosteroid resistance gene.

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.

Plasma metabolomics study of Vogt-Koyanagi-Harada disease identifies potential diagnostic biomarkers.

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.

Sequence analysis of four vitamin D family genes (VDR, CYP24A1, CYP27B1 and CYP2R1) in Vogt-Koyanagi-Harada (VKH) patients: identification of a potentially pathogenic variant in CYP2R1.

BACKGROUND: VKH is a rare autoimmune disease. Decreased level of vitamin D has recently been found to be involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. This study was designed to screen the vitamin D pathway genes for pathogenic mutations, if any, in VKH patients. METHODS: Genomic DNA was extracted from blood samples collected from patients with VKH disease and healthy controls. Entire coding region, exon-intron junctions of four genes were sequenced in DNA from 39 Saudi VKH patients and 50 ethnically matched healthy individuals. All patients and controls were unrelated. RESULTS: Vitamin D levels in VKH patients were found either insufficient (21-29 ng/mL) or deficient (<20 ng/mL). Sequencing analysis of the VDR, CYP24A1, CYP27B1 and CYP2R1 detected twelve nucleotide changes in these genes in our cohort of 39 patients; 4 of which were non-coding, 6 were synonymous coding and 2 were non-synonymous coding sequence changes. All synonymous coding variants were benign polymorphisms with no apparent clinical significance. A non-synonymous coding sequence variant (c.2 T > C; p.1Met?) found in VDR is an initiation coding change and was detected in control individuals as well, while another variant (c.852G > A; p.284 M > I) found in CYP2R1 is predicted to be disease causing by mutationtaster software. This potentially pathogenic variant was found in 17 out of 39 VKH patients. CONCLUSIONS: Screening of four Vitamin D pathway genes in 39 VKH patients shows that a potentially pathogenic sequence variant in CYP2R1 may cause VKH in a subset of patients. These findings support the previous observation that low vitamin D levels might play a role in VKH pathogenesis and mutations in genes involved in vitamin D anabolism and catabolism might be of importance in VKH pathobiology.

Elevated Serum Immunoglobulin E Levels are Associated with the Severity of Newly Diagnosed, Acute Vogt-Koyanagi-Harada Disease.

OBJECTIVE: To investigate the correlation between serum immunoglobulin E (IgE) levels and severity of Vogt-Koyanagi-Harada (VKH) disease. METHODS: The medical records of patients with VKH disease between 2015 and 2020 were reviewed. Serum immunoglobulins (IgA, IgE, IgG, and IgM), tumor necrosis factor α (TNFα) and C-reactive protein (CRP) were measured. Patients were divided into IgE-positive (IgE ≥ 100 IU/mL) and IgE-negative (IgE < 100 IU/mL) groups. The best-corrected visual acuity (BCVA) and macular morphologic characteristics including foveal thickness (FT), serous retinal detachment (SRD), sensory retinal thickness (SRT), central foveal thickness (CFT), cube volume (V), and cube average thickness (AT) were determined in patients in both groups. RESULTS: Of 128 patients included in the study, 35 (27.34%) patients were IgE-positive, BCVA (logMAR) was worse in the IgE-positive group. The mean CRP (P= .012) and TNFα (P≤ 0.001) levels were greater in the IgE-positive group than in the IgE-negative group. Regarding macular morphologic characteristics, FT (P= .010), SDR (P= .004), CFT (P= .008), V (P= .013), and AT (P= .006) were significantly greater in the IgE-positive group than in the IgE-negative group. CONCLUSIONS: Elevated serum IgE levels were associated with more severe macular changes in patients with VKH disease. These findings suggest that IgE may be involved in the progression of VKH disease.

Progranulin Suppressed Autoimmune Uveitis and Autoimmune Neuroinflammation by Inhibiting Th1/Th17 Cells and Promoting Treg Cells and M2 Macrophages.

BACKGROUND AND OBJECTIVES: Progranulin (PGRN) is an important immune regulatory molecule in several immune-mediated diseases. The objective of this study is to investigate the role of PGRN in uveitis and its counterpart, experimental autoimmune uveitis (EAU), and experimental autoimmune encephalomyelitis (EAE). METHODS: Serum PGRN levels in patients with Behcet disease (BD) or Vogt-Koyanagi-Harada (VKH) disease and normal controls were measured by ELISA. EAE and EAU were induced in B10RIII, wild-type, and PGRN-/- mice to evaluate the effect of PGRN on the development of these 2 immune-mediated disease models. The local and systemic immunologic alterations were detected by ELISA, flow cytometry, and real-time PCR. RNA sequencing was performed to identify the hub genes and key signaling pathway. RESULTS: A significantly decreased PGRN expression was observed in patients with active BD and active VKH. Recombinant PGRN significantly reduced EAU severity in association with a decreased frequency of Th17 and Th1 cells. PGRN-/- mice developed an exacerbated EAU and EAE in association with strikingly increased frequency of Th1 and Th17 cells and reduced frequency of regulatory T (Treg) cells. In vitro studies revealed that rPGRN could inhibit IRBP161-180-specific Th1 and Th17 cell response and promote Treg cell expansion. It promoted non-antigen-specific Treg cell polarization from naive CD4+ T cells in association with increased STAT5 phosphorylation. Using RAN sequencing, we identified 5 shared hub genes including Tnf, Il6, Il1b, Cxcl2, and Ccl2 and the most significantly enriched MAPK and tumor necrosis factor signaling pathway in PGRN-/- EAU mice. The aggravated EAE activity in PGRN-/- mice was associated with a skew from M2 to M1 macrophages. DISCUSSION: Our results collectively reveal an important protective role of PGRN in EAU and EAE. These studies suggest that PGRN could serve as an immunoregulatory target in the study of prevention and treatment for the Th1/Th17-mediated diseases.

Decreased 1,25-Dihydroxyvitamin D3 level is involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease.

PURPOSE: 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] has recently been found to be involved in the development of autoimmune diseases. This study was to investigate the expression and potential role of 1,25(OH)(2)D(3) in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. METHODS: Blood samples were obtained from VKH patients and healthy individuals. Serum 1,25(OH)(2)D(3) levels were measured using ELISA. Peripheral blood mononuclear cells (PBMCs) or cluster of differentiation (CD) 4(+) T cells were cultured with or without 1,25(OH)(2)D(3) in the presence of anti-CD3 and anti-CD28 for the measurement of cell proliferation and cytokines. The cell proliferation was detected using the Cell Counting Kit. The levels of interleukin (IL)-17 and interferon (IFN)-γ levels in the supernatants of PBMCs or CD4(+) T cells were detected by ELISA. RESULTS: 1,25(OH)(2)D(3) was significantly decreased in the serum of active VKH patients as compared with inactive VKH patients and controls. It significantly inhibited PBMCs proliferation and CD4(+) T cell proliferation. It was also able to significantly inhibit the production of IL-17 and IFN-γ by both PBMCs and CD4(+) T cells from VKH patients and controls. CONCLUSIONS: These findings suggest that decreased expression of 1,25(OH)(2)D(3) may be involved in the development of VKH disease. 1,25(OH)(2)D(3) may be potentially used in the treatment of this disease.

Proteomics Profiling of Plasma Exosomes in VKH Patients.

OBJECTIVES: Vogt-Koyanagi-Harada syndrome is common autoimmune uveitis that can cause blindness. Recent studies have shown that plasma exosomes carry disease-related proteins that may serve as biomarkers. Here, we aimed to find candidate biomarkers of Vogt-Koyanagi-Harada disease using proteomic analysis of plasma exosomes. METHODS: Exosomes were isolated from the plasma of normal controls and Vogt- Koyanagi-Harada patients in the following groups: a) initial inflammatory attack (active stage), b) remission after one month of treatment (unstable stage), and c) stationary phase after three months of treatment (stable stage). Groups were analyzed by mass spectrometry using isobaric tags for relative and absolute quantitation. After functional analysis, proteins of interest were verified by ELISA. RESULTS: 463 proteins were identified in the exosomes. Forty-three were upregulated at the active inflammation stage, including inflammation-associated proteins. Thirty-one were downregulated. Gene ontology and pathway analyses revealed differential proteins related to cell adhesion, cell phagocytosis, cytoskeleton movement, leukocyte migration across endothelial cells, and platelet activation. By ELISA, Carbonic anhydrase 2 and Ras-related protein Rap-1b were verified as more plentiful at the active stage compared to the normal control and stationary phase in exosomes, but not, however, in microvesicles or plasma. CONCLUSION: Plasma exosomes of Vogt-Koyanagi-Harada patients contain many proteins related to the degree of inflammation. The levels of Carbonic anhydrase 2 and Ras-related protein Rap-1b in exosomes can be used as biomarkers for active inflammation in Vogt-Koyanagi-Harada disease. Further investigation could help study the pathogenesis of Vogt-Koyanagi-Harada disease and identify therapeutic targets.

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.

[Expression of suppressor of cytokine signaling in peripheral blood monocular cells of patients with Vogt-Koyanagi-Harada disease].

OBJECTIVE: To investigate suppressor of cytokine signaling (SOCS) mRNA and protein expression in peripheral blood mononuclear cells (PBMC) of patients with Vogt-Koyanagi-Harada (VKH) disease. METHODS: Blood samples were taken from 15 VKH patients with active uveitis, 17 quiescent patients and 16 healthy individuals. IFN-gamma, IL-12 and IL-4 in the serum were measured by ELISA. PBMC were subjected to analysis of SOCS mRNA and protein expression using quantitative RT-PCR and western blot, respectively. RESULTS: The level of IL-4 in the serum of VKH patients and in controls were (28.40 +/- 5.93) ng/L, (34.5 +/- 9.47) ng/L and (11.25 +/- 4.43) ng/L, IL-12 were (24.33 +/- 8.55) ng/L, (11.53 +/- 6.11) ng/L and (5.19 +/- 2.43) ng/L, IFN-gamma were (18.05 +/- 2.23) ng/L, (15.53 +/- 2.63) ng/L and (1.61 +/- 3.47) ng/L, respectively. The level of IFN-gamma, IL-12 and IL-4 were all significantly higher in the serum of VKH patients than in controls(P < 0.01). IL-4 in quiescent patients was higher than in active patients (P < 0.01), IL-12 and IFN-gamma were lower in quiescent patients was higher than in active patients (P < 0.01, P < 0.05). Cytokine inducible SH2 containing protein (CIS) mRNA, SOCS1 mRNA, SOCS2 mRNA, SOCS3 mRNA and SOCS5 mRNA levels in PBMC of VKH patients with active uveitis are 0.72, 4.92, 1.09, 0.75 and 1.15 folds than that in healthy volunteers, respectively. They are 1.15, 2.25, 1.40, 0.69 and 1.16 folds in static patients, respectively. Marked decreased expression of CIS protein is detected in both active and quiescent patients with no significant difference between two groups (both P < 0.01). SOCS1 protein is up-regulated significantly in active patients compares to in quiescent patients nor in healthy volunteers (P < 0.01, P < 0.05). SOCS3 protein is significantly decreased in patients than in controls (both P < 0.05). SOCS5 protein is much higher in patients than in controls (both P < 0.01), and even higher in quiescent patients than in active episode (P < 0.05). CONCLUSIONS: Up regulation of SOCS1 and SOCS5 expression and down-regulation of SOCS3 and CIS may correlate with the development of a Th1 mediated immune response in VKH disease. There is insidious inflammation in VKH patients with clinically quiescent uveitis, and this may be one of the causes of persistence and recurrences of uveitis.

Glucocorticoid Receptor-α and MKP-1 as Candidate Biomarkers for Treatment Response and Disease Activity in Vogt-Koyanagi-Harada Disease.

PURPOSE: To investigate the potential of utilizing the expression of genes for glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase-1 (MKP-1) as biomarkers of corticosteroid (CS) refractoriness and disease activity in patients with Vogt-Koyanagi-Harada (VKH) disease. DESIGN: Prospective cohort study. METHODS: Twenty VKH patients receiving their first cycle of CS treatment in the absence of additional systemic immunosuppressive therapy and a control group of fifteen healthy volunteers were recruited from the University of Chile (Santiago, Chile) and US National Institutes of Health (Bethesda, United States). Intraocular inflammation was clinically quantified at enrolment and all follow-up visits. CS refractoriness was defined as an ocular reactivation of VKH upon CS withdrawal at a daily oral prednisone dose of 10 mg or more. Quantitative Reverse transcription polymerase chain reaction (qRT-PCR) was performed to measure the mRNA levels of the alpha (α) and beta (ß) isoforms of GR and MKP-1 in peripheral blood mononuclear cells (PBMC) after in vitro stimulation with either anti-CD3/anti-CD28 antibodies, lipopolysaccharide (LPS), or phytohemagglutinin (PHA), in the presence or absence of dexamethasone (Dex). RESULTS: After 6 hours of stimulation in the presence of Dex, PBMC from CS-refractory VKH patients had an impaired elevation in GRα expression (P = .03). Furthermore, inactive patients showed a significant Dex-induced upregulation of MKP-1 (P = .005). CONCLUSIONS: In this pilot study, the expression of GR isoforms and MKP-1 corresponded with patients' clinical response to systemic CS treatment and disease activity, respectively. Hence, these candidate biomarkers have potential clinical utility in the early identification of CS refractoriness and subclinical inflammation in patients with VKH disease.

HLA-DRB1*04:05 in two cases of Vogt-Koyanagi-Harada disease-like uveitis developing from an advanced melanoma patient treated by sequential administration of nivolumab and dabrafenib/trametinib therapy.

Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis. Our cases suggest a possible correlation between VKH-like uveitis as an AE and the clinical outcomes of sequential administration of nivolumab and dabrafenib/trametinib therapy for the treatment of advanced melanoma.

Increased Complement 3a Receptor is Associated with Behcet's disease and Vogt-Koyanagi-Harada disease.

Behcet's disease (BD) and Vogt-Koyanagi-Harada disease (VKH) are systemic and recurrent autoimmune diseases associated with abnormal T cell immune response. Complement 3a receptor (C3aR) and complement 5a receptor (C5aR) have been reported to be involved in T cell mediated autoimmune disease. This study aimed to investigate the role of C3aR and C5aR in these two diseases. The C3aR expression in PBMCs was increased in patients with active BD (aBD) and active VKH (aVKH). No statistical difference was found concerning the expression of C5aR in PBMCs between patients with aBD or aVKH and normal controls. After the intraocular inflammation in BD and VKH patients was controlled, the C3aR expression returned back to normal levels. The serum from patients with aBD and aVKH significantly induced C3aR expression by PBMCs. C3a induced IL-6, IL-1ß and TNF-α secretion, while inhibited the production of IL-10 by monocytes. Activation of C3aR in CD4+T cells could upregulate IL-17 production and inhibit IL-10 production, but had no detectable influence on IFN-γ production. Our data indicates that increased C3aR expression may lead to over activation of the Th17 cell response and may therefore contribute to the pathogenesis of BD and VKH disease.

Elevated serum levels of CXCL9/monokine induced by interferon-gamma and CXCL10/interferon-gamma-inducible protein-10 in ocular sarcoidosis.

PURPOSE: Sarcoidosis is a chronic multisystem granulomatous disorder characterized by an accumulation of activated CD4+ T cells and monocytes/macrophages in involved organs. Chemokines are required for the extravasation of leukocytes to the inflammation site. This study was undertaken to determine which chemokines are augmented in the serum of patients with active ocular sarcoidosis. METHODS: Seventeen patients with diagnosed ocular sarcoidosis, 28 with suspected ocular sarcoidosis, 16 with Behçet's disease, 17 with Vogt-Koyanagi-Harada disease, and 18 healthy subjects were studied. Serum levels of CCL2, CCL5, CXCL8, CXCL9, and CXCL10 were simultaneously measured by cytometric bead array using flow cytometer. In addition, serum CXCL9 and CXCL10 levels in the patients with diagnosed or suspected ocular sarcoidosis were compared with respect to ocular disease activity, the presence of bilateral hilar lymphadenopathy (BHL), and laboratory data. RESULTS: Serum levels of both CXCL9 and CXCL10 were markedly elevated in the patients with diagnosed or suspected ocular sarcoidosis compared with patients with other types of uveitis and healthy subjects. Although CCL2 and CXCL8 were detected in the serum of all subjects, the levels were extremely low with no significant differences between groups. Elevation of serum CXCL9 and CXCL10 in ocular sarcoidosis correlated significantly with ocular disease activity and ACE (angiotensin converting enzyme) levels and was unrelated to the presence of BHL, erythrocyte sedimentation rate, white blood cell count, serum IgG, or serum lysozyme. CONCLUSIONS: The results demonstrated that serum levels of CXCL9 and CXCL10 were elevated markedly in the patients with ocular sarcoidosis and correlated with ocular disease activity and ACE level.

Vogt-Koyanagi-Harada syndrome associated with renal failure: a case report.

Vogt-Koyanagi-Harada (VKH) syndrome is a rare entity characterized by depigmentation of the skin and eye lashes, chronic granulomatous iridocyclitis and exudative retinal detachment, as well as aseptic meningitis and encephalopathy. We describe a 22-year-old male intravenous drug addict, infected with hepatitis B and C virus, suffering from this syndrome, associated with progressive renal sclerosis, malignant hypertension, heart failure and chronic myeloproliferative disorder. The association with these various diseases is discussed and relevant cases are reviewed.

Chemokine profile in the cerebrospinal fluid and serum of Vogt-Koyanagi-Harada disease.

We analyzed the concentrations of four chemokines in the cerebrospinal fluid (CSF) and sera in Vogt-Koyanagi-Harada disease (VKH), an autoimmune uveomeningitis syndrome against melanocyte-associated proteins, with ELISA. CSF-CXCL10/IP-10 and CSF-CCL17/TARC were significantly elevated in VKH than in controls. In the majority of VKH cases and controls, CSF-CXCL10 was higher than serum-CXCL10, and CSF-CCL17 was lower than serum-CCL17. CCL11/Eotaxin was not different between groups. CSF-CCL2/MCP-1 was significantly lower in VKH than in control. The changes in VKH were essentially similar to those in multiple sclerosis, a known Th1-dominant condition.

Decrease in the glyceraldehyde derived advanced glycation end products in the sera of patients with Vogt-Koyanagi-Harada disease.

BACKGROUND/AIMS: Advanced glycation end products (AGEs) are considered to act as mediators of both age related pathologies and diabetic complications. It was recently reported that glyceraldehyde derived AGE (AGE-2) has a strong biological effect on various diseases. The aim of this study was to investigate the serum AGE-2 levels in Vogt-Koyanagi-Harada (VKH) disease. METHODS: Sera were obtained from 31 patients with active VKH. 20 of these 31 patients were treated with systemic corticosteroids. As controls, 33 healthy volunteers were also examined. The serum AGE-2 levels were determined with a competitive enzyme linked immunosorbent assay using AGE-2 polyclonal antibody. RESULTS: The mean AGE-2 level in the sera of patients with VKH disease was 4.91 (SD 2.23) U/ml, which was significantly lower than that of the healthy control subjects (8.32 (2.94), p<0.001). The average serum AGE-2 level significantly increased to 13.49 (2.17) U/ml after the patients were treated with systemic corticosteroids (p<0.001). CONCLUSIONS: These results suggest that AGE-2 may be involved in the onset of VKH disease.

A case of vogt-koyanagi-harada disease associated with malignant lymphoma.

BACKGROUND: Vogt-Koyanagi-Harada disease (VKH), an inflammatory ocular disorder characterized by bilateral granulomatous panuveitis and a variety of extraocular manifestations, has been reported to be associated with various immune disorders but has not been linked to malignant lymphoma (ML). CASE: We present here a case of VKH associated with a recurrence of ML. OBSERVATIONS: A 69-year-old man who initially had ML presented with a history of sudden bilateral visual acuity loss. Funduscopy showed papilloedema and serous retinal detachment in both eyes, and a diagnosis of VKH was reached soon thereafter. Chest X-ray and an abdominal computed tomography scan indicated the metastatic focus of the ML. A recurrence was suspected because the ML-associated soluble interleukin-2 receptor (sIL-2R) in the serum was highly elevated. Treatment successfully resolved both the ML and the VKH. The inflammatory activities of VKH and ML were found to correlate with the serum levels of sIL-2R. CONCLUSIONS: This case suggests an association between sIL-2R levels and disease activity in VKH and ML, and provides additional evidence that VKH can be induced by immune disorders caused by high sIL-2R levels in ML.

Prominent increase of macrophage migration inhibitory factor in the sera of patients with uveitis.

PURPOSE: To investigate pathogenesis underlying endogenous uveitis, macrophage migration inhibitory factor (MIF) was quantified in sera of patients. METHODS: Sera were obtained from the 55 patients with uveitis (24 with Behçet's disease; 9 with Vogt-Koyanagi-Harada's [VKH] disease; 22 with sarcoidosis) and 58 healthy control subjects. MIF levels were determined by a human MIF enzyme-linked immunosorbent assay. RESULTS: The mean MIF levels in the sera of the patients with Behçet's disease, VKH disease, and sarcoidosis and of healthy control subjects were 60.4+/-9.0 (mean+/-SE) ng/ml, 16.5+/-2.9 ng/ml, 27.1+/-5.6 ng/ml, and 5.4+/-0.04 ng/ml, respectively. The average levels of MIF in the sera of uveitis patients were significantly higher (P < 0.0001) than those of healthy control subjects. The high levels of MIF were especially noted in patients with Behçet's disease at the ocular exacerbation stage and patients with sarcoidosis at the severe uveitis stage. CONCLUSIONS: Significant increase of MIF in sera was characteristic of uveitis, and MIF may be a usefull laboratory parameter to use to comprehend the clinical course of uveitis.

Immunologic analysis of cerebrospinal fluid lymphocytes in Vogt-Koyanagi-Harada disease.

In this study, we focused upon the immunologic aspects of Vogt-Koyanagi-Harada disease (VKH) by comparing the cytotoxic activity of peripheral blood leukocytes (PBL) to that of cerebrospinal fluid leukocytes (CSFL) against the human melanoma cell line (P-36) and the human cervical carcinoma cell line (HeLa-S3). The PBL from patients with VKH showed significant cytotoxic activity against P-36 (P less than 0.01), but did not show cytotoxic activity against HeLa-S3. The CSFL showed significantly weaker cytotoxic activity against P-36 compared to that of PBL (P less than 0.02). We also analyzed the cell membrane surface markers applying monoclonal antibodies on PBL and CSFL. The percentage of OKT8+ (CD8: T cytotoxic/suppressor lymphocytes) cells was significantly lower in CSFL than in PBL (P less than 0.05). There was a tendency toward a higher percentage of HLA-DR+ cells (B lymphocytes, monocytes, macrophages, and activated T lymphocytes) and a higher ratio of OKT4+/8+ cells (CD4/CD8: T helper/inducer lymphocytes/T cytotoxic/suppressor lymphocytes) in CSFL from patients with VKH than in their PBL (P less than 0.1).