Immunohistochemical studies on the endotoxin-induced uveitis.
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OBJECTIVE: To investigate the longitudinal changes of macrophages and major histocompatibility complex (MHC) class II-positive cells in the iris and ciliary body of Lewis rats after lipopolysaccharide (LPS) injection. METHODS: Immunohistochemistry was performed using monoclonal antibodies to monocytes and macrophages (ED1) and MHC class II-positive cells (OX6) on wholemounts of the iris and ciliary body in endotoxin-induced uveitis (EIU). RESULTS: A network of macrophages (ED1+ cell) and MHC class II-positive cells, was present in the iris and ciliary body of normal Lewis rats. Most cells in the iris and ciliary body displayed dendritiform appearance. A severe involvement of the iris and ciliary body, as evidenced by a rapid influx of monocytes and macrophages and remarkable increase of MHC class II-positive cells, was observed after LPS injection. CONCLUSIONS: A network of macrophages and MHC class II-positive cells in the iris and ciliary body may play an important role in immune surveillance. LPS injection induces a severe inflammation in the anterior segment of the eye, which may serve as a model for acute anterior uveitis in human. (+info)
Estrogen protects against cellular infiltration by reducing the expressions of E-selectin and IL-6 in endotoxin-induced uveitis.
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Anterior uveitis associated with Behcet's disease and ankylosing spondylitis preferentially occurs in adult men, which may suggest the effects of sex hormones on acute anterior uveitis. Recently, estrogen receptors in the vascular endothelium have been reported to be involved in several pathological conditions. In the present study, we examined the gender differences in susceptibility to endotoxin-induced uveitis (EIU) and the effects of estrogen on anterior inflammation. EIU was induced in adult male, female, and ovariectomized female Lewis rats (200 g) by hind footpad injection of 200 microg of LPS. In EIU, cellular infiltration was more marked in male than in female rats, and ovariectomy increased cellular infiltration. Treatment with 10 microg of 17beta-estradiol significantly reduced the cell number in male and ovariectomized female rats with EIU. Estrogen receptor immunoreactivity was found in the nucleus of vascular endothelium and in some stromal cells of the iris-ciliary body. Semiquantitative PCR revealed that E-selectin and IL-6 gene expressions were increased in rats following LPS injection, and an overdose of tamoxifen, an estrogen receptor antagonist, reversed the effect of 17beta-estradiol on E-selectin, but not its effect on IL-6. These observations suggested that the down-modulation of these inflammatory genes by estrogen may contribute to the reduction in cellular infiltration in acute anterior uveitis. (+info)
HLA-B27 subtypes and HLA class II alleles in Japanese patients with anterior uveitis.
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PURPOSE: Some patients with anterior uveitis (AU) have ankylosing spondylitis (AS) and are HLA-B27 class I-positive. The purpose of this study was to investigate whether there are differences in HLA at the allele level among each group of patients with AU. METHODS: Seventy-three patients with AU were studied. They were classified into three groups: 31 with AS-associated AU, 14 with HLA-B27-associated AU, and 28 with idiopathic AU. Three control groups without AU were used: 138 random subjects, 33 HLA-B27-positive healthy subjects, and 19 HLA-B27-positive patients with AS. DRB1 and DQB1 genotyping was performed using polymerase chain reaction (PCR)-single-strand conformation polymorphism (PCR-SSCP) and PCR-restriction fragment length polymorphism. HLA-B27 subtype was determined by PCR-SSCP. RESULTS: There was no difference in the frequency of any class I antigen except HLA-B27 among the patients studied. The frequencies of HLA-DR12 in AS-associated AU and HLA-DR1 in HLA-B27-associated AU showed an increase. In HLA-B27-associated AU, DRB1*0101 and DQB1*0501 were increased compared with HLA-B27-positive control subjects. When HLA-B27 subtype distribution was compared among the groups, the proportion of B*2704 was significantly lower in HLA-B27-associated AU (P = 0.037), however, such a difference was not present in AS-associated groups. CONCLUSIONS: These results indicated that B*2704 seemed to be less susceptible to AU compared with B*2705 in Japanese subjects. The increase of HLA-DR12 and HLA-DR1 in AU may be caused by linkage disequilibrium with B*2704 and B*2705, respectively. (+info)
Molecular analysis of resolving immune responses in uveitis.
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To identify the cellular immune processes underlying intra-ocular inflammation, aqueous humour was obtained at cataract surgery from 22 patients with clinically inactive uveitis and 24 patients with age-related cataract. mRNA expression for the cytokines IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta); T cell subsets CD3, CD4, CD8; monocytes and macrophages (CD14); and B cells (CD19) was measured using reverse transcriptase-polymerase chain reaction (RT-PCR) and radiometric analysis. The majority of uveitis patients demonstrated a T cell-mediated inflammatory response, predominately involving a Th1-like cytokine profile with expression of IL-2 and IFN-gamma in 16/22 and 18/22 samples, respectively. These cytokines were present in only a small number of patients with age-related cataract. This Th1-like polarization was supported by an increased expression of CD8 in a number of patients. IL-1beta was expressed in only six uveitic eyes. Only four patients expressed either IL-4 or IL-10 and no patient expressed both. TGF-beta mRNA could be detected in 18/22 uveitis patients and 15/24 controls. IL-12, the paradigmatic Th1-inducing cytokine, was absent in all samples but CD14 was expressed in the majority of patients and controls. CD19 could not be detected in any sample. The cellular infiltrate in the uveitic eyes showed clear evidence of low IL-1 and absent IL-12 expression despite a Th1-like profile and high expression of macrophages. This strongly suggests that the systemic immunosuppressive therapy used prior to surgery in some patients and/or the chronicity of the uveitis had actively suppressed/switched off macrophage function, leading to resolution of T cell activity. (+info)
Fas-Fas ligand-mediated apoptosis within aqueous during idiopathic acute anterior uveitis.
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PURPOSE: Despite ocular immune privilege, (auto)immune-mediated acute anterior uveitis (AAU) is relatively common. However, although relapses of AAU are usually self-limiting, possible regulatory mechanisms remain undefined in humans. Experimentally, Fas-Ligand (FasL)-mediated apoptosis of Fas+ inflammatory cells contributes to the immune privilege within the anterior chamber and provides an explanation for the success of corneal allograft transplantation. Therefore, whether such mechanisms regulate the immune response in AAU was investigated. METHODS: Aqueous and peripheral blood samples from consecutive patients presenting with idiopathic AAU were obtained with consent. Leukocytic phenotype was analyzed by flow cytometry, and apoptosis was determined by both flow cytometry and TdT-dUTP terminal nick-end labeling analysis. Presence of soluble Fas and FasL was determined by western blot analysis and enzyme-linked immunosorbent assay and compared with control aqueous from patients undergoing cataract surgery. The ability of the aqueous to induce apoptosis in a Fas+ Jurkat cell line was also determined. RESULTS: During AAU aqueous-infiltrating Fas+ cells included CD3+ T cells and granulocytes, whereas FasL+ cells comprised predominantly of non-CD3+ T cells. Higher levels of functional soluble FasL were found in aqueous of AAU patients than in normal aqueous, capable of inducing apoptosis in 68.9% +/- 7.6% of Fas+ lymphoid cells. Compared with peripheral blood, the CD4+ T cells infiltrate within aqueous showed significantly increased CD69 and CD25(IL-2r) expression. Flow cytometric analysis of aqueous showed that 9.32% +/- 1.2% of infiltrating non-granulocyte CD45+ cells were apoptotic, confirmed as T cells on subsequent three-color flow cytometric analysis. CONCLUSIONS: Taken together with published experimental data, the present study provides evidence for FasL-mediated apoptotic cell death contributing to the local immune regulation of ocular inflammatory disease and provides a mechanism to account for the self-limiting clinical course of AAU. (+info)
Ocular manifestations in children and adolescents with Lyme arthritis.
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BACKGROUND: Lyme arthritis is the most frequent late manifestation of Lyme borreliosis and has been associated with ocular inflammation. METHODS: A group of 153 children and adolescents with arthritis, 84 of whom had Lyme arthritis and 69 other causes of arthritis, were followed prospectively for 22-73 (median 44) months in the course of a national study. RESULTS: Three of 84 patients with Lyme arthritis had ocular inflammation (4%), including keratitis, anterior uveitis, and uveitis intermedia. All three had symptoms of decreased visual acuity. Whereas anterior uveitis disappeared without sequelae, a corneal scar and a permanent loss of visual acuity in the patients with keratitis and intermediate uveitis remained. Systematic examination of all patients revealed no further ocular involvement. Of 69 patients with other causes of arthritis who were followed in parallel as a control group, four of 15 patients with early onset pauciarticular juvenile rheumatoid arthritis had chronic anterior uveitis and two of 12 patients with juvenile spondyloarthropathy had acute anterior uveitis. CONCLUSIONS: Ocular involvement with keratitis, anterior uveitis, and intermediate uveitis may occur in children and adolescents with Lyme arthritis. Visual loss appears to be symptomatic, making regular ocular screening of such patients unnecessary. (+info)
Anterior uveitis associated with intravenous cidofovir use in patients with cytomegalovirus retinitis.
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AIM: Intravenous cidofovir is used to treat cytomegalovirus (CMV) retinitis, and has been reported to cause anterior uveitis. Relations were sought between this complication and patient characteristics that might help predict its occurrence. METHODS: 17 patients with AIDS and CMV retinitis who were treated with intravenous cidofovir were identified, and the following data collected in a retrospective chart review: demographic characteristics, duration of CMV retinitis, retinal lesion characteristics, dose and duration of cidofovir therapy, tests of renal function, CD4+ T lymphocyte counts, visual acuity, intraocular pressure, iris colour, history of diabetes mellitus, and use of concomitant medications. Case-control analyses were performed to determine risk factors for developing cidofovir associated uveitis. RESULTS: Anterior uveitis characterised by pain, ciliary injection, and decreased visual acuity occurred in 10 patients (59%). Median interval to development of uveitis was 11 doses of cidofovir. Symptoms developed 4.4 (SD 2.5) days (median 3.5) after an infusion of cidofovir. Patients who developed uveitis had a significantly greater rise in CD4+ T lymphocyte count while receiving cidofovir (68.4 (75.7) x10(6)/l versus 5.0 (0.6) x10(6)/l, (p = 0.04)). By stepwise linear regression, this factor accounted for 33% (p = 0.03) of the effect of developing uveitis. Mean follow up time, intraocular pressure decline during cidofovir therapy, serum creatinine and urine protein concentrations, and rates of protease inhibitor use were not significantly different between patients who developed uveitis and those who did not. Uveitis responded to topical corticosteroids and cycloplegia. CONCLUSION: Anterior uveitis in patients receiving intravenous cidofovir therapy may be related to improving immune function. The uveitis responds to treatment and may not preclude continuation of cidofovir. (+info)
Endotoxin-induced uveitis is partially inhibited by anti-IL-8 antibody treatment.
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PURPOSE: To examine the potential therapeutic effect of a neutralizing anti-IL-8 monoclonal antibody in endotoxin-induced uveitis (EIU) in the rabbit. METHODS: An anti-IL-8 antibody (WS-4) was injected intravitreal 2 hours before, simultaneously with, or 6 hours after endotoxin challenge in rabbits. Eyes were examined for clinical signs of inflammation, and aqueous humor (AH) was sampled to study cellular infiltration and protein content. Leukocyte subset analysis was performed on Giemsa-stained AH cytospins. Histologic grading of inflammation was performed on hematoxylin-eosin-stained sagittal sections of enucleated eyes. In separate experiments, animals received the anti-IL-8 antibody simultaneously with the endotoxin challenge, before repeated anterior chamber paracentesis was performed (at 6, 12, 24, 48, and 72 hours after injection) to estimate the kinetics and durability of changes in total cell count and protein concentration in AH. RESULTS: Anti-IL-8 therapy caused a decrease in the clinical and histologic grade of inflammation in EIU. The mean cell count in the AH at the peak of inflammation (24 hours) in eyes receiving endotoxin only was 6419+/-1165/microl (mean +/- SE) compared to 2546+/-573/microl in rabbits treated simultaneously with 250 microg of anti-IL-8 antibody (P < 0.05). The protein concentration in the AH was not significantly altered by anti-IL-8 treatment. Kinetic analysis of the leukocyte count in the AH demonstrated persistent inhibition of leukocyte accumulation (range, 60%-91% compared to control eyes) by the anti-IL-8 antibody administered simultaneously with endotoxin. This inhibition was sustained for up to 72 hours after injection. CONCLUSIONS: Anti-IL-8 antibody treatment partially blocks EIU in rabbits. A consistent decrease in the recruitment of polymorphonuclear leukocytes into the anterior chamber was obtained when neutralizing antibody was injected simultaneously with endotoxin. These findings suggest that IL-8 contributes to the chemotactic signal for the recruitment of leukocytes in EIU. (+info)