Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis.

Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a common feature in NIU, however, detection of the major angiogenic factor-vascular endothelial growth factor A (VEGF-A)-in intraocular fluids in animal models of uveitis may be an indication for a role for this cytokine in a highly inflammatory condition. Suppression of VEGF-A by directly targeting the leukotriene B4 (LTB4) receptor (BLT1) pathway indicates a connection between leukotrienes (LTs), which have prominent roles in initiating and propagating inflammatory responses, and VEGF-A in retinal inflammatory diseases. Further research is needed to understand how LTs interact with intraocular cytokines in retinal inflammatory diseases to guide the development of novel therapeutic approaches targeting both inflammatory mediator pathways.

High-dose intravenous steroid pulse therapy in ocular involvement of Behcet's disease: a pilot double-blind controlled study.

AIM: To evaluate the efficacy of intravenous high-dose pulses of methylprednisolone (IVPM) for treatment of ocular involvement in Behcet's disease (BD). METHOD: In a double-blind control study, we randomized BD patients with posterior uveitis (PU) and/or retinal vasculitis (RV) into two groups. They received either IVPM (1000 mg methylprednisolone) or placebo for 3 consecutive days. Both groups received combination therapy with IV cyclophosphamide, azathioprine and prednisolone for 6 months. Visual acuity (VA), Disease Activity Index (DAI) based on the inflammatory state of each section of each eye, total inflammatory (TIAI) and adjusted DAI (TADAI) for each patient were calculated. The comparisons were done by paired t- and Mann-Whitney U-test. RESULTS: Seventeen patients in each group completed the treatment. The mean VA improved from 0.5 to 0.8 (P < 0.000001) for the study and from 0.6 to 0.7 (P < 0.02) for the placebo group. The difference was significant (P = 0.01). The comparison showed no significant difference regarding DAI improvement in other items (P > 0.2): PU, 1.9 to 0.5 (P < 0.0006) versus 2.3 to 0.8 (P < 0.0002); RV: 4.0 to 1.1 (P < 0.0004) versus 3.1 to 1.1 (P < 0.0005); TIAI: 23 to 5.7 (P < 0.0002) versus 24.8 to 8.4 (P < 0.003); TADAI: 24.1 to 7.3 (P < 0.0002) versus 25.9 to 7.9 (P < 0.004). We had one flare in the study versus seven in the placebo group (P < 0.005). CONCLUSION: Adding high-dose intravenous steroid pulse therapy to conventional combination therapy for severe ocular lesions of BD may cause better improvement on VA and fewer flares during the first 6 months of treatment.

Decreased B and T lymphocyte attenuator in Behcet's disease may trigger abnormal Th17 and Th1 immune responses.

Behcet's disease (BD) is a chronic, systemic and recurrent inflammatory disease associated with hyperactive Th17 and Th1 immune responses. Recent studies have shown that B and T lymphocyte attenuator (BTLA) negatively regulates the immune response. In this study, we investigated whether BTLA activation could be exploited to inhibit the development of abnormal immune responses in BD patients. BTLA expression in PBMCs and CD4(+) T cells was significantly decreased in active BD patients. Decreased BTLA level was associated with increased Th17 and Th1 responses. Activation of BTLA inhibited the abnormal Th17 and Th1 responses and IL-22 expression in both patients and controls. Addition of an agonistic anti-BTLA antibody remarkably inhibited DC-induced Th17 and Th1 cell responses, resulted in decreased production of the Th17 and Th1-related cytokines IL-1beta, IL-6, IL-23 and IL-12p70 and reduced CD40 expression in DCs. In conclusion, decreased BTLA expression in ocular BD may lead to inappropriate control of the Th17 and Th1 immune responses and DC functions. Therefore, BTLA may be involved in the development and recurrence of this disease. Agonistic agents of BTLA may represent a potential therapeutic approach for the treatment of BD and other inflammatory diseases mediated by abnormal Th17 and Th1 immune responses.

The clinical characteristics of retinal vasculitis in HLA-B27-positive patients.

PURPOSE: To investigate the ocular and systemic manifestations of retinal vasculitis in HLA-B27-positive patients. METHODS: Retrospective noncomparative case series of 9 HLA-B27-positive patients with uveitis and retinal vasculitis. Main outcome measures consisted of ocular and angiographic findings and assessment of any additional systemic disorders. RESULTS: Three male and 6 female HLA-B27-positive patients with a median age of 32 years were diagnosed with retinal vasculitis. Concurrent intraocular inflammation was noted in all patients. All patients suffered from extensive vasculitis of the large retinal veins. Five patients developed retinal vasculitis at the onset of uveitis and the remaining 4 exhibited retinal vasculitis 1-15 years after the onset of uveitis. Vascular occlusions occurred in 4 patients and subsequent neovascularizations developed in 3. Three patients were diagnosed with an HLA-B27-associated systemic disease. CONCLUSION: Retinal vasculitis may develop in the wake of HLA-B27-associated uveitis and might represent a rare manifestation of HLA-B27-associated disease.

Profiling of human leukocyte antigens in Eales disease and tuberculosis.

To analyze the association between Eales disease, histocompatibility leukocyte antigen alleles (HLA-A/B, HLA-DRB/DQB) and tuberculosis infection, and to explore susceptible genes and protective genes associated with Eales disease and tuberculosis infection in a population of Han nationals from Zunyi City in Guizhou Province, China. The subjects were analyzed by a case-control study consisting of three groups--Eales disease group (47 cases), pulmonary tuberculosis group (36 cases) and normal control group (100 cases). The Eales disease group was divided into four parts. Part one consisted of 12 patients who had suffered from pulmonary tuberculosis. Part two consisted of 27 patients who had not suffered from pulmonary tuberculosis. Parts three and four consisted of 27 patients with a positive purified protein derivative test and 12 patients with a negative test, respectively. DNA samples from 47 patients with Eales disease, 36 patients with pulmonary tuberculosis and 100 healthy people were detected by polymerase chain reaction with sequence-specific primers. The 59 HLA-A/B and HLA-DRB/DQB alleles from Eales disease were compared with those from tuberculosis and normal control, and a correlativity test of common susceptible genes was performed to analyze the potential relationship between Eales disease and pulmonary tuberculosis. The frequency distribution of HLA-A*02 alleles (OR 9.719, OR 95 % CI 4.377-21.580, P = 0.000) and HLA-B*07 (OR 11.605, OR 95 % CI 2.397-56.191, P = 0.001) in the Eales disease group was higher than in the normal control group, but the HLA-A*11 alleles (OR 0.495, OR 95 % CI 0.245-1.000, P = 0.048) were lower than in the normal control group, showing a significant difference. Compared with parts two and four, the frequency distribution of HLA-A*02, HLA-A*11 and HLA-B*07 alleles in parts one and three showed no significant difference (P > 0.05). HLA-A*A02, HLA-A*24, HLA-B*07 and HLA-DRB*16 alleles between the Eales disease, pulmonary tuberculosis and normal control group showed statistical significance (P < 0.05). HLA-A*24 alleles in the pulmonary tuberculosis group were lower than the Eales disease group (χ(2) 7.289, P = 0.007), but HLA-A*02 alleles showed no significant difference (P > 0.05) between the two groups. The results show that HLA-A*02 and HLA-B*07 may be genetic predisposing genes, but HLA-A*11 alleles may be protective genes of Eales disease, the HLA-A*02 allele may be a common susceptible gene of Eales disease and pulmonary tuberculosis. HLA-A*11 and HLA-A24 alleles are protective genes of Eales disease and pulmonary tuberculosis, respectively. In summary, the frequency distribution of susceptible genes of Eales disease and pulmonary tuberculosis in a population of Han nationals from Zunyi City in Guizhou Province, China showed no significant difference.

Retinal vasculitis revealing immunoglobulin G subclass deficiency.

Immunoglobulin G (IgG) subclass deficiency is a rare primary immunodeficiency syndrome characterized by recurrent infections and autoimmune disorders. However, there have been no reports of ocular involvement, either inflammatory or infectious, in association with IgG subclass deficiency. The authors report the first case of retinal vasculitis that led to the diagnosis of IgG subclass deficiency, in a patient with a history of inflammatory bowel disease and recurrent infections of previously unknown origin.

The relationship between retinal vessel calibre and knee cartilage and BMLs.

BACKGROUND: Whether the increase in vascular disease prevalence and mortality in OA populations is a result of co-occurrence of cardiovascular disease and OA, which are both common in the older population, is due to OA treatments or to the common association with reduced physical activity and/or obesity is unclear. One way to explore this non-invasively is to examine the cross-sectional relationship between changes in retinal microvasculature, which have been shown to be markers of generalized vascular pathology, and knee structural changes in an asymptomatic community-based population. METHODS: A community sample of 289 (61% women) aged 50-79 years with no knee symptoms underwent magnetic resonance imaging (MRI) of their dominant knee in 2003. Cartilage volume and bone marrow lesions (BMLs) were determined. All subjects also had retinal photographs taken from which retinal arteriolar and venular diameters were determined and summarized as the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE). RESULTS: Retinal venular diameter was significantly wider in subjects with a BML compared with subjects without a BML (mean (SD) 214.2 (2.8) µm versus 207.5 (1.1) µm respectively independent of age, gender and BMI. A trend for decreased medial tibial cartilage with increasing CRAE was also observed (regression coefficient -2.70 µl, 95%CI-5.74, 0.5, p=0.08). CONCLUSION: These findings suggest that vascular pathology, indicative of inflammatory processes, is associated with early structural knee changes. The role of micro-vascular changes in the pathogenesis of OA warrants further investigation.

[Efficacy of TNF-alpha antagonist and other immunomodulators in the treatment of patients with ophthalmologic manifestations of Behcet's disease and HLA B51 positive vasculitis].

BACKGROUND/AIM: Behcet's disease is genetically conditioned, immune-mediated multisystem occlusive vasculitis of small blood vessels, espesially venules, of unknown etiology. The aim of this study was to analyze the clinical features, disease activity and therapy of the patients with ophthalmologic manifestation of Behcet's disease. METHODS: In this study symptoms and signs of the disease were analyzed both prospectively and retrospectively during the active manifestation of the disease. The diagnosis was reached according to the International Criteria for Behcet's Disease (2006). The treatment effects were evaluated based on the presence of the best corrected visual acuity and the inflammation of the vitreous humour before and after the application of our therapeutic method. The applied therapeutic modality consisted of the primary application of corticosteroid therapy in the active stage of the disease complemented with the choice of drugs from the immunosuppressive group. In this study there drugs were cyclosporine or methotrexate. A treatment refractory patients with poor vision prognosis were treated with a third drug, the biological preparation infliximab, a tumor necrosis factor-alpha (TNF-alpha) antagonist. RESULTS: The mean age of 11 patients with ophthalmologic manifestation of Behcet's disease was 50.6 years. HLA B-5 (51) was positive in 81% of the patients while 36% of the patients had positive pathergy test. Changes in affected eyes included vitritis (100%), posterior uveitis (45%), panuveitis (54%), retinal vasculitis (54%), cystoid macular edema (54%), and cystoid degeneration (18%). Increased intraocular pressure was observed in 27% of the patients. There was no statistically significant variation in disease activity parameters in any of the patients (p > 0.05). A statistically significant improvement in visual acuity (p < 0.05) and a high statistically significant decrease of inflammation of the worst affected eyes (p = 0.001) were detected. CONCLUSION: Our therapeutic method is useful for producing the optimal therapeutic plan for the acute--chronic stage of the difficult ophtamological manifestation of Behcet's desease as well as the prevention of relapse. However the high cost of the therapy and the potential complications should be taken into consideration when prescribing this therapy, especially a TNF-alpha antagonist.

Impact of interleukin-6 promoter polymorphism and serum interleukin-6 level on the acute inflammation and neovascularization stages of patients with Eales' disease.

PURPOSE: To evaluate the role of interleukin-6 (IL-6) in the inflammatory and proliferative stages of Eales' disease (ED) and to determine the influence of IL-6-174G/C polymorphism in the IL-6 and IL-6-regulated protein expression, as well as the development of ED. METHODS: One hundred and twenty-one patients diagnosed with ED, 223 matched healthy controls, and 16 control patients with macular holes were recruited from the eastern Indian population. Serum and vitreous levels of IL-6 and vascular endothelial growth factors (VEGF) were measured by enzyme-linked immunosorbent assay. Serum levels of high-sensitivity C-reactive protein (hsCRP) were measured by enzyme immunoassay. Subjects were genotyped for the IL-6-174G/C polymorphism (rs1800795) by a custom TaqMan single-nucleotide polymorphism (SNP) Genotyping Assays system. RESULTS: Serum IL-6 (p<0.0001), hsCRP (p<0.0001), and VEGF (p=0.0031) levels were significantly higher in the inflammatory stage of ED than in healthy controls. Serum IL-6 also significantly correlated with hsCRP (Spearman's correlation coefficient; r=0.4992, p=0.0009), but not with VEGF in this stage in ED patients. At the proliferative stage of ED, significantly higher levels of vitreous IL-6 (p=<0.0001) and VEGF (p=<0.0001) were found compared with the vitreous of patients with macular holes. A significant correlation was observed between vitreous IL-6 and VEGF in ED patients (Spearman's correlation coefficient; r=0.5834, p=0.0087). A statistically significant association was found between the -174GG genotype (p=0.006) and occurrence of ED. Mean serum and vitreous concentrations of IL-6 were also higher in the subjects with the GG genotype than in those with the GC or CC genotype in this population. CONCLUSIONS: IL-6 expression, regulated by the allelic distribution of -174 loci and the enhanced level of IL-6, modulates CRP and VEGF concentration depending respectively on the acute inflammatory stimulation at the initial stage and angiogenic stimulation at the advanced stage of ED.

[Janus-faced?: Effects and side-effects of interferon therapy in ophthalmology]. / Ein Januskopf?: Wirkungen und Nebenwirkungen der Interferontherapie in der Augenheilkunde.

Interferon alpha (IFN-α) and interferon beta (IFN-ß) are naturally occurring cytokines, which belong to the type I interferons and share the same receptor leading to very similar therapeutic effects. The immunomodulatory effect of type I interferons includes modulation of antibody production, inhibition of lymphocyte proliferation, inhibition of delayed-type hypersensitivity and enhancement of T-cell and NK-cell cytotoxicity. An increasing number of open clinical studies and case reports have demonstrated the efficacy of IFN-α for severe ocular inflammation in patients with Behçet's disease and of interferon-ß, which has been used mainly for the treatment of multiple sclerosis.

Ocular syphilis unmasked following intravitreal triamcinolone injection.

PURPOSE: To report intravitreal triamcinolone (IVTA)-induced unmasking of ocular syphilis. DESIGN: Two case reports. METHODS: A homosexual, diabetic male with macular edema treated with bilateral IVTA and a male with bilateral panuveitis and macular edema who underwent vitrectomy and IVTA. Both developed occlusive retinal vasculitis and panuveitis postinjection. Syphilis serology was positive although both denied previous symptoms. RESULTS: Intramuscular penicillin lead to resolution of inflammation but both sustained severe loss of vision. Cause-and-effect relationship demonstrated between IVTA and reactivation of syphilis. CONCLUSIONS: Intravitreal corticosteroid can modulate the immune response to intraocular syphilis; vigilance is required, particularly in high-risk patients.

Posterior segment involvement in Korean patients with HLA-B27-associated uveitis.

PURPOSE: To compare clinical characteristics and visual prognosis between HLA-B27-associated uveitis patients with and without posterior segment involvement. METHODS: Medical records of 78 patients with HLA-B27-associated uveitis were retrospectively analyzed. RESULTS: Neither demographic nor clinical characteristics were associated with the presence of posterior segment involvement. In patients with posterior segment involvement, more aggressive therapeutic strategies, including immunomodulatory therapy, were frequently required. The rate of visual acuity 20/50 or worse was higher in patients with posterior involvement than in patients without posterior involvement. CONCLUSION: Patients with posterior segment involvement showed worse visual outcome than patients without posterior involvement.

Clinical and immunological features of retinal vasculitis in systemic diseases.

BACKGROUND/AIM: Vasculitis is a clinical, pathologic process characterized by inflammation and necrosis of blood vessel occuring anywhere in the body. The aim of the study was to present some clinical and immunologic features of retinal vasculitis in systemic diseases: systemic lupus erythematosus, multiple sclerosis, sarcoidosis, Behcet's diseases, and others. METHODS: A total of 1 254 peatients with uveitis were included in the study. The immunochemical diagnostic methods were used to determine the pathogenesis of ocular manifestations. Ocular manifestations were examined using biomicroscope, direct or indirect ophtalmoscopy. RESULTS: Primary retinal vasculitis was diagnosed in 85/1254 (6.8%) of total uveitis. In more than half of the cases of vasculitis (58.8%), both arteries and veins were involved in inflammatory process. Periphlebitis was diagnosed far more commonly (36.5%) than periarteritis (4.7%). Retinal vasculitis associated with systemic lupus erythematosus was characterized by microinfarctions and the consequent foci of inflammatory cells or diseases of large arteries manifesting in vasospasm and occlusions. Cotton wool spots occured in 38.3% and retinal hemorrhages in 34% of the cases. In this study periphlebitis of the retina was one of the less frequent ocular manifestations of multiple sclerosis. Comparing with the other changes of the retinal blood vessels, venous sheating occured in 25.1% and occlusion and vein thrombosis in 43.75% of the cases. Retinal vasculitis associated with chronic sarcoidosis occured in 37.5% of patients with sarcoidosis. The most frequent manifestation of ocular sarcoidosis was intermediary uveitis (43.75%). Anterior granulomatous uveitis occured in 37.5% of patients with sarcoidoses. Immune complexes occured in 13/20 (65%) of the patients. Antiretinal anti-S antibody in the serum occured in 73% of the patients with retinal detachment as a complication of primary disease and in 25% those with vasculitis. CONCLUSION: Systemic diseases such as Behcet's syndrome, collagen vascular diseases, systemic granulomatous diseases (sarcoidosis and tuberculosis) were the main causes of retinal vasculitis. Knowledge of the symptomatology and pathogenesis of retinal vasculitis is of the major significance for the diagnosis and therapy of the disease.

[Incomplete Vogt-Koyanagi-Harada syndrome associated with HLA DRB1*01 in a 4-year-old child: case report]. / Síndrome de Vogt-Koyanagi-Harada incompleta associada a HLA DRB1*01 em criança de quatro anos de idade: relato de caso.

Vogt-Koyanagi-Harada syndrome is chronic systemic autoimmune disease with ocular, nervous, auditory and tegumental manifestations. We report here the case of a child with onset of symptoms at four years and two months of age, with positive HLA DRB1*01.

Síndrome de Vogt-Koyanagi-Harada incompleta associada a HLA DRB1*01 em criança de quatro anos de idade: relato de caso / Incomplete Vogt-Koyanagi-Harada syndrome associated with HLA DRB1*01 in a 4-year-old child: case report

A síndrome de Vogt-Koyanagi-Harada é doença crônica, sistêmica e auto-imune, com manifestações oculares, nervosas, auditivas e tegumentares. Descrevemos aqui o caso de uma criança com início dos sintomas aos quatro anos e dois meses de idade, com positividade para o HLA DRB1*01.

Vogt-Koyanagi-Harada syndrome is chronic systemic autoimmune disease with ocular, nervous, auditory and tegumental manifestations. We report here the case of a child with onset of symptoms at four years and two months of age, with positive HLA DRB1*01.

Interferon-beta and adhesion molecules (E-selectin and s-intracellular adhesion molecule-1) are detected in sera from patients with retinal vasculitis and are induced in retinal vascular endothelial cells by Toll-like receptor 3 signalling.

Retinal vasculitis is a major component of ocular inflammation that plays a role in retinal tissue damage in patients with idiopathic uveitis and Behçet's disease. Here we show that type 1 interferons (IFN alpha/beta) were not detected in sera from normal individuals but were identified in up to 46% of the sera from retinal vasculitis patients. The predominant form of IFN observed was IFN-beta, which was detected in 39% of Behçet's disease patients and 47% of idiopathic uveitis patients. Seven patients whose sera contained IFN-beta were monitored prospectively. IFN-beta was shown to be present for 6-12 months in all seven of the sera samples tested. Furthermore, the adhesion molecule profile identified in this study was strikingly different when Behçet's and uveitis patient sera were compared to sera from normal controls. Sera from Behçet's disease patients contained significantly elevated levels of the soluble adhesion molecules, sE-selectin and s-intracellular adhesion molecule-1 (sICAM-1), whereas sera from patients with idiopathic uveitis contained significantly increased sE-selectin. In vitro studies evaluating the cell source of these cytokines revealed that polyriboinosinic polyribocytidylic acid (poly I:C) activated retinal vascular endothelial cells produce sE-selectin, sICAM-1 and IFN-beta. Production of these molecules was inhibited by pretreatment with anti-Toll-like receptor 3 (TLR-3) antibody. In conclusion, IFN-beta, sE-selectin and sICAM-1 are elevated in patients with retinal vasculitis and are induced in retinal vascular endothelial cells in vitro by activating the innate immune system through TLR-3. Further analysis of innate immune signalling may prove to be a novel target for future studies on pathogenic mechanisms and therapeutic approaches in retinal vasculitis.