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Uveitis is an inflammatory disease, a leading cause of blindness, the pathogenesis of which is not fully understood.In recent years, it has been found that interleukin (IL)-23/IL-17 pathway plays an important role in the occurrence of uveitis.The IL-23/IL-17 pathway mainly acts on target cells through activating the T helper 17 cells, resulting in the production of inflammatory factors and chemokines as well as the damage of retinal pigment epithelium, which can cause uveitis.The IL-23/IL-17 pathway is regulated by a giant network, and the regulation of it by its positive and negative factors can lead to immune disorders and participate in the occurrence of uveitis.The polymorphism of genes in IL-23/IL-17 pathway and regulatory network is closely related to uveitis, which provides an important basis for the genetic pathogenesis of uveitis.In addition, clinical trials have confirmed the efficacy of biological agents targeting IL-23/IL-17 pathway, which provides a new research direction for the treatment of uveitis.The IL-23/IL-17 pathway and its physiological function, the positive and negative factors and gene polymorphism of IL-23/IL-17 pathway and its regulatory network in uveitis were summarized, and the research progress of biological agents of IL-23/IL-17 pathway in uveitis were reviewed in this article in order to deepen the understanding of the pathogenesis of uveitis and guide clinical practice.
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Background The conventional study of antigen-presenting cells(APCs)in eye relies on in vitro histoimmunochemistry,but its outcome is influenced by many factors.The anterior chamber injection of fluoresceinmarked antibody was used as a new approach before,however,it is liable to lead to injury of cornea.The intravitreal injection of fluorescein-labeled antibody may be important for the in vivo study of the phenotype features of APCs in iris,which is significant for evaluating the function of APCs in immune homeostasis.Objective This study was to investigate the phenotype characters,distribution and morphology of different types of APCs in the normal murine iris.Methods Fifty-one SPF female BALB/c mice(from 6-to 8-week old)were randomized into 17 groups according to the injection of different antibodies.Alexa Fluor 594 or Alexa Fluor 488-tagged ovalbumin (OVA),CD11 c,major histocompatibility complex Ⅱ (MHC-Ⅱ),F4/80,B7-1 and B7-2 monoclonal antibodies or mixtures of two antibodies (2.0 μl)were intravitreally injected at 0.5 mm far from corneal limbus with microneedle under the biomicroscope.The iris tissues were isolated 24 hours after injection.The phenotype characters,precise distribution and morphology of different types of APCs were identified by epifluorescence microscope and laser confocal microscope.In vitro staining was also performed to validate the in vivo staining results.Results After in vivo staining via intravitreal injection,the cell positive for OVA as well as MHC-Ⅱ,F4/80,CD11 c,B7-1 and B7-2 were exhibited with the regular networkline appearance throughout the normal murine iris.Positive cells tagged with Alexa Fluor 594 or Alexa Fluor 488 presented the red or green fluorescence.Double-fluorescein staining showed that about 90％ of F4/80+ cells were OVA+,and MHC-Ⅱ was expressed in about 60％ of F4/80+ cells and CD11c+cells,and about 35％ of F4/80+ cells and CD1 1 c+ cells expressed B7-1 and B7-2 simultaneously,and over 70％ of OVA+ cells were positive to MHC-Ⅱ.These labeled cells were identified as two populations based on their shape.One type was dendritiform cell (DC) with a small cell body and many long dendrites,including OVA+,CD1 1 c+,F4/80+ cells and MHC-Ⅱ + cells ; and the other types were polymorphic population being round,pleomorphic or irregular shape with a large cell body and a few short dendrities,including B7-1 + and B7-2+ cells.Conclusions In vivo intravitreal injection of labeled antibodies can be adapted to visualize the labeled cells in the murine iris.APCs with distinct morphologies,phenotypes and distribution may contribute to the immunologically privileged feature and inflammation of the eye.
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Background Research determined that TLR4 is positively expressed on the macrophages in iris and ciliary in acute endotoxin-induced uveitis(EIU),indicating that TLR4 participated in the pathogenesis of the anterior uveitis.Objective The aim of this study is to observe the expressions of toll-like receptor-4(TLR4),Myeloid differentiation factor 88(MyD88),NF-κB p65 in iris tissue in the eyes with endotoxin-induced acute anterior uveitis.Methods Animal models of acute anterior uveitis were established by a hind footpad injection of 200μg Cholera vibrio LPS in 40 SPF Wistar rats with the age of 6-8 weeks.Other 10 age-matched rats were as normal controls.Ocular inflammation was examined under the slit lamp microscope at the 2-hour interval after the injection and intensity of inflammation was scored according to the standard of Lajavardi[4].Histopathology examination was performed for the evaluation of inflammatory reaction of iris and ciliary tissues by HE staining at 24 hours after LPS injection.Expressions of TLR4,MyD88 and NF-κB p65 in iris and ciliary body tissue were detected through immunohistochemistry.TLR4~+,MyD88~+ and NF-κB p65~+ cells were counted.Results The inflammatory reaction was gradually enhanced after injection of LPS and peaked at 24 hours and allivated 48 hours later.The infiltration of lots of inflammatory cells and fibrinous exudate were exhibited in the anterior chamber,posterior chamber,iris and ciliary tissue under the optical microscope at 24 hours after injection of LPS.No positive expressions of TLR4,MyD88 and NF-κB p65 in iris-ciliary body complex were found in normal control rats.The positive cells for TLR4,MyD88 and NF-κB p65 in iris-ciliary body complex were significantly different among 12 hours group,48 hours group and 72 hours groups(F=46.79,P＜0.05;F=54.37,P＜0.05;F=85.32,P＜0.05),and the positive cells for TLR4,MyD88 and NF-κB p65 peaked at 24 hours after injection of LPS.Conclusion The expression of TLR4 and its downstream signal transduction molecules MyD88,NF-κB p65 vary in uvea during EIU,indicating the potential role of LR4-MyD88 dependent pathway in the pathogenesis of acute anterior uveitis.
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Objective To investigate the association between interleukin-23 receptor (IL-23R) gene rs1343151 single nucleotide polymorphism and ankylosing spondylitis (AS) in Chinese Han patients. Methods The genotypes of IL-23R SNP was detected in 104 Chinese AS patients and 95 ethnically matched blood donors by TaqMan probe assays. The allele and genotype frequencies and risk factors of AS were analyzed by Chi-square test in both groups. Results The rs 1343151 genotypes in AS patients consisted of homozygote C/C (90.4%),C/T (9.6%), while The rs1343151 genotypes in the controls were. composed of C/C (91.6%), C/T (8.4%). No significant difference was found in the distribution of rs1343151 genotypes between these two groups (x2=0.086, P>0.05). The frequency of rs1343151 allele in AS patients was also not significantly increased when compared with the control group (x2 =0.082,P>0.05). Conclusion There may be no association between the IL-23R gene rs1343151 SNP and ankylosing spondylitis in Chinese Hart population.
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The knowledge of uveitis of Chinese eye doctors has been improved in general.While the usage of glucocorticoid agents Was more reasonable,other non-corticoid immunosuppressant get moreattention recently.The usage of antibiotics also has being reduced gradually.The international impact of our uveitis research has been enhanced.However there are still some problems,such as big difference between different regions of uveitis research,still many misunderstandings on the treatment of uveitis complications,and the reasonable evaluation of intravitreal injection with glucocorticoid needs emphasis.In China Behcet's disease and Vogt-Koyangi-Harada syndrome are the most common uveitis subtypes which can lead to blindness,but some rare subtypes of uveitis are also increasing such as syphilitic uveitis,acquired immune deficiency syndrome(AIDS),mycotic endophthalmitis and masquerade syndrome.In the future we need cooperative studies between multicenters to investigate the effectiveness of different treatment strategies for Behcet's disease and Vogt-Koyangi-Harada syndrome,and to optimizing the best therapeutic schedule.We also need to pay more attentions to the clinical features of those uveitis subtypes which increased recently;and to investigate the prevention and therapeutic effect of induction of immune tolerance to uveitis.
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Objective To investigate the features and main reasons of blindness induced by uveitis in China. Methods A retrospective analysis was performed on the data from 1 214 patients with uveitis, referring to Zhongshan Ophthalmic Center, with special respect to the incidence of blindness in different uveitis entities, the characteristics of blindness, and possible causes for the blindness. Results In the affected 1 892 eyes of 1 214 patients with uveitis, 355 eyes (18.83%) were blind. The mean age at the onset of blindness was 34.38 years and the gender ratio of male to female was 1.52:1. The blindness led by panuveitis was found in 248 eyes (26.27%), including 128 (51.61%) and 73 (29.44%) blind eyes caused by Behcet's disease and Vogt-Koyanagi-Harada syndrome. Complicated cataract, vitreous opacity and secondary glaucoma were responsible for the blindness of the patients with panuveitis [89(35.89%), 53 (21.37%), and 30 eyes (12.10%), respectively]. Blindness caused by anterior uveitis was noted in 79 eyes (10.73%) with the main reasons of complicated cataract [56 eyes (70.89%)] and secondary glaucoma [16 eyes (20.25%)], posterior uveitis in 15 eyes (15.63%) with the main reason of vitreous opacity [9 eyes (60.00%)], macular diseases in 3 eyes (20.00%), intermediate uveitis in 13 eyes (11.21%) with the main reasons of vitreous opacity [8 eyes (61.54%)], and complicated cataract in 5 eyes (38.46%). Conclusions Uveitis is one of the important causes leading to blindness, especially in the young adults. Panuveitis, especially Behcet's disease and Vogt-Koyanagi-Harada syndrome, are the most common entities responsible for blindness in patients with uveitis. Complicated cataract and secondary glaucoma are the main causes of blindness in uveitis.
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Objective To investigate the clinical manifestations and possible reasons of the missed and inaccurate diagnosis of Fuchs syndrome. Methods The clinical data of 85 patients with Fuchs syndrome who were diagnosed and treated from June 1999 to December 2003 were retrospectively analyzed. The disease history of each patient was carefully recorded. Slit-lamp microscopy was performed on the patients. The character and distribution of keratic precipitates (KP), color of the iris, depigmentation, and complications were noted in detail. The data recorded in other hospitals were analyzed and the reasons of missed and inaccurate diagnosis were statistically analyzed. Results The age of the patients ranged from 13 to 72 years, and binocular involvement was noted in 76 patients. None of the patients showed ciliary congestion and iris synechiae. Middle-sized or stellated KP was found. Triangle-distributed KP was seen in 13 patients, and diffuse distribution behind the corneal or in the pupil area was in 72. Anterior-chamber flare was observed in all of the patients, while anterior-chamber cells were only noted in 42 patients. The iris with different degrees of depigmentation was found in all the patients. Complicated cataract and increased intraocular pressure occured in 44 and 19 patients, respectively. The diagnosis in other hospitals mainly included uveitis, anterior uveitis and complicated cataract. Conclusions Fuchs syndrome is characterized by depigmented iris and typical KP. Missed and inaccurate diagnosis is mainly due to the unawareness of its clinical features.
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Objective To detect the changes of function of blood-aqueous barrier in different Syndrome stages of patients with Vogt-Koyanagi-Harada (VKH) syndrome in order to provide the appropriate therapy. Methods According to clinical manifestation, 77 patients (144 eyes) with VKH syndrome were divided into 4 groups: 10 cases in posterior uvietis stage group (20 eyes), 27 in anterior uveal involvement stage group (50 eyes), 23 in recurrent anterior uvitis stage group (41 eyes), and 17 in convalescent stage group (33 eyes). The other 50 cases (100 eyes) were in the control group. Flare and cells of anterior chamber in patient with VKH Syndrome at different stages were graded and measured by laser flare and cell meter (LFCM) and slitlamp microscope. Results According to the results of slitlamp biomicroscopy, anterior chamber flare and cells were at the 0 grade in the patients at posterior uvietis stage (20 eyes). The results of LFCM examination revealed that the flare value and cells were (9.7?3.4) pc/ms and (0.9?0.6)/0.5 mm3 in posterior uvietis stage group, and (5.3?2.3) pc/ms and (0.8? 0.6)/0.5 mm3 in the control group. The differences between the two groups were significant (P
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Objective To investigate the expression of costimulatory molecules( B7, CD28, and CTLA-4) of peripheral blood lymphocytes in patients with Behcet′s ) disease(BD). Methods Lymphocytes were obtained in 24 patients with BD and 20 healthy individuals, and the expression of CD80(B7-1), CD86(B7-2), CD28 and CTLA-4 on T and B cells were detected by direct three-color immunofluorescence flow cytometry. Results Significantly increased expression of CTLA-4 on CD4 + T cells [(3. 18?1. 18)%] was found in BD patients compared with that in controls [(1. 73?0. 66) %] ( t=-3. 722,P
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Objective To investigate the expression of T cell receptor (TCR) V ?8.3 gene on CD4+ T lymphocytes in the rats with experimental autoimmune uveoretinitis (EAU). Methods Eighteen Lewis rats were divided into EAU, complete Freund′s adjuvant, and the control group. Interphotoreceptor retinoid-binding protein (IRBP) R16 peptide was synthesized using Fmoc procedure for induction of EAU. Magnetic absorption cell sorting (MACS) method was used to isolate the CD4+ T lymphocytes from the spleen of the rats. Flow cytometry was used to monitor the efficiency of isolation. The expression of TCR V ?8.3 gene segment on CD4+T lymphocytes was determined by fluorescent quantitative polymerase chain reaction. Results EAU was successfully induced in the Lewis rats immunized with IRBP R16 peptide. The proportion of CD4+ T lymphocytes isolated by means of MACS was statistically higher than that before isolation (P
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Objective To investigate the expression and significance of T-bet in experimental autoimmune uveoretinitis (EAU). Methods EAU was induced in 24 Lewis rats by immunization with retinal S-antigen (50 ?g) and complete Freund′s adjuvant, and another 4 rats were the healthy control. The rats with EAU were executed 7, 12, 15, 21 days after immunization, respectively. Immunohistochemical single and double staining were performed using monoclonal antibodies of T-bet or CD4 on the ocular wholemounts and the consecutive sections of the eye and spleen from both 24 immunized Lewis rats and 4 normal controls. The positive cells were counted under the optic microscope and the data were analyzed by SPSS 11.0 statistic software. Results A few T-bet positive cells were observed in the normal ocular tissues and spleen. The expressions of T-bet in the iris, retina, and spleen increased 7 days after immunization, reached the peak at the 15th day, and decreased at the 21st day, which were higher than those in the control. Double staining on the consecutive sections revealed that most of the T-bet positive cells were positive for CD4 monoclonal antibody. Conclusion T-bet may affect the occurrence of EAU by activating Th1 cells.
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Objective To evaluate the expression of Fas/FasL antigen on peripheral blood T lymphocytes and its possible role in Behcet disease. Methods The expression of Fas and FasL antigen on peripheral blood T lymphocytes was determined by flow cytometry and three-colour double marked immunofluorescence methods in 26 patients with Behcet disease and 43 healthy individuals. Results The difference was significant between Behcet disease (25.70%±7.32%) and controls (14.02%±6.30%) concerning the Fas expression on CD4+ T lymphocytes(P＜0.01) . But no difference was found concerning the expression of FasL antigen between Behcet disease and controls (P＞0.05).The expression of Fas antigen on CD8+ T lymphocytes from Behcet disease (9.47%±6.97%)was significantly higher than that in control group(3.47%±2.75%), but no difference was found concerning FasL antigen expression on CD8+ T lymphocytes between Behcet disease and controls(P＞0.05).Conclusion These results indicate the imbalance of the expression of Fas and FasL on T lymphocytes in Behcet disease is responsible for the perpetuation and recurrence of Behcet disease for the activated lymphocytes would not be eliminated through apoptosis mediated by Fas/FasL system.
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Objective To study the clinical classification and etiologies of uveitis based on 1 214 uveitis patients reffered to Zhongshan Ophthalmic Center. Methods A retrospective analysis was made on the patients with uveitis, coming from all over China between January 1996 and December 2001. All kinds of uveitis were classified according to the anatomical criteria and etiological criteria. The relevant data of these patients, such as the age at uveitis onset and sex were also analyzed. Results The total number of the patients is 1 214 (male 698, female 516), with the average age at disease onset being 34.43. Anterior uveitis, the most common type, was seen in 546 cases, accounting for 44.98% of all the patients, followed in descending order by panuveitis (530 cases, 43.66%), intermediate uveitis(78 cases, 6.43%) and posterior uveitis(60 cases, 4.94%). Etiological factors and clinical entities were identified in 703 patients, accounting for 57.91% of all the patients, and the other 511 patients were idiopathic ones. The most common types of anterior uveitis were idiopathic uveitis(316 cases, 57.88%), followed by Fuchs syndrome(85 cases) and ankylosing spondylitis(45 cases). Behcet ) disease(218 cases, 41.13%) and Vogt-Koyanagi-Harada syndrome(196 cases, 36.98%) were the most common entities in panuveitis. Neither etiological factors nor clinical entities could be identified in the patients with intermediate uveitis and those with posterior uveitis. Conclusions Uveitis occurs mostly in young and middle-aged adults. In general, a predilection was seen in the male as compared with the female in the development of uveitis. Idiopathic anterior uveitis, Behcet ) disease and Vogt-Koyanagi-Harada syndrome are the most common entities of uveitis seen in China. Classification based on etiological and anatomical factors may provide a reasonable system for the study of uveitis.
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Objective To investigate the effects of ?-interferon (IFN-? on the expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86) and Fas/FasL in human retina. Methods Nine human eyes were obtained from the eye-bank of Zhongshan Ophthalmic Center. Six eyes were used for making retinal wholemounts, and 12 retinal wholemounts from each eye were put into the 24-hole culture board which had 2ml DMEM/F12 culture medium in each hole. The wholemounts were divided into 3 groups whose concentration of IFN-? was 0, 200, and 1 000 U/ml respectively. After cultured in 37℃ culture box (95%O2,5%CO2) for 24 hours, the expressions of B7-1 (CD80), B7-2 (CD86), and Fas/FasL on these retinal wholemounts were detected by immunohistochemical method. The retinal wholemounts from 3 healthy people were detected by immunohistochemical method as the control. Results Expression of FasL but not B7-1, B7-2 or Fas was found in the control group, while the expression of B7-1, B7-2 and Fas and increased expression of FasL were found after cultured with IFN-?. Conclusion IFN-? may be involved in the occurrence of ocular immune response and induction of apoptosis via the stimulation of expression of costimulatory molecules and Fas/FasL, which plays an important role in the activation of T lymphocytes.
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Objective To investigate the expression and significance of inducible co-stimulator (ICOS) in experimental autoimmune uveoretinitis (EAU). Methods EAU was induced in 24 Lewis rats (immune group) by immunization with retinal S-antigen (50 ?g) and complete Freund′s adjuvant, and another 4 rats were in the control group. Anterior segment of the rats′ eyes were observed by split microscope every day. Immunohistochemical staining was performed using polyclonal antibodies to ICOS on the sections of the spleen which were obtained from the rats in immune group at the 7th, 12th, 15th and 21st days after immunisation respectively. Western blotting was performed to investigate the dynamic expression of ICOS protein in the spleen. The same procedures were made at the corresponding time points in the rats in control group. Results A few ICOS positive cells were observed in the normal spleen. The number of ICOS positive cells in immune group increased obviously at the 7th and 12th days after immunization, reached the peak at the 15th day, and decreased at the 21st day which was still higher than that in the control group. The result of Western blotting showed that the dynamic changes of ICOS protein was identical with the changes of positive-cell number detected by immunohistochemistry. Conclusions The enhanced expression of ICOS happens before EAU occurs, which increases when the inflammation occurs and deteriorates, and decreases at the alleviative stage of EAU. It suggests that ICOS participates in the formation, development and disappearance of EAU and plays an important role in the incidence of EAU.
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ObjectiveTo investigate the expression of costimulatory molecules, Fas/FasL, and major histocompatibility complex (MHC)-class Ⅱ antigens in normal ocular tissues.MethodsTwelve eyes were obtained from the eye bank of Zhongshan Ophthalmic Center within 16 to 24 hours postmortem. Six eyes were used for making the retinal wholemounts, and the tissues (iris and ciliary body, choroid, and retina) of the others were used for making the frozen sections. Immunohistochemical staining was carried out on these retinal wholemounts as well as on tissue sections to investigate the exprenion of B7-1 and B7-2 (costimulatory molecules), HLA-DR(MHC class Ⅱ), CD68 (macrophages), Fas/FasL.ResultsThe results of immunohistochemical staining showed the presence of B7-2, FasL, CD68 and HLA-DR in the iris and ciliary body. Expression of B7-1, FasL, CD68, and HLA-DR was found in the choroid while HLA-DR, CD68 and FasL were detectable in the retina.ConclusionExpression of costimulatory molecules, MHC-class Ⅱ molecules and molecules related to apoptosis is different in the iris, ciliary body, choroid, and retina, which may play an important role in the stability of the immunological microenvironment of these tissues.
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Studies on uveitis have gained a great achievement during recent years in China.A number of studies have provided evidences to support the opinion that both Th1 and Th17 cells are involved in the pathogenesis of uveitis.Increased resistance of lym- phocytes to apoptosis due to disturbed expression and Fas/FasL,decreased frequencies and function of CD4+CD25high T cells,in- creased leptin and polymorphisms of certain Cytokines are also involved in the development or recurrence of uveitis.Clinical studies have revealed distinctive features of Vogt-Koyanagi-Harada syndrome and Fuchs syndrome in Chinese patients.Studies using Laser flare-cell meter and multifocal electroretinography have greatly contributed to our understanding of the pathophysiological alterations of uveitis.A number of papers on uveitis have been published in the top journels of ophthalmology in the world.However,it is worthwhile to point that there are very few doctors engaged in uveitis study and that diagnosis and treatment of uveitis should be further improved in future in China.