非感染性葡萄膜炎的系统治疗进展

葡萄膜炎是发生于眼内组织的炎症反应。其中,非感染性葡萄膜炎是T细胞介导的自身免疫性炎症反应。尽管非感染性葡萄膜炎的系统治疗方案多种多样,但主要原理都是抑制自身免疫反应。在本综述中,我们回顾了非感染性葡萄膜炎系统治疗的历史,详细叙述了系统治疗的现状,总结了各治疗方案的利弊,同时对非感染性葡萄膜炎的系统治疗进行一定的展望。     

Cataract Surgery in HIV Seropositive Patients: Long-Term Follow-Up

Purpose: To study epidemiology and clinical findings of cataract in HIV+ patients.

Methods: A total of 32 HIV+ patients, 11 with uveitis/retinitis before surgery and 21 without, mean follow-up 44.9 ± 36.6 months, and 114 HIV- patients, 57 with uveitis/retinitis before surgery and 57 without, were retrospectively compared.

Results: Visual acuity improved in all HIV+ patients (p < 0.001), who were younger (p = 0.01) and more frequently males (p = 0.027). HIV+ patients with uveitis prior surgery improved less (p = 0.046) than HIV- (p < 0.001); their anterior chamber inflammation was similar to baseline. Male sex (p = 0.005), younger age (p < 0.001), dyslipidaemia (p = 0.058), HBV+ (p = 0.037), and unilateral cataract (p = 0.001) were more frequent in HIV+ patients with senile cataract, but they showed the same postoperative course as HIV- patients.

Conclusion: Cataract surgery in HIV+ patients is safe and effective. Uveitis prior to surgery did not significantly affect the postoperative course. Systemic comorbidities are more frequent in HIV+ patients with senile cataract than in HIV- subjects.     

Emerging Viral Infections Causing Anterior Uveitis

Purpose: To review the systemic and ocular manifestations of specific emergent viral infectious diseases relevant to the ophthalmologist with particular emphasis on anterior uveitis

Methods: Review of literature.

Results: Arboviral diseases are among the most important emergent and resurgent human infections, occurring mostly in tropical and subtropical zones, but appearing in virtually all regions of the world as a result of climate change, travel, and globalization. Arboviral infections are transmitted to humans by the bite of hematophagous arthropods, mainly mosquitoes. Systemic disease may range from asymptomatic to life-threatening. A wide variety of ocular manifestations, including uveitis, has been reported in association with these emerging viral diseases. Numerous viruses other than arboviruses also have been recently recognized as a potential cause of uveitis.

Conclusions: Proper clinical diagnosis of any emerging infectious disease is based on epidemiological data, history, systemic symptoms and signs, and the pattern of ocular involvement. The diagnosis is usually confirmed by detection of virus-specific DNA or antivirus antibodies in serum.     

内毒素诱导的葡萄膜炎中虹膜固有组织细胞上MyD88与TLR-4的共表达

目的观察小鼠内毒素诱导的葡萄膜炎(endotoxin-induced uveitis,EIU)模型中Toll样受体-4(Toll-like receptor-4,TLR-4)、髓样分化因子88(myeloid differentiation factor 88,MyD88)、CD163的共表达。方法 6～8周龄雄性C3H/HeN(野生型)小鼠25只,C3H/HeJ(TLR-4基因缺陷型)小鼠5只,分别腹腔注射霍乱弧菌内毒素细胞壁脂多糖(lipopolysaccharide,LPS)诱导急性前葡萄膜炎动物模型,处死小鼠后虹膜、睫状体铺片,用免疫荧光三标记的方法检测虹膜、睫状体组织内不同时间CD163、TLR-4、MyD88的表达,并对虹膜内CD163、TLR-4和MyD88阳性细胞进行计数分析。结果 C3H/HeN小鼠LPS注射后12h结膜囊内出现炎症反应,24～48h达到高峰,72h炎症逐渐消退,而C3H/HeJ小鼠LPS注射后没有发现炎症反应。在内毒素诱导的C3H/HeJ小鼠虹膜中未检测到CD163、TLR-4和MyD88阳性细胞。C3H/HeN小鼠腹腔注射LPS后在虹膜铺片内0h未见CD163、TLR-4与MyD88阳性表达,12h后可见阳性细胞(40.3±8.9、45.2±6.3、42.5±4.1),24h阳性细胞数(121.0±39.5、138.6±28.3、125.5±36.1)较12h明显增多,差异均有统计学意义(均为P<0.05);48h阳性细胞数(132.3±54.5、129.9±36.2、122.1±29.3)与24h相比,差异均无统计学意义(均为P>0.05);72h阳性细胞数(12.8±3.2、10.4±5.6、9.3±5.2)较48h减少,差异均有显著统计学意义(均为P<0.01)。结论小鼠EIU模型中,LPS激活了CD163标记的巨噬细胞膜表面的TLR-4,TLR-4与MyD88途径可能是EIU主要的信号传导途径。     

Increased presence of Epstein-Barr virus DNA in ocular fluid samples from HIV negative immunocompromised patients with uveitis

AIMS—To investigate whether routine testing for Epstein-Barr virus (EBV) is necessary in the examination of a patient with uveitis.
METHODS—Intraocular EBV DNA was determined in 183 ocular fluid samples taken from patients with AIDS and uveitis, HIV negative immunocompromised uveitis, acute retinal necrosis, toxoplasma chorioretinitis, intraocular lymphoma, anterior uveitis, and miscellaneous uveitis of unknown cause. In 82 samples from this group of patients paired serum/ocular fluid analysis was performed to detect local antibody production against EBV. Controls (n=46) included ocular fluid samples taken during surgery for diabetic retinopathy, macular pucker, or cataract.
RESULTS—Serum antibody titres to EBV capsid antigen proved to be significantly increased in HIV negative immunocompromised patients with uveitis (p<0.01) compared with controls. Local antibody production revealed only three positive cases out of 82 patients tested, two results were borderline positive and one patient had uveitis caused by VZV. EBV DNA was detected in three out of 46 control ocular fluid samples. In the different uveitis groups EBV DNA was noted, but was not significantly higher than in the controls, except in six out of 11 HIV negative immunocompromised patients (p=0.0008). In four out of these six cases another infectious agent (VZV, HSV, CMV, or Toxoplasma gondii) had previously been identified as the cause of the uveitis.
CONCLUSIONS—When comparing various groups of uveitis patients, EBV DNA was found more often in HIV negative immunocompromised patients with uveitis. Testing for EBV does not have to be included in the routine management of patients with uveitis, since indications for an important role of this virus were not found in the pathogenesis of intraocular inflammation.

Keywords: Epstein-Barr virus; intraocular fluid; polymerase chain reaction; uveitis     

Vitreous intercellular adhesion molecule 1 in uveitis complicated by retinal detachment

AIMS—The vitreous levels of soluble intercellular adhesion molecule 1 (sICAM-1) were investigated in uveitic eyes undergoing vitrectomy for retinal detachment (RD) or other complications, and the presence of this molecule was related to disease activity and vitreous levels of the cytokine tumour necrosis factor α (TNFα), known to upregulate ICAM-1 expression on various cells.
METHODS—Vitreous and serum samples from 23 patients with either active or quiescent uveitis undergoing retinal surgery were examined for the levels of immunoreactive sICAM-1 and TNFα by ELISA methods, and for the presence of biologically active TNFα. Vitreous from non-uveitic eyes with rhegmatogenous retinal detachment (RRD), macular holes or cadaveric eyes were used as controls.
RESULTS—As a whole, vitreous from uveitic eyes complicated or uncomplicated by RRD contained significantly higher levels of sICAM-1 than vitreous from non-uveitic eyes with RRD alone (p < 0.0005), eyes with macular holes (p< 0.0001), or normal cadaveric vitreous (p < 0.0001). The proportion of vitreous containing >20 ng/ml sICAM-1 (> four times the normal values) was significantly higher in eyes with uveitis complicated by RRD than in those eyes without RRD (Fisher's test, p= 0.02), and although levels of sICAM-1 were higher in eyes with active uveitis than in those with quiet disease (p < 0.02), this could not be dissociated from the increase caused by RRD. There was a relation between the vitreous levels of sICAM-1 and those of immunoreactive TNFα (Spearman's correlation coefficient; r = 0.601, p = 0.006), but not between the vitreous levels of sICAM-1 and those of biologically active TNFα.
CONCLUSION—Increased vitreous sICAM-1 levels and the association of this molecule with the presence of immunoreactive TNFα in uveitic eyes confirm the operation of cytokine mediated vascular reactions at the blood-retinal barrier during the development of this condition. The persistence of high vitreous levels of sICAM-1 in eyes with uveitis complicated by RRD despite previous immunosuppression may indicate a low rate of clearance of inflammatory molecules from the vitreous cavity and an exacerbation of the existing inflammatory process by the retinal detachment itself.

Keywords: vitreous; retinal detachment; ICAM-1; TNFα; uveitis     

龙胆泻肝汤抑制葡萄膜炎大鼠Notch信号通路活化的作用

目的　探讨龙胆泻肝汤（Longdan Xiegan Decoction，LXD）对实验性自身免疫性葡萄膜炎（experimental autoimmune uveitis，EAU）大鼠Notch信号通路活化的抑制作用及其对辅助性T细胞17（T helper 17，Th17）和调节性T细胞（regulatory T cell，Treg）表达水平的影响。方法　随机将雌性Lewis大鼠分为正常对照（NC）组、EAU模型组、LXD干预组。EAU模型组和LXD干预组大鼠诱导EAU，免疫后LXD干预组大鼠每天给予LXD灌胃处理，EAU模型组大鼠给予等量生理盐水灌胃。免疫后12 d观察大鼠眼部炎症表现，取三组大鼠眼球进行病理切片，观察病理学变化；实时荧光定量PCR（quantitative polymerase chain reaction，QT-PCR）和酶联免疫吸附实验（enzyme-linked immunosorbent assay，ELISA）检测免疫后12 d三组大鼠脾脏、淋巴结及眼组织中Notch1、DLL4、白细胞介素10（interleukin 10,IL-10）和IL-17 mRNA及蛋白的表达；流式细胞仪检测三组大鼠各组织中Th17、Treg细胞的表达。结果　病理检查结果表明，LXD对EAU大鼠眼部组织结构有明显的保护作用。QT-PCR和ELISA检测结果发现，与NC组相比，LXD干预组大鼠脾脏、淋巴结和眼组织中Notch1、DLL4、IL-10、IL-17 mRNA和蛋白表达水平均升高，但除IL-10外，其他明显低于EAU模型组（均为P<0.05）；流式细胞仪检测结果发现，EAU模型组大鼠的各组织中Th17/Treg比例均高于NC组，经LXD干预后，Th17细胞表达水平下降，Treg表达水平升高，两者比例趋向平衡。结论　LXD可有效降低EAU大鼠脾脏、淋巴结、眼组织中Notch1、DLL4、IL-10和IL-17 mRNA和蛋白的表达水平，改善Th17/Treg细胞比例的平衡，从而有效减轻EAU大鼠的眼部炎症，保护眼部组织结构，调节全身及眼部的免疫状态。     

Gut microbiota as a source of a surrogate antigen that triggers autoimmunity in an immune privileged site

Recent discoveries on the role of commensal microbiota have significantly changed our understanding of human physiology. The host-microbiota interplay is now an important aspect to take into account to understand immune responses and immunological diseases. Autoimmune uveitis is a sight-threatening disease that arises without a known infectious etiology. It is unknown where and how autoreactive T cells become primed to trigger disease in the eye, which is an immune privileged site. We recently reported data supporting the notion that retina-specific T cells receive a signal in the gut from commensal microbiota-derived cross-reactive antigen(s) and trigger autoimmune uveitis in the R161H mouse model. Here we discuss our published findings, as well as our recent attempts to identify the responsible microbe(s) by using different antibiotic treatments, 16S rDNA sequencing and homology searches for candidate antigenic mimic(s) of the retinal antigen.