细胞毒性T淋巴细胞相关抗原-4融合蛋白对鼠单纯疱疹性角膜基质炎抑制作用的研究

研究细胞毒性T淋巴细胞相关抗原-4融合蛋白(cytotoxic Tlymphocyte-associated antigen-4 immunoglobulin,CTIA-4Ig)对鼠单纯疱疹性角膜基质炎(herpetic stromal kerafifis,HSK)的抑制作用。方法用单纯疱疹病毒1型(herpes simplex virus type 1,HSV-1)接种于BALB／c鼠角膜上建立HSK动物模型,采用CTIA-4Ig阻断B7：CD28／CTIA-4协同刺激途径,抑制T淋巴细胞增殖、分化为效应细胞;观察HSK的发病率、临床特征、角膜组织学改变、角膜病毒滴度、迟发型超敏反应及抗原刺激脾细胞分泌细胞因子的情况。结果CTIA-4Ig可减少小鼠外周血中CD4^ T淋巴细胞(81．6％)及CD8^ T淋巴细胞(67．9％),阻止鼠发生HSK、减轻角膜混浊程度及角膜内炎性细胞的浸润、损伤鼠的迟发型超敏反应能力,抑制鼠脾细胞分泌辅助性T淋巴细胞1型(T-helper 1,Th1)细胞因子;但不影响角膜病毒滴度及小鼠死亡率。结论用CTIA-4Ig阻断B7：CD28／CTIA-4协同刺激途径,能够抑制T淋巴细胞增殖并抑制CIM^ Th1细胞的功能,阻止HSK发病,减轻HSK的严重程度。     

OX40-Ig融合蛋白对鼠单纯疱疹性角膜基质炎的抑制作用

目的研究OX40-Ig融合蛋白对鼠单纯疱疹性角膜基质炎(HSK)的免疫抑制作用。方法将1×106PFU的单纯疱疹病毒1型(HSV-1)Mckrae毒株接种于BALB/c鼠的角膜上建立HSK模型;分别于接种病毒的当天、接种后第2、4d将OX40-Ig融合蛋白100μg注射到鼠的腹膜下,观察OX40-Ig融合蛋白对鼠HSK的影响。结果OX40-Ig融合蛋白使鼠外周血中CD4 T细胞减少了78·2%,使鼠HSK发病率由83·3%下降到20·0%。OX40-Ig治疗组的小鼠角膜基质混浊程度较对照组明显减轻,角膜内炎性细胞浸润也明显减少,迟发型超敏反应能力显著下降。结论OX40-Ig融合蛋白能够阻断OX-40/OX-40L协同刺激途径,抑制CD4 T细胞增生,阻止HSK的发病,减轻HSK的严重程度。     

IL-17在单纯疱疹性角膜基质炎小鼠中表达的变化

目的:研究IL-17在小鼠单纯疱疹性角膜基质炎模型中的表达。方法:将1.0×106空斑单位的单纯疱疹病毒1型KOS毒株接种于BALB/c鼠的角膜上,建立HSK动物模型。免疫组织化学染色观察IL-17在角膜中的表达。分别取正常小鼠及接种病毒后的第1～3,7,10,14,21,28d,用毛细管取小鼠的左眼眼眶静脉窦血1mL,分离淋巴细胞,行荧光抗体染色,用流式细胞仪检测IL-17阳性的CD4+T细胞的表达。在裂隙灯显微镜下观察角膜的变化,检查角膜的组织学病理改变。结果:实验组中,角膜和外周血均有IL-17表达。实验组角膜基质内炎性细胞、角膜混浊程度非常严重。IL-17的表达与HSK小鼠炎症表现的严重程度成正相关(r=0.609,P<0.01)。结论:IL-17在HSK小鼠模型中呈高表达,且IL-17在HSK的发病过程中起一定作用。     

单纯疱疹病毒性角膜炎小鼠模型的建立及鉴定

目的：探讨建立不同感染时期HSK小鼠动物模型,为HSK的深入研究建立基础。方法：Balb/c小鼠125只麻醉后在显微镜下用刀片背面尖端于角膜＂#＂字划痕,其中100只小鼠接种HSV-Ⅰ病毒,另25只小鼠不接种病毒作为正常对照组。术后每天用10g/L荧光素钠染色后裂隙灯显微镜下观察角膜病变发生情况,并取角膜表面泪液进行HEK293T细胞检测以确定裂隙灯显微镜下有无病毒复制。对潜伏感染期小鼠模型采用紫外线B光照射以诱导HSK复发。结果：接种HSV-Ⅰ病毒的小鼠模型眼于接种后3d内全部出现急性上皮性角膜炎表现。经阿昔洛韦滴眼液治疗1wk后角膜炎症消失,但角膜和三叉神经节中PCR检测病毒仍为阳性。潜伏感染期小鼠模型经紫外线B光照射后也都在1wk内复发,并表现为以基质型角膜炎为主要临床表现的角膜病变。结论：采用角膜划痕法对Balb/c小鼠接种HSV-Ⅰ病毒和紫外线B光照射可以成功地制作出原发感染期、潜伏感染期和复发感染期等不同感染时期的HSK模型,而且操作相对简单、方便易行。     

细胞因子在鼠复发性单纯疱疹性角膜基质炎角膜组织中的表达

目的探讨CD4^ T辅助细胞1型(Th1)和T辅助细胞2型(Th2)分泌的细胞因子在鼠复发性单纯疱疹性角膜基质炎(HSK)角膜组织中的表达水平,及其与复发性HSK的关系。方法制备复发性HSK的BALB／c鼠模型,用紫外线B光照射鼠的角膜诱导HSK复发;分别于紫外线照射前,照射后第3、7、10、14、21及28天,取角膜中央直径为2mm的角膜环,用逆转录聚合酶链反应(RT-PCR)检测Th1型细胞因子(IFN-γ、IL-12)和Th2型细胞因子(IL4、IL-10)的表达水平。结果处于病毒潜伏感染期的小鼠经紫外线照射诱导病毒复发后,角膜基质混浊于紫外线照射后的7～14d达到高峰;在此期间,IFN-γ、IL-12、IL-10和IL-4mRNA在角膜组织中均有表达。其中,IFN—γ和IL-10在临床疾病的发生、发展过程中(病毒激活后第3～14天)高表达,在疾病恢复期(14d后)表达减弱,与角膜基质混浊程度密切相关;IL-12是角膜组织内表达最丰富的细胞因子,在病毒激活后的第3天即开始高表达,高表达持续经过整个观察期;IL-4在病毒激活后的第3～14天有明显表达。结论在复发性HSK的角膜损伤早期,Th1型细胞因子和Th2型细胞因子同时表达于角膜组织中,与T细胞的免疫记忆性有关。IL-10的表达趋势平行于IFN-γ的表达,其表达水平与HSK的疾病程度密切相关。复发性HSK无法严格区分是由Th1细胞介导的还是由Th2细胞介导的,角膜的损伤与修复可能依赖于损伤性细胞因子和保护性细胞因子在病毒复发位置上的平衡。     

小鼠单纯疱疹病毒性角膜炎中基质金属蛋白酶的表达及活性研究

目的 探讨角膜感染Ⅰ型单纯疱疹病毒(HSV-1)后基质金属蛋白酶(MMPs)及其组织抑制剂(TIMPs)在角膜中的分布及酶活性表达。方法 BALB／c小鼠眼角膜接种HSV-1(KOS株)以诱发单纯疱疹病毒性角膜炎(HSK)。分别收集正常眼球及感染后第2、7、14及28天的感染眼球。应用免疫组织化学法和Western blot方法检测MMP-2、-8、-9及TIMP-1、-2在角膜组织中的表达,并应用酶谱(Zymography)技术检测MMPs的酶活性。结果 感染后第2天,感染眼的MMP-2、-9及TIMP-1、-2表达比未感染眼增加且表达主要位于浅表基质层及上皮下的炎性细胞中。感染后第14和28天可见坏死性角膜炎及角膜溃疡形成,同时角膜基质和浸润的炎性细胞中尤其溃疡处,可见MMP-2、-9及TIMP-1、-2表达显著增加。溃疡区域有大量MMP-8阳性染色的中性粒细胞。角膜感染HSV-1后,明胶酶(MMP-2、-9)活性和胶原酶(MMP-8)活性均增强。结论 HSV-1角膜感染后,由角膜细胞和浸润的炎性细胞分泌产生的MMPs可能对上皮性角膜炎与溃疡形成过程起重要的促进作用。MMPs与TIMPs的相互作用可能对HSK的坏死性病变起重要调节作用。（中华眼科杂志,2004,40：395-399)     

转录因子T-bet在单纯疱疹病毒感染小鼠外周血中的表达

目的研究单纯疱疹病毒Ⅰ型(herpes si mplex virus type1,HSV-1)感染小鼠眼球以后转录因子T-bet在小鼠外周血中的表达,探讨T-bet的表达与单纯疱疹性角膜基质炎之间的关系。方法将106空斑单位(plague forming unit,PFU)·L-1的HSV-1Mckrae毒株接种于BALB/c鼠的角膜上建立单纯疱疹性角膜基质炎(herpetic stromal keratitis,HSK)动物模型,分别于角膜接种病毒后的第1d、3d、7d、10d、14d、21d及28d,用毛细管取小鼠的左眼眼眶静脉窦血1mL,提取淋巴细胞,用半定量逆转录聚合酶链反应(RT-PCR)检测T-bet mRNA的表达水平;在裂隙灯显微镜下观察小鼠角膜的临床变化,组织学检查角膜的病理改变;用ELISA法检测T-bet蛋白在角膜组织中的表达水平。结果BALB/c鼠的角膜接种HSV-1后的1~5d,角膜擦拭液中均检测出HSV-1复制,表明小鼠感染了单纯疱疹病毒;裂隙灯显微镜观察:HSV-1感染鼠的角膜后,小鼠均患了急性角膜上皮炎,并于感染后1周内痊愈。其中81.7%(49/60)的小鼠自感染病毒后第10d起开始出现角膜基质炎改变,表现为灶状角膜基质混浊,局部角膜新生血管化,角膜基质内大量的炎性细胞浸润。角膜基质混浊逐渐进展,在病毒感染后的第14~21d达到高峰。RT-PCR检测的数据显示:未感染HSV-1的对照组小鼠的外周血中不表达T-bet mRNA;HSV-1感染小鼠的早期即可诱导T-bet mRNA在小鼠外周血中的表达,并且表达持续存在;T-bet mRNA表达的高峰时间(10~28d),位于角膜基质炎发生和发展的过程中。ELISA法检测角膜提取物中的T-bet蛋白显示了相似的结果。结论HSV-1上调T-bet mRNA在小鼠外周血中的表达;T-bet的表达与角膜基质炎的发生和发展密切相关。     

协同刺激分子在单纯疱疹性角膜基质炎鼠外周血中的表达

目的研究鼠单纯疱疹性角膜基质炎发生和发展过程中协同刺激分子在外周血中的表达水平,探讨协同刺激分子的表达与单纯疱疹性角膜基质炎之间的关系。方法用单纯疱疹病毒1型(herpessimplexvirustype1,HSV1)接种于BALB/c鼠角膜上建立单纯疱疹性角膜基质炎(herpeticstromalkeratitis,HSK)动物模型,分别于角膜接种病毒前和接种病毒后的第1d、3d、7d、10d、14d、21d及28d,用毛细管取小鼠的左眼眼眶静脉窦血1mL,提取淋巴细胞,用半定量逆转录聚合酶链反应检测协同刺激分子B71、B72、CD28、CTLA4的表达水平;同时,在裂隙灯显微镜下观察鼠角膜的临床变化。结果HSV1感染鼠的角膜后,小鼠均患了急性角膜上皮炎,并于感染后1周内痊愈。86.7%(78/90)的小鼠自感染病毒后第10d起开始出现角膜基质炎改变,典型的表现为灶状角膜基质混浊,局部角膜新生血管化,炎性细胞浸润。角膜基质混浊逐渐进展,于3周时达到高峰,4周时开始修复。鼠在感染病毒之前,外周血中表达微弱的CD28mRNA,不表达CTLA4、B71及B72mRNA。鼠感染病毒后,外周血中CD28、CTLA4和B71的表达量均显著增加,B72仍无表达;CD28在HSK的发生和发展过程中表达水平较高,在疾病愈合过程中表达减弱;B71表达的高峰时间是病毒感染后的3～21d,以稍低的表达水平平行于CD28的表达。结论在鼠单纯疱疹性角膜基质炎的发病过程中,协同刺激分子CD28/CTLA4:B71在外周血中的表达明显增强,在诱导CD4 T细胞介导的单纯疱疹性角膜基质炎中起关键性作用。     

玉屏风散对单纯疱疹病毒性角膜炎模型小鼠细胞免疫功能的影响

目的 观察中药玉屏风散对不同感染时期单纯疱疹病毒性角膜炎(herpes simplex keratitis,HSK)小鼠模型细胞免疫水平的影响,探讨其抗HSK复发的作用及其机制.方法 采用流式细胞术分析不同感染时期HSK模型小鼠脾脏CD3+、CD4+、CD8+T淋巴细胞表达水平,ELISA法检测血清γ-IFN、IL-2、IL-4及IL-10水平改变.观察并比较玉屏风散对不同感染时期HSK小鼠模型CD3+、CD4+、CD8+T淋巴细胞和血清γ-IFN、IL-2、IL-4及IL-10水平改变的影响.结果 与正常对照组比较,HSK潜伏期(PI28 d)和复发期(UVB 3 d)模型小鼠CD3+、CD4+T淋巴细胞表达明显降低,CD8+T淋巴细胞表达明显升高;外周血Th1型细胞因子IL-2、γ-IFN水平显著降低,Th2型细胞因子IL-4、IL-10水平显著增高.CD4+T淋巴细胞表达的降低与IL-2、γ-IFN水平的降低呈显著正相关.在同一感染期内,玉屏风散治疗组、玉屏风散+阿昔洛韦治疗组治疗末期与治疗开始时比较,HSK模型小鼠体内CD3+、CD4+、CD8+T淋巴细胞表达水平和外周血Th1型细胞因子IL-2、γ-IFN,Th2型细胞因子IL-4、IL-10表达水平均有明显改善,并显著优于单纯阿昔洛韦治疗组及空白对照组.结论 玉屏风散具有提高HSK潜伏期和复发期模型小鼠体内CD3+、CD4+T淋巴细胞表达,降低CD8+T淋巴细胞表达,改善CD4+/CD8+比值水平,调节机体细胞免疫功能的作用.     

Role of CD160/BTLA-HVEM-LIGHT/LT-α signaling pathway related to herpetic stromal keratitis北大核心CSCD

Ocular infection of herpes simplex virus-1 (HSV1) can result in herpetic stromal keratitis (HSK), which impairs vision and is a common cause of human blindness. Studies indicated that HSK lesions are mainly orchestrated by CD4+ T cells. Herpesvirus entry mediator (HVEM), a tumor necrosis factor receptor superfamily member, facilitates virus entry through interactions with viral glycoprotein D (gD). HVEM, a widely expressed tumor necrosis factor (TNF) receptor superfamily member with diverse roles in immune signaling. Intriguingly, HVEM has five receptors: two costimulatory molecules (LIGHT and LT-α), two coinhibitory molecules (BTLA and CD160), and the HSV-gD. HVEM is referred to as a molecular switch because of its capacity to deliver costimulatory signals when bound to LIGHT/LT-α and to produce inhibitory signals when bound to BTLA/CD160.In this paper, the researching progress of the five receptors functions of HVEM and CD160/BTLA-HVEM-LIGHT/LT-α signaling pathway in the HSK were reviewed. We have to provide an insight into the pathogenesis of HSK and clinical ideas for the effective treatment of HSK. Through effective clinical intervention, the inflammatory immune response is reduced, thereby achieving therapeutic effects on recurrence of autoimmune diseases and chronic immune diseases. Copyright © 2018 by the Chinese Medical Association.     

小鼠B、T淋巴细胞衰减因子真核表达载体的构建及在HEK293细胞中的表达

目的构建小鼠B、T淋巴细胞衰减因子（BTLA）的真核表达载体,并分析其在人胚肾HEK293细胞中的表达,为单纯疱疹性角膜基质炎的免疫治疗奠定基础。方法应用PCR法获得小鼠BTLA胞外功能区的cDNA片段,将其插入真核表达载体pcDNA3.1中,获得重组表达质粒pBTLA,经酶切鉴定和测序正确后转染HEK293细胞,并利用间接免疫荧光法、实时定量PCR（real-time PCR）、Western blot技术检测BTLA在细胞中的表达。结果重组质粒pBTLA经酶切鉴定和测序,确认插入序列正确,与基因文库中提供的基因序列同源性达98%～100%。Real-time PCR检测可见转染了重组质粒pBTLA的HEK293细胞内BTLA mRNA表达增强（P=0.00）,3个组间HEK293细胞内BTLA mRNA表达差异有统计学意义（F=167.83,P=0.00）;Western blot结果显示,转染重组质粒pBTLA的HEK293细胞内BTLA蛋白表达明显增强,转染后24～48 h表达最强。间接免疫荧光结果显示BTLA蛋白主要表达在HEK293细胞的细胞膜和细胞质中。结论成功构建了BTLA的真核表达载体,该重组质粒在HEK293细胞中能够表达BTLA,为后续研究BTLA在抗病毒免疫中的作用奠定基础。     

Herpetic stromal keratitis: an immunopathologic disease mediated by CD4+ T lymphocytes.

To investigate the role of T cell subsets in the development of herpetic stromal keratitis (HSK) in a well defined model, we used an adoptive transfer approach in which thymectomized and T cell-depleted mice [T(-)] were reconstituted with different numbers of syngeneic immune T lymphocytes after topical corneal challenge with RE strain of herpes simplex virus-1. In vitro stimulated or unstimulated immune T cells obtained from cervical and retropharyngeal lymph nodes of mice with HSK were used in adoptive transfer experiments. Although T(-) mice developed an initial epithelial inflammation, stromal keratitis did not occur. Reconstitution experiments revealed that mice that received 2 x 10(7) or more unfractionated immune T cells could develop HSK lesions with severity comparable to immuno-competent control mice. In mice receiving CD8(+)-depleted populations, even fewer cells (5 x 10(6)/mouse) were able to induce significant HSK. In contrast, mice that received similar or increased numbers of cells depleted of CD4+ T lymphocytes did not develop HSK. Immune T lymphocytes transferred to mice that were mock infected on the cornea did not develop HSK, indicating that the immunopathogenic cells were virus specific and not merely reacting to autoantigens. Histopathologic examination of the diseased corneas demonstrated that the stromal inflammation in euthymic normal and T(-)-reconstituted mice was characterized by extensive polymorphonuclear leukocyte infiltration. Scattered lymphocytes, and occasional macrophages also were observed. These results provide further evidence that HSK represents an immunopathologic process mediated mainly by CD4+ T cells.     

Activated inflammatory infiltrate in HSV-1-infected corneas without herpes stromal keratitis

PURPOSE: To investigate herpes stromal keratitis (HSK) immunopathology by studying HSV-1-infected corneas that fail to develop HSK. METHODS: Plaque assay quantified HSV-1 in the tear film of infected mice. FACS analysis enumerated corneal leukocytic infiltrate and characterized infiltrate phenotypically after staining for activation and regulatory T cell (Treg) markers and for markers of antigen-presenting cell (APC) maturation. Treg cells were depleted in vivo using anti-CD25 mAb. Luminex analysis quantified the amount of cytokines and chemokines expressed in corneal tissue homogenate. RESULTS: Infected corneas without HSK exhibited a pronounced leukocytic infiltrate containing a significantly higher proportion and nearly identical absolute number of activated CD4+ T cells 15 days after infection when compared with those with HSK. Moreover, the frequency and absolute number of regulatory CD4+ T cells (Tregs) was lower in nondiseased corneas, and Treg depletion did not influence HSK incidence. The frequency of mature, immunogenic DCs and the ratio of mature DCs to CD4+ T cells were nearly identical in corneas with and without HSK. The authors observed a reduced population of neutrophils and reduced expression of neutrophil chemoattractants MIP-1beta and keratinocyte chemoattractant and the neutrophil-attracting cytokine IL-6 in corneas without HSK. CONCLUSIONS: These findings demonstrate that HSV-1-infected corneas can retain clarity in the presence of a substantial secondary leukocytic infiltrate, that activated CD4+ T cells, while necessary, are not sufficient for HSK development, that susceptibility to HSK is not determined by Tregs, and that clinical disease correlates with the accumulation of a critical mass of neutrophils through chemoattraction.     

CD8 T cells mediate transient herpes stromal keratitis in CD4-deficient mice

PURPOSE: To evaluate the role of CD4(+) T cells in the development of murine herpes stromal keratitis (HSK). METHODS: The corneas of wild-type (WT) BALB/c mice and three types of CD4-deficient BALB/c mice (CD4(-/-), CD4-depleted, CD4 and CD8 double-depleted) were infected with different doses of HSV-1 RE, and HSK incidence and severity were monitored. Corneal infiltrates were quantitatively and functionally assayed by flow cytometric analysis of individually digested diseased corneas and documented histologically. RESULTS: At a relatively high infectious dose (1 x 10(5) pfu/cornea): (1) CD4-deficient and WT BALB/c mice had severe HSK with a similar incidence (80%-100%), whereas HSK did not develop in mice deficient in both CD4(+) and CD8(+) T cells; (2) neutrophils were the predominate leukocyte in the corneas of CD4-deficient and WT mice; (3) the corneas of WT mice had activated, HSV-1-specific CD4(+) T cells, but few if any CD8(+) T cells; (4) the corneas of CD4-deficient mice had activated, HSV-1-specific CD8(+) T cells; and (5) HSK in CD4-deficient mice was transient, showing loss of CD8(+) T cells at 2 to 3 weeks after infection (pi) followed by a loss of neutrophils. At a relatively low infectious dose of HSV-1 (10(3) pfu/cornea) severe HSK developed in 80% to 90% of WT mice, but in only 30% to 40% of CD4-deficient mice. CONCLUSIONS: CD4(+) T cells preferentially mediate HSK, but, in their absence, a high infectious dose of HSV-1 can induce histologically similar but transient HSK that is mediated by CD8(+) T cells.     

胸腺肽应用于复发性单纯疱疹病毒性角膜炎外周血T淋巴细胞亚群观察

目的:探讨胸腺肽(thymosin)治疗复发性单纯疱疹性病毒性角膜炎外周血T淋巴细胞亚群。方法:收集复发性单纯疱疹病毒性角膜炎患者33例、健康对照者28例,应用流式细胞仪技术测定T细胞亚群。结果:复发性单纯疱疹病毒性角膜炎患者治疗前CD3、CD4明显下降(P<0.05),CD8升高,CD4/CD8比值下降(P<0.05)。23例痊愈患者治疗后T淋巴细胞亚群接近正常水平,而6例未痊愈患者治疗后T淋巴细胞亚群虽有所提高,但仍低于健康对照(P<0.05)。结论:复发性单纯疱疹病毒性角膜炎患者细胞免疫功能降低,胸腺肽肠溶片能够增强患者细胞免疫功能,取得较好效果。     

Influence of dimethylfumarate on experimental HSV-1 necrotizing keratitis

Background This study was performed to investigate the influence of fumaric acid esters on the course of herpes stromal keratitis (HSK).Methods The corneas of BALB/c mice were inoculated with 105 plaque-forming units of herpes simplex virus 1 (HSV-1, KOS strain). Groups of mice were treated intraperitoneally with phosphate buffered saline (PBS) (control mice), or with dimethylfumarate (DMF) at 15 mg/kg of body weight dissolved in PBS daily for 28 days pre-infection and for 14 days post-infection. The course of HSV-1 keratitis was studied clinically. Corneal sections were examined for inflammatory cell infiltration. The numbers of CD3, GR-1, CD11b and F4/80-expressing cells infiltrating the corneas were analyzed by immunohistochemistry.Results On day 14 after HSV infection, 72% of the mice in the control group had severe HSK. The development of HSK was reduced by DMF treatment in the DMF group (22%) (P=0.004). The total number of inflammatory cells and infiltration of polymorphonuclear-neutrophils (PMNs) were reduced in the corneas of DMF-treated mice. Compared to the PBS-treated mice, numbers of CD3, CD11b, GR-1 and F4/80-positive cells were reduced in the DMF group of mice.Conclusions The course of experimental herpes stromal keratitis can be improved with systemic fumaric acid ester treatment. The improvement of keratitis correlates with a reduced corneal infiltration of T cells and mononuclear cells.The authors have no financial interest in any of the reagents used in this study     

Immunological Aspects of Herpetic Stromal Keratitis

Herpetic stromal keratitis (HSK) is an immune reaction related to herpes simplex virus (HSV) corneal infection, and has many important immunological aspects. CD4⁺ T lymphocytes, especially Th1 cells, are the principal mediators for HSK. In addition, neutrophils and antigen-presenting cells play vital roles in HSK. CD8⁺ T lymphocytes, B cells, and natural killer cells all participate in the pathogenesis of HSK under certain circumstances. Many molecules are involved in the pathogenesis of HSK. Th1 cytokines such as interleukin 2 (IL-2), IL-12 and interferon γ, and inflammatory cytokines such as IL-1α and IL-6 are especially important ones. Among various chemokines that take part in HSK, MIP-1α is one of the most important aggravating factors. Vaccination therapy against HSK has been developed; glycoprotein D is a particularly promising candidate. However, the possibility of HSK exacerbation due to vaccination is the final problem to be solved before vaccination can be clinically applied to HSK. Molecular mimicry theory and bystander activation theory are the two new autoimmune theories that have been advocated. Since genuine autoimmune HSK without HSV growth can hardly be the case in clinical practice, some part of these new theories remains controversial. In the future, better understanding of the pathogenesis of HSK is essential to resolve the paradox between suppressing the immune reaction to avoid corneal scarring and preventing viral proliferation.     

Immunological aspects of herpetic stromal keratitis

Herpetic stromal keratitis (HSK) is an immune reaction related to herpes simplex virus (HSV) corneal infection, and has many important immunological aspects. CD4(+) T lymphocytes, especially Th1 cells, are the principal mediators for HSK. In addition, neutrophils and antigen-presenting cells play vital roles in HSK. CD8(+) T lymphocytes, B cells, and natural killer cells all participate in the pathogenesis of HSK under certain circumstances. Many molecules are involved in the pathogenesis of HSK. Th1 cytokines such as interleukin 2 (IL-2), IL-12 and interferon gamma, and inflammatory cytokines such as IL-1alpha and IL-6 are especially important ones. Among various chemokines that take part in HSK, MIP-1alpha is one of the most important aggravating factors. Vaccination therapy against HSK has been developed; glycoprotein D is a particularly promising candidate. However, the possibility of HSK exacerbation due to vaccination is the final problem to be solved before vaccination can be clinically applied to HSK. Molecular mimicry theory and bystander activation theory are the two new autoimmune theories that have been advocated. Since genuine autoimmune HSK without HSV growth can hardly be the case in clinical practice, some part of these new theories remains controversial. In the future, better understanding of the pathogenesis of HSK is essential to resolve the paradox between suppressing the immune reaction to avoid corneal scarring and preventing viral proliferation.