MECHNISM OF HERPES ST ROMAL KERATITIS

疱疹病毒性角膜炎的机制

• 批准号: 6078884
• 负责人: EDOUARD M CANTIN
• 金额: $ 17.6万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6078884
• 关键词: CD4 molecule; CD8 molecule; CpG islands; Herpes simplex disease; T lymphocyte; antigen presentation; cell proliferation; cornea; cytokine; gender difference; herpes simplex virus 1; keratitis; laboratory mouse; sex hormones; virus DNA; virus infection mechanism; virus replication

Herpes stromal keratitis (HSK), a leading cause of infectious blindness in the western world, is an inflammatory disease that results from herpes simplex virus type 1 (HSV) infection of the human eye. Recent results suggest that HSK is an autoimmune disease triggered by HSV infection, through a mechanism involving molecular mimicry whereby ocular-antigen reactive T cells are activated by cross recognition of an HSV-1 capsid antigen. However, other studies have shown that while viral replication is required for clinical HSK, recognition of HSV antigens by CD4+ T cells may not obligatory. Rather, it appears that HSV infection serves to provoke the proinflammatory environment responsible for recruitment and activation of effector CD4+ T cells in the cornea. The observation that pathogenic CD4+ T cells infiltrate the cornea at a time when neither infectious HSV nor viral antigen can be detected in the cornea raises questions about the precise role of HSV replication in this process. However, an important observation is that HSV DNA persists in the cornea for months and is found localized to sites of inflammatory lesions by in situ-PCR. Intriguingly, there is a correlation between persistence of HSV DNA and the propensity of different HSV strains to induce HSK; thus DNA from HSV RE, a strong inducer of HSK compared to KOS persists, while HSV KOS DNA does not. We propose testing the hypothesize that HSV DNA persisting in the cornea can induce the proinflammatory environment that drives activation of CD4+ T cells, perhaps of indiscriminant specificity, into effectors mediating HSK. In support of this hypothesis are our results demonstrating that HSV DNA contains potent immunostimulatory CpG motifs (CpG) that can both activate spleen cell proliferation and cytokine synthesis in vitro, and act as a potent adjuvant priming Th1-type CD4+ and CD8+ T cell responses to a protein antigen (ovalbumin) in vivo. We recently observed that gender strongly influenced the outcome of HSV infection including the severity of HSV eye disease and showed that in part, this could be due to the effects of sex hormones on the immune response to HSV. Given that sex hormones are known to affect antigen presentation we propose examining their effects on inflammatory responses mediated by HSV-1 DNA in vitro and the incidence and/or severity of HSK in vivo.

疱疹性基质角膜炎 (HSK) 是西方世界感染性失明的主要原因，是一种由人眼单纯疱疹病毒 1 型 (HSV) 感染引起的炎症性疾病。 最近的结果表明，HSK 是一种由 HSV 感染引发的自身免疫性疾病，通过涉及分子拟态的机制，通过交叉识别 HSV-1 衣壳抗原来激活眼抗原反应性 T 细胞。然而，其他研究表明，虽然临床 HSK 需要病毒复制，但 CD4+ T 细胞对 HSV 抗原的识别可能不是必需的。 相反，HSV 感染似乎会激发促炎环境，从而负责角膜中效应 CD4+ T 细胞的募集和激活。 当角膜中既未检测到传染性 HSV 也未检测到病毒抗原时，致病性 CD4+ T 细胞会浸润角膜，这一观察结果引发了关于 HSV 复制在此过程中的精确作用的疑问。 然而，一个重要的观察结果是，HSV DNA 在角膜中持续存在数月，并通过原位 PCR 发现位于炎症病变部位。 有趣的是，HSV DNA 的持久性与不同 HSV 毒株诱导 HSK 的倾向之间存在相关性。因此，与 KOS 相比，HSV RE 是 HSK 的强诱导剂，HSV RE 的 DNA 会持续存在，而 HSV KOS DNA 则不会。 我们建议测试以下假设：持续存在于角膜中的 HSV DNA 可以诱导促炎环境，从而驱动 CD4+ T 细胞（可能具有不加区别的特异性）激活为介导 HSK 的效应细胞。 我们的结果支持了这一假设，证明 HSV DNA 含有有效的免疫刺激 CpG 基序 (CpG)，它既可以在体外激活脾细胞增殖和细胞因子合成，又可以作为有效的佐剂在体内引发 Th1 型 CD4+ 和 CD8+ T 细胞对蛋白质抗原（卵清蛋白）的反应。 我们最近观察到，性别强烈影响 HSV 感染的结果，包括 HSV 眼病的严重程度，并表明，这在一定程度上可能是由于性激素对 HSV 免疫反应的影响。 鉴于已知性激素会影响抗原呈递，我们建议检查它们对体外 HSV-1 DNA 介导的炎症反应的影响以及体内 HSK 的发生率和/或严重程度。