MECHNISM OF HERPES ST ROMAL KERATITIS

疱疹间质角膜炎（HSK）是一种由人眼感染单纯疱疹病毒1型（HSV）引起的炎症性疾病，是西方世界传染性失明的主要原因。最近的研究结果表明，HSK是一种由HSV感染引发的自身免疫性疾病，其机制涉及分子模仿，即通过交叉识别HSV-1衣壳抗原激活眼抗原反应性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细胞识别HSV抗原可能不是强制性的。更确切地说，似乎HSV感染可以激发促炎环境，负责招募和激活角膜中的效应CD4+ T细胞。在角膜中检测不到感染性HSV和病毒抗原时，致病性CD4+ T细胞浸润角膜，这一观察结果对HSV复制在这一过程中的确切作用提出了疑问。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发现其定位于炎性病变部位。有趣的是，HSV DNA的持久性与不同HSV菌株诱导HSK的倾向之间存在相关性；因此，与KOS相比，HSV RE的DNA是HSK的强诱导剂，而HSV KOS的DNA则没有。我们提出测试假设，即持续存在于角膜中的HSV DNA可以诱导促炎环境，驱动CD4+ T细胞的激活，可能是不加区分的特异性，成为介导HSK的效应物。为了支持这一假设，我们的研究结果表明，HSV DNA含有有效的免疫刺激CpG基序（CpG），它可以在体外激活脾细胞增殖和细胞因子合成，并在体内作为一种有效的佐剂，启动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，并表明这可能部分是由于性激素对HSV免疫反应的影响。鉴于性激素已知会影响抗原呈递，我们建议在体外研究它们对HSV-1 DNA介导的炎症反应的影响，以及体内HSK的发病率和/或严重程度。

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.