MECHNISM OF HERPES ST ROMAL KERATITIS

单纯疱疹性角膜基质炎（HSK）是西方世界感染性失明的主要原因，是由1型单纯疱疹病毒（HSV）感染人眼引起的炎性疾病。 最近的研究结果表明，HSK是一种自身免疫性疾病引发的HSV感染，通过涉及分子模拟的机制，其中眼部抗原反应性T细胞被激活的HSV-1衣壳抗原的交叉识别。然而，其他研究表明，虽然临床HSK需要病毒复制，但CD 4 + T细胞对HSV抗原的识别可能不是强制性的。 相反，似乎HSV感染用于引起负责角膜中效应CD 4 + T细胞的募集和活化的促炎环境。 当角膜中既不能检测到感染性HSV也不能检测到病毒抗原时，致病性CD 4 + T细胞浸润角膜的观察结果提出了关于HSV复制在此过程中的确切作用的问题。 然而，一个重要的观察结果是HSV DNA在角膜中持续数月，并且通过原位PCR发现其定位于炎性病变部位。 有趣的是，HSV DNA的持续存在与不同HSV株诱导HSK的倾向之间存在相关性;因此，来自HSV RE的DNA（与科斯相比，HSK的强诱导剂）持续存在，而HSV科斯DNA不存在。 我们建议测试的假设，HSV DNA持续在角膜可以诱导促炎环境，驱动激活的CD 4 + T细胞，也许不加区分的特异性，到效应介导HSK。 在支持这一假设是我们的研究结果表明，HSV DNA含有有效的免疫刺激CpG基序（CpG），既可以激活脾细胞增殖和细胞因子的合成在体外，并作为一个有效的佐剂启动Th 1型CD 4+和CD 8 + T细胞的蛋白抗原（卵清蛋白）在体内的反应。 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，并表明部分原因可能是性激素对HSV免疫反应的影响。 鉴于性激素是已知的影响抗原呈递，我们建议检查其对HSV-1 DNA介导的炎症反应在体外和HSK的发病率和/或严重程度在体内的影响。

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.