Autoimmunity and Age-Related Macular Degeneration

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是一种高度普遍、多因素、多基因的复杂疾病。炎症和免疫系统在AMD的发病机制中起着直接的作用，这一点已被广泛接受。随着年龄的增长，炎症的积累，尤其是在AMD中，我们假设一个恶性循环正在启动，使黄斑组织暴露于越来越多的炎症和免疫介导的损伤中。我们认为这种机制对AMD的发展和进展至关重要。我们有强有力的证据表明，早期和晚期AMD患者表达针对黄斑人类组织抗原的自身抗体（auto-Abs）明显比老年对照组更常见和更强烈。然而，这并不能证明自体抗体在促进疾病发生和/或进展中具有直接作用。为了了解自身抗体在AMD中的作用，有必要发现其靶点的身份，并提供疾病与自身抗体存在之间的因果关系。为了解决这些至关重要的问题，我们提出了以下一系列目标：1)发现我们初步研究中发现的所有统计上显著的黄斑抗原的身份，并验证野生型（WT）小鼠免疫这些抗原后产生针对这些抗原的自身抗体并与AMD表型一致的变化的假设。2)验证早发性小鼠AMD模型中产生的自身抗体可通过过继性血清IgG转移加速晚发性AMD模型的疾病出现并增加其严重程度的假设。3)验证相似的自身免疫反应模式不仅在不同物种之间，而且在不同的AMD动物模型中都存在，并建立自身抗体发生的时间进程与表型发生时间之间的关系。这些研究将使我们能够发现AMD中自身反应性的靶点，调查不同物种和模型的共性（和差异），检验AMD中自身免疫假说的因果关系，定义“自身反应性序列”，识别早期疾病标志物和进展风险标志物，并为自身免疫在AMD中的作用建立更完善的致病框架。我们预测，这些研究最终将为利用现有的AMD模型和我们计划诱导的模型来研究和开发针对AMD表现的新治疗方法铺平道路，并且有可能将这些治疗方法转化为床边的人体临床试验。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a highly prevalent, multifactorial, polygenic complex disease. It is now widely accepted that inflammation and the immune system play a direct role in the pathogenesis of AMD. As inflammation builds up in aging and, much more so, in AMD, we hypothesize that a vicious cycle is set in motion that exposes macular tissues to an increasing amount of inflammatory and immune-mediated damage. We propose that this mechanism is critical to AMD development and progression. We have strong evidence that patients with early and advanced AMD express auto-antibodies (auto-Abs) against macular human tissue antigens significantly more commonly and more intensely than elderly controls. However, having shown this does not prove that the auto-Abs have a direct role in contributing to disease development and/or progression. To understand the role of auto-Abs in AMD, it is essential to discover the identity of their targets, and provide prof of a causal link between disease and presence of auto-Abs. To tackle these critically important questions, we propose the following series of Aims: 1) To discover the identity of all statisticall significant macular antigens identified in our preliminary investigations and test the hypothesis that wild-type (WT) mice immunized against these antigens develop auto-Abs towards them and changes consistent with an AMD phenotype. 2) To test the hypothesis that auto-Abs that develop in an early-onset murine model of AMD can be used to accelerate disease appearance and increase its severity in a late-onset model via adoptive transfer of serum IgG. 3) To test the hypothesis that similar autoimmune reactivity patterns occur not only across species but also across animal models of AMD, and to establish a relationship between time course of auto-Ab development and time of onset of phenotypes. These studies will allow us to discover targets of autoreactivity in AMD, investigate commonalities (and differences) across species and models, test the causality of the autoimmune hypothesis in AMD, define an "autoreactivity sequence", identify early disease markers and progression risk markers, and develop a much more refined pathogenic framework for the role of autoimmunity in AMD. We predict that these studies will ultimately pave the way toward using the existing AMD models and those that we plan to induce to investigate and develop new treatments for the manifestations of AMD, and that it will be possible to translate these treatments back to bedside in human clinical trials.