Autoimmunity and Age-Related Macular Degeneration

描述(申请人提供)：年龄相关性黄斑变性(AMD)是一种高度流行的，多因素，多基因复杂的疾病。现在人们普遍认为炎症和免疫系统在AMD的发病机制中起着直接作用。随着炎症随着年龄的增长而积累，尤其是在AMD中，我们假设启动了一个恶性循环，使黄斑组织暴露在越来越多的炎症和免疫介导的损害之下。我们认为这一机制对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患者比老年对照组更常见、更强烈地表达针对黄斑部人类组织抗原的自身抗体。然而，已经证明这一点并不能证明自动抗体在疾病的发展和/或进展中具有直接作用。要了解自身抗体在AMD中的作用，必须发现其靶标的身份，并提供疾病与自身抗体存在之间的因果联系的教授。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)发现在我们的初步调查中发现的所有统计的所有重要黄斑抗原的身份，并检验针对这些抗原免疫的野生型(WT)小鼠产生针对它们的自身抗体并与AMD表型一致的变化的假设。2)验证早发性AMD小鼠模型中产生的自身抗体可以通过过继转移血清免疫球蛋白来加速AMD模型中疾病的出现和加重其严重程度的假说。3)验证类似的自身免疫反应模式不仅发生在物种之间，而且发生在AMD动物模型之间的假设，并建立自身抗体形成的时间过程与表型开始时间之间的关系。这些研究将使我们能够发现AMD自身反应的靶点，调查跨物种和模型的共性(和差异)，测试AMD中自身免疫假说的因果关系，定义“自身反应序列”，识别早期疾病标记物和进展风险标记物，并为自身免疫在AMD中的作用开发更精细的致病框架。我们预测，这些研究最终将为使用现有的AMD模型和我们计划诱导的AMD模型来研究和开发治疗AMD表现的新方法铺平道路，并有可能在人类临床试验中将这些治疗方法转换回床边。 公共卫生相关性：炎症的作用最近已成为年龄相关性黄斑变性(AMD)的关键致病因素。我们已经证明，AMD患者有针对黄斑组织抗原的自身抗体(自身抗体)，明显比对照组更常见和更强烈。我们现在建议：(1)用免疫沉淀和质谱学实验鉴定这些自体抗体所识别的抗原；(2)检验这样的假设：这些自体抗体是致病的，并且a)通过免疫小鼠来对抗它们识别的抗原，小鼠会出现类似AMD的眼底病变，以及b)被动(过继地)将这些小鼠产生的自体抗体转移到幼小鼠身上也会导致这些小鼠的疾病发展；(3)检验这样的假设，即现有的AMD小鼠模型也像人类一样对眼组织抗原产生自体反应；(4)验证迟发性AMD小鼠模型可通过被动转移其他也存在疾病的模型中的自体抗体而加速其疾病出现或加重其病情的假说；(5)前瞻性地研究AMD小鼠模型，以表征导致自体抗体形成和眼底病变发展的事件序列。这一系列研究将使我们能够确定自身免疫在AMD中所起的作用，并最终为使用现有的AMD模型和我们计划诱导的那些探索AMD表现的治疗方法铺平道路。

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. PUBLIC HEALTH RELEVANCE: The role of inflammation has recently emerged as a key pathogenic factor in age-related macular degeneration (AMD). We have documented that AMD patients have autoantibodies (auto-Abs) against macular tissue antigens significantly more commonly and more intensely than controls. We now propose to: (1) identify the antigens recognized by these auto-Abs with immunoprecipitation and mass spectrometry experiments; (2) test the hypothesis that these auto-Abs are pathogenic and that a) by immunizing mice against the antigens that they recognize mice will develop AMD-like fundus lesions and b) that passive (adoptive) transfer of the auto-Abs developed by these mice to naive mice will lead to disease development also in these mice; (3) test the hypothesis that, like human beings, existing mouse models of AMD also develop autoreactivities against ocular tissue antigens; (4) to test the hypothesis that late-onset mouse models of AMD can have their disease appearance be sped up or its severity made worse by passive transfer of auto-Abs from other models in which disease also is present; and (5) to investigate mouse models of AMD prospectively to characterize the sequence of events leading up to auto-Ab formation and development of fundus lesions. This series of studies will allow us to define the role that autoimmunity has in AMD and, ultimately, to pave the way toward using the existing AMD models and those that we plan to induce to explore treatments of the manifestations of AMD.