Effects of aging on immunity and autoimmunity

描述（由申请人提供）： 重症肌无力（MG）是一种进行性自身免疫性疾病，患者出现严重的肌无力，伴有疲劳。这些症状是由于针对位于神经肌肉接头处的乙酰胆碱受体（AChR）的自身抗体引起的。对于许多MG患者（40-60%），疾病发作发生在40岁之后。此外，在超过70%的MG患者中发现胸腺细胞异常和/或胸腺瘤（肿瘤），这表明胸腺在疾病进展中也起作用。由于胸腺是T细胞成熟的部位，并负责消除“自身”反应性T细胞，因此MG可能是由于胸腺在维持免疫耐受方面的缺陷而引起的。考虑到胸腺随年龄的增长而变化，我们推测与胸腺控制丧失相关的免疫失调可能在老年人迟发性MG和其他自身免疫性疾病中发挥作用。目前的应用程序是集中在评估为什么免疫和自身免疫的差异受衰老的影响，确定胸腺在建立和维持自身AChR的耐受性的作用，并测试潜在的治疗目标在一个新的晚发型模型MG。目的I中的实验将集中于MG小鼠模型中对自身与外来决定簇的抗体应答。使用先前从用来自加利福尼亚电鳐的乙酰胆碱受体免疫的小鼠收集的血清，ELISA将用于评估识别“自身”小鼠AChR的抗体相对于对外源蛋白电鳐AChR的反应性的滴度。在目标II中，我们将直接询问胸腺是否是产生对乙酰胆碱受体耐受所必需的。将在裸（无胸腺）小鼠上进行胸腺移植，以产生仅在胸腺中、仅在肌肉中、在两种组织中或在两种组织中都不表达TAChR转基因的动物。这些嵌合动物将被免疫，并将测量T细胞耐受性（缺乏增殖）的水平。我们还将重点关注AIRE，自身免疫调节因子，一种控制胸腺外周抗原表达的转录因子。我们将确定AIRE是否参与AChR的调节，如果是这样，AIRE敲除小鼠是否对自身免疫性MG更敏感。目的III旨在测试先前在我们的新型迟发性MG模型中在年轻小鼠中探索的治疗方法。我们将能够第一次询问MG的免疫疗法是否对老年人有效。总之，我们独特的定位，以阐明老化的耐受性和免疫力的AChR，在MG的自身抗原的影响。拟议的研究结果可能会提供新的见解与迟发性疾病病因的其他自身免疫性疾病，包括干燥综合征，特发性炎性肌病，恶性贫血。使用新的TAChR转基因小鼠模型和迟发型重症肌无力（MG）的第一个模型，我们的实验室是独特的定位，以阐明老化的耐受性和免疫力的AChR，在MG的自身抗原的影响。 拟议的研究结果可能会提供新的见解与迟发性疾病病因的其他自身免疫性疾病，包括干燥综合征，特发性炎性肌病，恶性贫血。了解自身蛋白耐受的机制以及胸腺退化和/或年龄相关免疫失调对这些过程的破坏是开发新治疗方法的关键第一步。

DESCRIPTION (provided by applicant): Myasthenia gravis (MG) is a progressive autoimmune disorder in which patients develop severe muscle weakness which worsens with fatigue. The symptoms are due to autoantibodies directed against acetylcholine receptors (AChR) located at the neuromuscular junctions. For many MG patients (40-60%), disease onset occurs after the age of 40. In addition, thymus cellular abnormalities and/or thymomas (tumors) are found in more than 70% of MG patients, suggesting that the thymus plays a role in disease progression as well. Since the thymus is the site of T cell maturation and is responsible for eliminating 'self' reactive T cells, it is possible that MG arises due to thymic deficiencies in maintaining immune tolerance. Given that the thymus involutes with aging, we hypothesize that immune dysregulation associated with the loss of thymic controls may play a role in late onset MG and in other autoimmune disorders in the elderly. The current application is focused on assessing why immunity and autoimmunity are differentially affected by aging, determining the role of the thymus in establishing and maintaining tolerance to self AChR, and testing potential therapeutic targets in a novel late-onset model of MG. Experiments in Aim I will focus on antibody responses to self versus foreign determinants in the murine model of MG. Using previously collected sera from mice immunized with the acetylcholine receptor from Torpedo californica, ELISAs will be used to assess the titers of antibodies that recognize 'self', mouse AChR, relative to reactivities to the foreign protein, Torpedo AChR. In Aim II, we will ask directly whether the thymus is required for generating tolerance to AChR. Thymic grafts will be performed onto nude (athymic) mice in order to generate animals which express the TAChR transgene only in thymus, only in muscle, in both tissues, or in neither. These chimeric animals will be immunized and the level of T cell tolerance (lack of proliferation) will be measured. We will also focus on AIRE, the autoimmune regulator, a transcription factor that controls expression of peripheral antigens in the thymus. We will determine whether AIRE is involved in the regulation of AChR, and if so, whether AIRE knock-out mice are more susceptible to autoimmune MG. Aim III is designed to test therapeutic approaches previously explored in young mice in our novel late onset MG model. We will be able to ask, for the first time, whether immunotherapies for MG will be effective in older individuals. In summary, we are uniquely positioned to elucidate the effects of aging on tolerance and immunity to AChR, the autoantigen in MG. The results of the proposed studies may provide novel insights into other autoimmune disorders with late onset disease etiologies, including Sjogren syndrome, idiopathic inflammatory myopathy, and pernicious anemia. Using both the novel TAChR transgenic mouse model and the first model of late-onset Myasthenia gravis (MG), our laboratory is uniquely positioned to elucidate the effects of aging on tolerance and immunity to AChR, the autoantigen in MG. The results of the proposed studies may provide novel insights into other autoimmune disorders with late onset disease etiologies, including Sjogren syndrome, idiopathic inflammatory myopathy, and pernicious anemia. Understanding the mechanisms of tolerance to self proteins and the disruption of these processes by thymic involution and/or age-associated immune dysregulation is a crical first step in developing novel therapeutic approaches.