Effects of aging on immunity and autoimmunity

衰老对免疫力和自身免疫的影响

• 批准号: 7210146
• 负责人: EARLANDA LYNN WILLIAMS
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210146
• 关键词: Affect; Age; Aging; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Cell Maturation; Cholinergic Receptors; Condition; Disease Progression; Disease Resistance; Disruption; Elderly; Epitopes; Etiology; Event; Exhibits; Fatigue; Hand; Human; Hyperplasia; Idiopathic Inflammatory Myopathies; Immune; Immune Tolerance; Immune response; Immunity; Immunization; Immunotherapy; Individual; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Laboratories; Ligands; Measures; Modeling; Multiple Sclerosis; Mus; Muscle; Muscle Proteins; Muscle Weakness; Myasthenia Gravis; Neuromuscular Junction; Nude Mice; Onset of illness; Patients; Pattern; Peripheral; Pernicious Anemia; Play; Positioning Attribute; Process; Proteins; Protocols documentation; Regulation; Relative (related person); Rheumatoid Arthritis; Role; Serum; Site; Sjogren' s Syndrome; Symptoms; T-Lymphocyte; Testing; Therapeutic; Thymic epithelial cell; Thymoma; Thymus Gland; Thymus Neoplasms; Time; Tissues; To autoantigen; Torpedo; Transgenes; Transgenic Organisms; age effect; base; design; insight; juvenile animal; mouse model; neurotransmission; novel; novel therapeutics; research study; response; therapeutic target; transcription factor; tumor

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.

描述（由申请人提供）：肌无力重症（MG）是一种进行性自身免疫性疾病，患者会出现严重的肌肉无力，导致疲劳恶化。症状是由于针对位于神经肌肉连接处的乙酰胆碱受体（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，超过70％的MG患者发现了胸腺细胞异常和/或胸腺瘤（肿瘤）（肿瘤），这表明胸腺还在疾病进展中起作用。由于胸腺是T细胞成熟的部位，并负责消除“自我”反应性T细胞，因此由于胸腺缺乏在维持免疫耐受性方面，MG可能产生。鉴于胸腺随着衰老而偏离，我们假设与胸腺控制丧失相关的免疫失调可能在后期MG和老年人的其他自身免疫性疾病中起作用。当前的应用集中在评估为什么免疫和自身免疫会受到衰老的差异影响，从而确定胸腺在建立和维持对自我ACHR的耐受性方面的作用，并在新型的MG晚期模型中测试潜在的治疗靶标。 AIM中的实验我将重点介绍对MG鼠模型中对自我决定因素的抗体反应。使用先前收集的从鱼雷加州乙酰胆碱受体免疫的小鼠的血清，ELISA将用于评估识别“自我”，小鼠ACHR的抗体的滴度，相对于对异物蛋白质的反应率，Torpedo achR。在AIM II中，我们将直接询问是否需要胸腺产生对ACHR的耐受性。胸腺移植物将在裸（无胸腺）小鼠上进行，以产生仅在胸腺中，仅在肌肉，两种组织中或两者中表达taChR转基因的动物。这些嵌合动物将被免疫，将测量T细胞耐受性水平（缺乏增殖）。我们还将关注自身免疫调节剂AIRE，这是一种转录因子，该转录因子控制胸腺中外周抗原的表达。我们将确定AIRE是否参与了ACHR的调节，如果是，AIRE敲除小鼠是否更容易受到自身免疫性Mg的影响。 AIM III旨在测试我们新颖的晚期MG模型中年轻小鼠中先前探索的治疗方法。我们将能够第一次询问MG免疫疗法是否对老年人有效。总而言之，我们可以独特地定位，以阐明衰老对MG中自动抗原AChR的耐受性和免疫力的影响。拟议研究的结果可能会提供对其他患有发作疾病病因的其他自身免疫性疾病的新见解，包括术语综合征，特发性炎症性肌病和恶性贫血。使用新型的TACHR转基因小鼠模型和第一个晚期肌无力重症（MG）的模型，我们的实验室具有独特的位置，可以阐明衰老对MG中自动抗原的耐受性和对ACHR的耐受性的影响。 拟议研究的结果可能会提供对其他患有发作疾病病因的其他自身免疫性疾病的新见解，包括术语综合征，特发性炎症性肌病和恶性贫血。了解对自我蛋白质的耐受性的机制以及通过胸腺涉及和/或与年龄相关的免疫失调对这些过程的破坏是开发新型治疗方法的第一步。