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）：重症肌无力（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，并会因疲劳而恶化。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%）来说，疾病发作发生在 40 岁之后。此外，超过 70% 的 MG 患者发现胸腺细胞异常和/或胸腺瘤（肿瘤），表明胸腺在疾病进展中也发挥着作用。由于胸腺是 T 细胞成熟的场所，并负责消除“自身”反应性 T 细胞，因此 MG 的出现可能是由于胸腺在维持免疫耐受方面的缺陷所致。鉴于胸腺随着衰老而退化，我们推测与胸腺控制丧失相关的免疫失调可能在晚发性重症肌无力和老年人的其他自身免疫性疾病中发挥作用。目前的应用重点是评估为什么免疫和自身免疫会受到衰老的不同影响，确定胸腺在建立和维持对自身 AChR 耐受性中的作用，并在新型迟发性 MG 模型中测试潜在的治疗靶点。目标 I 中的实验将重点关注 MG 小鼠模型中抗体对自身决定因素与外来决定因素的反应。使用先前收集的来自鱼雷乙酰胆碱受体免疫小鼠的血清，ELISA 将用于评估识别“自身”小鼠 AChR 的抗体相对于外源蛋白鱼雷 AChR 的反应性的滴度。在目标 II 中，我们将直接询问胸腺是否需要产生对 AChR 的耐受性。将在裸鼠（无胸腺）上进行胸腺移植，以产生仅在胸腺中、仅在肌肉中、在两种组织中或两者都不表达TAChR转基因的动物。这些嵌合动物将被免疫并测量 T 细胞耐受水平（缺乏增殖）。我们还将重点关注 AIRE，即自身免疫调节因子，它是一种控制胸腺中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，如果参与，AIRE基因敲除小鼠是否更容易患自身免疫性重症肌无力。 Aim III 旨在测试之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。我们将首次询问重症肌无力的免疫疗法对老年人是否有效。总之，我们具有独特的优势来阐明衰老对 AChR（MG 自身抗原）的耐受性和免疫力的影响。拟议研究的结果可能为其他具有迟发型疾病病因的自身免疫性疾病提供新的见解，包括干燥综合征、特发性炎症性肌病和恶性贫血。我们的实验室利用新型 TAChR 转基因小鼠模型和第一个迟发性重症肌无力 (MG) 模型，在阐明衰老对 AChR（MG 自身抗原）耐受性和免疫力的影响方面具有独特的优势。 拟议研究的结果可能为其他具有迟发型疾病病因的自身免疫性疾病提供新的见解，包括干燥综合征、特发性炎症性肌病和恶性贫血。了解自身蛋白的耐受机制以及胸腺退化和/或年龄相关的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。