Autoimmune Basis of Diabetic Neuropathy

糖尿病神经病变的自身免疫基础

• 批准号: 6951998
• 负责人: HELENE BOUR-JORDAN
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951998
• 关键词: NOD mouse; autoantibody; autoantigens; autoimmunity; clinical research; diabetic neuropathy; diagnosis design /evaluation; disease /disorder etiology; disease /disorder model; genetically modified animals; human subject; immunologic assay /test; immunopathology diagnosis; insulin dependent diabetes mellitus; model design /development; monoclonal antibody; neuroimmunomodulation; proteomics

DESCRIPTION (provided by applicant): Neuropathy is one of the most common and debilitating complications occurring in patients suffering from type 1 diabetes (TID). Diabetic neuropathy has been assumed to be a consequence of chronic hyperglycemia rather than an autoimmune manifestation. However, mounting evidence suggests that the neuropathy that develops in T1D patients could have an autoimmune basis. The applicant's group reported that under certain conditions spontaneously autoimmune non-obese diabetic (NOD) mice developed a spontaneous autoimmune neuropathy affecting the peripheral nervous system (PNS). In addition, T cell responses and auto-antibodies directed at neural cell antigens have been found in both T1D patients and the NOD mouse. Therefore, the applicant hypothesizes that diabetic neuropathy can have an autoimmune basis in many patients, and proposes to use proteomics to examine whether autoantibodies specific for neural auto-antigens are detected in the serum in mouse models and diabetic patients. The following specific aims are proposed to address this hypothesis: Specific aim #1: To develop and validate an autoantigen array for the detection of auto-antibodies against the nervous system. This will be carried out by a modification of the current "myelin" array to include proteins specifically expressed in the PNS. Specific aim #2: To develop mouse models aimed at defining autoantigens and study the relationship between T1D and autoimmune neuropathy. The applicant proposes to probe the array developed above with sera from different mouse models in order to identify autoantigens targeted in the neuropathy and determine how the auto-antibody repertoire against the PNS is influenced by autoimmune diabetes. Specific aim #3: To determine if auto-antibodies against neural antigens are present in diabetic patients using autoantigen arrays. They will evaluate whether auto-antibodies specific for neural antigens are present in the serum of patients with type 1 diabetes who suffer from different types of neuropathy. This approach is expected to assess the autoimmune basis of diabetic neuropathy as well as to define potential autoantigens in the nerves. These studies are expected to provide insights into the cellular mechanisms underlying diabetic neuropathy and potentially result in diagnostic tools and new therapeutic avenues for this debilitating disease.

描述（由申请人提供）： 神经病变是 1 型糖尿病 (TID) 患者最常见且使人衰弱的并发症之一。糖尿病神经病变被认为是慢性高血糖的结果，而不是自身免疫表现。然而，越来越多的证据表明，1 型糖尿病患者发生的神经病变可能具有自身免疫基础。 申请人的小组报告说，在某些条件下，自发性自身免疫性非肥胖糖尿病（NOD）小鼠出现影响周围神经系统（PNS）的自发性自身免疫性神经病。此外，在 T1D 患者和 NOD 小鼠中都发现了针对神经细胞抗原的 T 细胞反应和自身抗体。 因此，申请人假设糖尿病神经病变在许多患者中可能具有自身免疫基础，并提出使用蛋白质组学来检查小鼠模型和糖尿病患者的血清中是否检测到神经自身抗原特异性的自身抗体。提出以下具体目标来解决这一假设： 具体目标#1：开发和验证用于检测针对神经系统的自身抗体的自身抗原阵列。这将通过修改当前的“髓磷脂”阵列来实现，以包括在三七总皂甙中特异性表达的蛋白质。具体目标#2：开发旨在定义自身抗原的小鼠模型并研究 T1D 和自身免疫性神经病之间的关系。 申请人提议用来自不同小鼠模型的血清探测上述开发的阵列，以鉴定神经病变中靶向的自身抗原并确定针对PNS的自身抗体库如何受到自身免疫性糖尿病的影响。具体目标#3：使用自身抗原阵列确定糖尿病患者中是否存在针对神经抗原的自身抗体。他们将评估患有不同类型神经病的 1 型糖尿病患者的血清中是否存在针对神经抗原的特异性自身抗体。这种方法有望评估糖尿病神经病变的自身免疫基础，并确定神经中潜在的自身抗原。这些研究有望深入了解糖尿病神经病变的细胞机制，并有可能为这种使人衰弱的疾病提供诊断工具和新的治疗途径。