Autoimmune and Diabetic Dysmotility

胃肠道（GI）运动障碍是糖尿病患者发病的一个重要原因，但这种并发症的病理生理尚未建立。自身免疫是青少年糖尿病的基础，可能占成人发病糖尿病的10%。自身免疫性糖尿病患者易发生器官特异性自身免疫的其他表现。我们建议测试的假设，糖尿病胃肠道动力障碍的结果从自身免疫性破坏的内在和/或外在的肠神经系统。该假设基于1）报告称，几种神经元和肌肉自身抗体可作为自身免疫性GI运动障碍的标志物，以及2）我们发现，神经节神经元乙酰胆碱受体（AChR，自主神经节和肠神经节中快速突触传递的关键介质）特异性IgG既是严重GI运动不足的标志物，也是其原因。我们已经建立了自身免疫性胃肠炎的动物模型， 通过用神经节AChR蛋白主动免疫和通过神经节AChR特异性IgG的被动转移来检测运动障碍。我们建议表征和比较两种小鼠模型的自身免疫性胃肠道动力障碍与自发性胃肠道动力障碍的糖尿病NOD小鼠，寻找共同的免疫组织病理学和电生理特征。我们将在常规小鼠中详细研究IgG介导的GI运动障碍的机制，并确定NOD小鼠是否对IgG介导的运动障碍表现出更高的敏感性。在平行的血清学研究中，我们将确定糖尿病患者运动障碍的神经元和其他器官特异性自身抗体的频率，特别是寻找新的肠神经系统特异性抗体。我们还将在小鼠中研究注射含有新型肠道自身抗体的人IgG对GI运动的影响。我们的项目将联合收割机结合动物和人体研究来阐明自身免疫是否参与糖尿病运动障碍，IgG介导的运动障碍涉及什么机制，以及血清自身抗体谱是否有助于糖尿病运动障碍的治疗。 自身免疫性胃肠道动力障碍的诊断和证明免疫调节治疗的合理性。

Gastrointestinal (GI) dysmotilty is a significant cause of morbidity in diabetic patients, but the patho-physiology of this complication has not been established. Autoimmunity is the basis of juvenile diabetes and may account for 10% of adult-onset diabetes. Patients with autoimmune diabetes are predisposed to other manifestations of organ-specific autoimmunity. We propose to test the hypothesis that diabetic GI dysmotility results from autoimmune disruption of the intrinsic and/or extrinsic enteric nervous system. This hypothesis is based on 1) reports that several neuronal and muscle autoantibodies serve as markers of autoimmune GI dysmotility and 2) our discovery that IgG specific for ganglionic neuronal acetylcholine receptor (AChR, a critical mediator of fast synaptic transmission in autonomic and enteric ganglia) is both a marker and cause of severe GI hypomotility. We have developed animal models of autoimmune GI dysmotility by active immunization with ganglionic AChR protein and by passive transfer of ganglionic AChR-specific IgG. We propose to characterize and compare two mouse models of autoimmune GI dysmotility with spontaneous GI dysmotility in the diabetic NOD mouse, looking for common immuno-histopathological and electrophysiological features. We will investigate the mechanism of lgG-meditated GI dysmotility in detail in conventional mice and determine whether NOD mice exhibit heightened sensitivity to IgG-mediated dysmotility. In parallel serological studies, we will determine the frequency of neuronal and other organ-specific autoantibodies in diabetic patients with dysmotility, searching in particular for novel enteric nervous system-specific antibodies. We will also investigate in mice the effects on GI motility of injecting human IgG containing novel enteric autoantibodies. Our project will combine both animal and human studies to elucidate whether or not autoimmunity is involved in diabetic dysmotility, what mechanism are involved in IgG-mediated dysmotility and whether serum autoantibody profiles might aid the diagnosis of autoimmune GI dysmotility and justify immunomodulatory therapy.