Autoimmune and Diabetic Dysmotility

胃肠动力障碍是糖尿病患者发病的一个重要原因，但该并发症的病理生理学机制尚未建立。自身免疫是青少年糖尿病的基础，可能占成人糖尿病发病的10%。自身免疫性糖尿病患者容易出现器官特异性自身免疫的其他表现。我们建议检验这一假设，即糖尿病胃肠道动力障碍是由内在和/或外源性肠道神经系统的自身免疫性破坏引起的。这一假说基于以下两点：1)报道了多种神经元和肌肉自身抗体可作为自身免疫性胃肠动力障碍的标志物；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)特异性免疫球蛋白G既是自身免疫性胃肠动力障碍的标志物，也是严重胃肠动力低下的原因。我们已经建立了自身免疫性胃肠道疾病的动物模型 通过主动免疫神经节AChR蛋白和被动转移神经节AChR特异性免疫球蛋白造成的运动障碍。我们建议在糖尿病NOD小鼠中描述和比较两种自发性胃肠动力障碍和自身免疫性胃肠动力障碍的小鼠模型，以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免疫球蛋白介导的胃肠动力障碍的机制，并确定NOD小鼠是否对免疫球蛋白介导的运动障碍表现出高度的敏感性。在平行的血清学研究中，我们将确定患有运动障碍的糖尿病患者中神经元和其他器官特异性自身抗体的频率，特别是寻找新的肠道神经系统特异性抗体。我们还将在小鼠身上研究注射含有新型肠道自身抗体的人免疫球蛋白对胃肠动力的影响。我们的项目将结合动物和人类研究来阐明自身免疫是否与糖尿病运动障碍有关，免疫球蛋白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 自身免疫性胃肠动力障碍的诊断和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.