Characterization of Agrin/LRP4 Antibody-Positive Myasthenia Gravis

Agrin/LRP4 抗体阳性重症肌无力的特征

• 批准号: 8977954
• 负责人: Lin Mei
• 金额: $ 59.98万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8977954
• 关键词: Abbreviations; Acetylcholine; Action Potentials; Address; Affect; Age of Onset; Agrin; Alkaline Phosphatase; Americas; Amyotrophic Lateral Sclerosis; Antibodies; Autoantibodies; Autoimmune Process; Bungarotoxins; Centers for Disease Control and Prevention (U.S.); Cerebrospinal Fluid; Cholinergic Receptors; Clinical; Complement-Dependent Cytotoxicity; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Electromyography; Electron Microscopy; Epidemiology; Experimental Autoimmune Myasthenia Gravis; Foundations; Freund' s Adjuvant; Human; Immune response; Immunosuppressive Agents; Institutes; Intravenous Immunoglobulins; Lactate Dehydrogenase; Lambert-Eaton Myasthenic Syndrome; Left; Literature; Low Density Lipoprotein Receptor; Modeling; Molecular; Muscle; Myasthenia Gravis; Nerve; Neuromuscular Diseases; Neuromuscular Junction; Neuromuscular Junction Diseases; Nicotinic Receptors; Optics; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Physicians; Plasma Exchange; Population; Prevalence; Prevention; Publishing; Receptor Protein-Tyrosine Kinases; Relative (related person); Research; Rhodamine; Serum; Severities; Signal Transduction; Specificity; Testing; Therapeutic; Thymectomy; Treatment Efficacy; United States; Universities; antibody-dependent cell cytotoxicity; clinical epidemiology; clinically significant; cobra venom factor; cohort; corticosteroid inhibitor; density; disorder control; follow-up; inclusion criteria; incomplete Freund' s adjuvant; neurofilament; nitrophenylphosphate; novel therapeutics; public health relevance; response

 DESCRIPTION (provided by applicant): Myasthenia gravis (MG) is the most common disorder of the neuromuscular junction (NMJ), affecting 400-600 per million people in various populations. It is caused by autoantibodies against muscle nicotinic acetylcholine receptor (AChR) and MuSK, a receptor tyrosine kinase that is critical for Agrin-induced AChR concentration at the NMJ. However, some MG patients do not carry AChR or MuSK antibodies (Abs) (hereafter referred to as double seronegative MG, DNMG). The pathological mechanisms of DNMG are not well understood, leaving a void that hinders diagnosis and efficient treatment of inflicted patients. Recent studies including ours demonstrate that Agrin and LRP4 Abs are present in DNMG patients, identifying potential pathological mechanisms. However, the clinical significance of these findings is unknown. The prevalence of the Abs in DNMG is either unknown or extremely variable in the literature. Due to limited number of DNMG patients and inconsistent inclusion criteria and limited patient follow-up in previous studies, little is known about epidemiology and clinical features of Agrin or LRP4 Ab+ MG. Whether and how these Abs are pathogenic remain poorly understood. In this study, we will collaborate with 27 MG Centers in the United States that routinely see > 4,500 MG patients including 789 DNMG. We will determine the prevalence of Agrin and LRP4 Abs in this large cohort of DNMG patients and characterize the epidemiology, clinical feature and responses to treatments of DNMG patients with Agrin and LRP4 Abs. We will determine whether Agrin and LRP4 Abs are pathogenic and investigate molecular and cellular pathological mechanisms of Agrin and LRP4 Abs. This multicenter proposal will allow us to identify two new causes for MG. It will provide valuable information regarding the prevalence of Agrin and LRP4 Abs in DNMG patients, the epidemiology of these new forms of MG and association with clinical features, severity, diagnostic tests and responses to treatments, and pathological mechanisms. It will contribute to the development of novel therapeutic strategies against this devastating disease.

 描述（由申请人提供）：重症肌无力（MG）是最常见的神经肌肉接头（NMJ）疾病，在不同人群中每百万人中有400-600人受累。它是由针对肌肉尼古丁乙酰胆碱受体（AChR）和MuSK的自身抗体引起的，MuSK是一种受体酪氨酸激酶，对于Agrin诱导的NMJ AChR浓度至关重要。然而，一些MG患者不携带AChR或MuSK抗体（Abs）（下文称为双血清阴性MG，DNMG）。DNMG的病理机制尚未得到很好的理解，留下了阻碍诊断和有效治疗患者的空白。最近的研究，包括我们的研究表明，聚集蛋白和LRP 4抗体存在于DNMG患者，确定潜在的病理机制。然而，这些发现的临床意义尚不清楚。在文献中，DNMG中Abs的患病率要么未知，要么变化极大。由于DNMG患者数量有限、入选标准不一致以及既往研究中患者随访有限，因此对聚集蛋白或LRP 4 Ab+ MG的流行病学和临床特征知之甚少。这些抗体是否以及如何致病仍然知之甚少。在这项研究中，我们将与美国的27个MG中心合作，这些中心常规接诊> 4，500名MG患者，包括789名DNMG患者。我们将确定聚集蛋白和LRP 4抗体在这个大的DNMG患者队列中的流行率，并表征用聚集蛋白和LRP 4抗体治疗的DNMG患者的流行病学、临床特征和反应。我们将确定聚集蛋白和LRP 4抗体是否是致病性的，并研究聚集蛋白和LRP 4抗体的分子和细胞病理机制。这项多中心的建议将使我们能够确定MG的两个新原因。它将提供有关DNMG患者中聚集蛋白和LRP 4抗体的患病率，这些新形式MG的流行病学以及与临床特征，严重程度，诊断测试和治疗反应以及病理机制的相关性的有价值的信息。它将有助于开发针对这种毁灭性疾病的新型治疗策略。