Characterization of Agrin/LRP4 Antibody-Positive Myasthenia Gravis

Agrin/LRP4 抗体阳性重症肌无力的特征

基本信息

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
项目类别：
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&apos 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&apos s adjuvant neurofilament nitrophenylphosphate novel therapeutics public health relevance response

项目摘要

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，影响各个人群中每百万人 400-600 人，它是由针对肌肉烟碱乙酰胆碱受体 (AChR) 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 处的 AChR 浓度至关重要，但是，一些 MG 患者则不然。携带 AChR 或 MuSK 抗体 (Abs)（以下称为双血清阴性 MG，DNMG）的病理机制尚不清楚，这导致了阻碍患者诊断和有效治疗的空白。 DNMG 患者中存在 LRP4 和 LRP4 抗体，从而确定了潜在的病理机制。然而，这些发现的临床意义尚不清楚。 DNMG 中抗体的患病率未知或差异极大。由于 DNMG 患者数量有限、纳入标准不一致以及患者随访有限，人们对 Agrin 或 LRP4 Ab+ MG 的流行病学和临床特征知之甚少。在这项研究中，我们将与美国 27 个 MG 中心合作，这些中心定期接诊超过 4,500 名 MG 患者，其中包括 789 名 DNMG。我们将确定 Agrin 和 LRP4 Abs 的患病率。我们将确定 Agrin 和 LRP4 抗体是否具有致病性，并研究 Agrin 和 LRP4 抗体的分子和细胞病理机制。多中心提案将使我们能够确定 MG 的两种新病因，它将提供有关 DNMG 患者中 Agrin 和 LRP4 Abs 的流行率以及这些新形式的流行病学的有价值的信息。 MG 及其与临床特征、严重程度、诊断测试和治疗反应以及病理机制的关联，将有助于针对这种破坏性疾病的新治疗策略的开发。