Characterization of Agrin/LRP4 Antibody-Positive Myasthenia Gravis

 描述(申请人提供)：重症肌无力(MG)是神经肌肉接头(NMJ)最常见的疾病，在不同人群中每百万人中有400-600人受到影响。它是由针对肌肉烟碱型乙酰胆碱受体(AChR)和穆斯克的自身抗体引起的，穆斯克是一种受体酪氨酸激酶，对农业诱导的AChR在NMJ的浓度至关重要。然而，一些MG患者并不携带AChR或麝香抗体(Abs)(以下简称双阴性MG，DNMG)。DNMG的发病机制尚不清楚，给患者的诊断和有效治疗留下了一个空白。最近的研究包括我们的研究表明，在DNMG患者中存在AGRIN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Abs的患病率在文献中要么是未知的，要么是非常可变的。由于DNMG患者数量有限，纳入标准不一致，患者随访有限，对AGRIN或LRP4Ab+MG的流行病学和临床特征知之甚少。这些抗体是否致病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，这些中心经常看到4500名MG患者，其中包括789名DNMG。我们将确定在这一大群DNMG患者中AGRIN和LRP4抗体的患病率，并对应用AGRIN和LRP4抗体的DNMG患者的流行病学、临床特征和治疗反应进行表征。我们将确定AGRIN和LRP4抗体是否是致病的，并研究AGRIN和LRP4抗体的分子和细胞病理机制。这一多中心提案将使我们能够确定MG的两个新原因。它将提供有关DNMG患者中AGRIN和LRP4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、诊断试验和治疗反应以及病理机制的关系的有价值的信息。它将有助于开发针对这种毁灭性疾病的新治疗策略。

 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.