Characterization of Autoreactivity to Muscle Proteins in Inclusion Body Myositis

描述（由申请人提供）：包涵体肌炎（IBM）是老年人常见的炎性肌病。其特征是缓慢进行性虚弱，导致难以使用手臂和腿，受损的手臂和吞咽。没有一种已知的免疫疗法被证明是有效的治疗。在缺乏该疾病的血清生物标志物的情况下，诊断依赖于肌肉活检的表现。尽管如此，IBM仍然可能被误诊为其他炎性肌病，导致数月的糖皮质激素药物或免疫抑制剂的不必要治疗，并产生显著的副作用。虽然不常见，但也可能被误诊为肌萎缩侧索硬化症（ALS），并造成严重的情绪和心理后果。虽然IBM是一种缓慢进展的肌肉疾病，预期寿命正常，但ALS是一种快速进展的运动神经元疾病，将导致机械通气，中位生存时间为2-4年。为IBM开发一种可靠的血清生物标志物不仅在避免误诊及其偶尔的破坏性后果方面非常有价值，而且可能避免痛苦和侵入性肌肉活检的需要。在进行基于血清的IBM诊断测定时，我们已经在IBM患者的血液中鉴定出循环抗体，其在所研究的少量样品中对该疾病具有100%特异性和52%敏感性。基于这一发现，我们提出了一个项目，以进一步表征这种反应的性质，通过（1）确定其在大量IBM和对照受试者中的敏感性和特异性，特别是那些可能被误诊为IBM的受试者，（2）描述这些血清在肌肉组织活检载玻片上是否具有特异性染色模式，以及（3）反应性或染色模式的存在是否意味着具有治疗和 预后意义我们计划通过首先确定IBM，炎性和非炎性肌病以及ALS的受试者来实现我们的目标，并收集他们的血液样本。然后，我们将使用蛋白质印迹法检查他们的血清对这种43 kDa肌肉蛋白的反应性，并确定那些被证明具有反应性的组织染色模式。最后我们 将比较反应性和非反应性IBM受试者的详细人口统计学和临床数据，以确定我们是否可以识别疾病亚组。

DESCRIPTION (provided by applicant): Inclusion body myositis (IBM) is a common inflammatory myopathy of the elderly. It is characterized by slowly progressive weakness that leads to difficulty using the arms and legs, impaired ambulation and swallowing. None of the known immune therapies have proven to be effective for its treatment. In the absence of serum biomarkers for the disease, diagnosis relies on the performance of muscle biopsies. Despite this, IBM may still be misdiagnosed with other inflammatory myopathies, leading to months of unnecessary treatment with glucocorticoid drugs or immunosuppressive agents with significant side effects. While not common, it may also be misdiagnosed for amyotrophic lateral sclerosis (ALS), with major emotional and psychological consequences. While IBM is a slowly progressive muscle disease with normal life expectancy, ALS is a rapidly progressive motor neuron disorder that will lead to mechanical ventilation and carries a median survival time of 2-4 years. Developing a reliable serum biomarker for IBM will not only be extremely valuable in avoiding misdiagnosis and its occasional devastating consequences, but may circumvent the need for painful and invasive muscle biopsies. In pursuing a serum based diagnostic assay for IBM we have identified a circulating antibody in the blood of IBM patients that is 100% specific and 52% sensitive for this disease among a small number of samples studied. Based on this finding, we propose a project to further characterize the nature of this reactivity by (1) determining its sensitivity and specificity in a larger number of IBM and control subjects, in particular those that can be misdiagnosed with IBM, (2) describe whether or not these sera have specific staining patterns on muscle tissue biopsy slides and (3) whether the presence of reactivity or staining pattern signifies a particular subgroup of IBM patients with therapeutic and prognostic implications. We plan to pursue our goals by first identifying subjects with IBM, inflammatory and non-inflammatory myopathies as well as ALS, and collect their blood samples. We will then examine their sera for reactivity against this 43 kDa muscle protein, using western blots, and also determine tissue staining patterns for those that prove to be reactive. Finally, we will compare detailed demographic and clinical data between reactive and non-reactive IBM subjects to determine if we can identify disease subgroups.