Characterization of Autoreactivity to Muscle Proteins in Inclusion Body Myositis

描述(申请人提供)：包涵体肌炎(IBM)是一种常见的老年人炎症性肌病。它的特征是缓慢进行性的虚弱，导致使用手臂和腿的困难，行走和吞咽障碍。已知的免疫疗法都没有被证明对它的治疗有效。在缺乏这种疾病的血清生物标志物的情况下，诊断依赖于肌肉活组织检查的表现。尽管如此，IBM仍可能被误诊为其他炎症性肌病，导致数月来不必要的糖皮质激素药物或免疫抑制剂治疗，并产生明显的副作用。虽然不常见，但它也可能被误诊为肌萎缩侧索硬化症(ALS)，造成严重的情感和心理后果。虽然IBM是一种进展缓慢的肌肉疾病，具有正常的预期寿命，但ALS是一种进展迅速的运动神经元疾病，将导致机械通气，中位生存期为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具有极其重要的价值，而且可能避免痛苦和侵入性肌肉活检的需要。在寻求一种基于血清的IBM诊断试验中，我们在IBM患者的血液中发现了一种循环抗体，在少数研究样本中对这种疾病具有100%的特异性和52%的敏感性。基于这一发现，我们提出了一个项目，通过(1)在更多的IBM和对照对象中确定其敏感性和特异性，特别是那些可能被IBM误诊的人，(2)描述这些血清在肌肉组织活组织切片上是否具有特定的染色模式，以及(3)反应性或染色模式的存在是否意味着特定的IBM患者亚组具有治疗性和 预示着未来。我们计划通过首先确定患有IBM、炎症性和非炎症性肌病以及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。 公共卫生相关性：包涵体肌炎是老年人最常见的炎症性肌病，临床上可能与其他形式的肌肉疾病甚至肌萎缩侧索硬化症(ALS)误诊。由于鉴别需要进行痛苦的肌肉活组织检查，鉴定血清标志物和发展对该疾病的诊断生物测定将具有重要价值。此外，根据这些标记物识别疾病亚组可能对IBM患者具有预后和治疗意义。

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. PUBLIC HEALTH RELEVANCE: Inclusion body myositis is the most common inflammatory myopathy of the elderly that may be clinically mistaken with other forms of muscle disease and even amyotrophic lateral sclerosis (ALS). Since differentiation requires performance of painful muscle biopsies, identification of serum markers and development of diagnostic bioassays for the disorder would be of great value. In addition, identifying disease subgroups based on these markers may have prognostic and therapeutic implications for IBM patients.