Immunoprofiling to develop a novel diagnostic array for cardiac sarcoidosis

免疫分析用于开发心脏结节病的新型诊断阵列

• 批准号: 9907835
• 负责人: Martyn Darby
• 金额: $ 29.98万
• 依托单位: AFFINERGY, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-20 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907835
• 关键词: Adrenal Cortex Hormones; Affect; Age; Antibodies; Arrhythmia; Atrioventricular Block; Autoantigens; Autopsy; B-Cell Activation; Bacteriophages; Binding; Biological Assay; Biological Markers; Biopsy; Blood; Blood Tests; Cardiac; Cardiac Sarcoidosis; Cells; Clinical; Collaborations; Competence; Detection; Devices; Diagnosis; Diagnostic; Disease; Early Intervention; Early identification; Ethnic Origin; Etiology; Exposure to; Foundations; Future; Gender; Gold; Granuloma; Heart; Heart failure; Hypergammaglobulinemia; Image; Immobilization; Immune; Immune response; Immunoglobulin G; Immunoglobulins; In Vitro; Incubated; Intervention; Ionizing radiation; Lesion; Life; Magnetic Resonance; Methods; Morbidity - disease rate; Myocarditis; Nature; Organ; Pathologic; Patients; Pattern; Peptides; Performance; Phage Display; Pharmacology; Phase; Procedures; Production; Race; Radiation exposure; Research; Risk; Sampling; Sarcoidosis; Sensitivity and Specificity; Serum; Signal Transduction; Specificity; Specimen; Stimulus; Symptoms; Testing; Time; United States; Validation; Ventricular Dysfunction; Work; base; cardiac device; cardiac implant; clinical Diagnosis; cohort; commercialization; cost; diagnostic assay; fluorodeoxyglucose positron emission tomography; imaging approach; imaging modality; improved; ischemic cardiomyopathy; mortality; next generation; novel; novel diagnostics; novel strategies; outcome forecast; patient population; prognostic value; prospective test; protein aminoacid sequence; prototype; scale up; serological marker; success; sudden cardiac death; tool

SUMMARY/ABSTRACT Sarcoidosis is a disease of unknown etiology thought to arise after exposure to an antigenic stimulus and characterized by the formation of non-necrotizing granulomas containing immune cells. Systemic sarcoidosis affects over 25,000 people in the United States each year, with 150,000-200,000 total cases. Sarcoidosis granulomas can form in almost any organ of the body. Granulomas in the heart, classified as cardiac sarcoidosis (CS), can occur as part of systemic sarcoidosis or potentially as an isolated condition. Diagnosed clinically in only 5% of sarcoidosis patients, CS has been observed in as many as 27% of cases reviewed at autopsy and accounts for the majority of the morbidity and mortality associated with sarcoidosis, with the most frequent clinical manifestations being atrioventricular block, arrhythmias, heart failure, and sudden cardiac death. Early identification of CS is critical, as administration of corticosteroids prior to ventricular dysfunction greatly improves prognosis. Unfortunately, diagnosis of cardiac sarcoidosis is extremely challenging, with the median time from symptom onset to diagnosis averaging 9 months. Endomyocardial biopsy is the gold standard for diagnostic confirmation of CS, however the sensitivity is <25% due to the focal nature of the granulomas and the procedure is invasive. Newer imaging modalities such as cardiac magnetic resonance and 18F- fluorodeoxyglucose-positron emission tomography have greatly improved the sensitivity for detection of cardiac lesions. Both imaging approaches, however, are costly, suffer from lower specificity, and are often incompatible with the implanted cardiac devices common in this patient population or cannot be used repeatedly due to ionizing radiation exposure. Patients with sarcoidosis frequently have hypergammaglobulinemia, with increased levels of circulating immunoglobulins from aberrant B cell activation. Significantly, a recent study has demonstrated the presence of autoantigen reactivity in the immunoglobulin G fraction of systemic sarcoidosis serum specimens. Antibodies, pathological or otherwise, are the serological markers of a dysregulated immune response and identification of an antibody “signature” for a particular disease is a promising new approach for developing diagnostics. In this Phase I application, we propose to identify an immunosignature present in CS patients which, in future work, we will expand into a novel, easy-to-use, noninvasive, in vitro diagnostic assay for detection of patients most at risk for cardiac involvement. Such a test would ultimately allow for earlier intervention and reduce the CS-associated morbidity and mortality.

总结/摘要 结节病是一种病因不明的疾病，被认为是在暴露于抗原刺激后引起的， 其特征在于形成含有免疫细胞的非坏死性肉芽肿。系统性结节病 在美国，每年影响超过25，000人，总病例数为150，000 - 200，000。结节病 肉芽肿可以在身体的几乎任何器官中形成。心脏肉芽肿，分类为心脏结节病 (CS)可以作为系统性结节病的一部分或潜在地作为孤立的病症发生。临床诊断， 只有5%的结节病患者，在尸检时审查的病例中观察到27%的CS， 占结节病相关发病率和死亡率的大部分，最常见的临床 表现为房室传导阻滞、心律失常、心力衰竭和心源性猝死。 CS的早期识别是至关重要的，因为在心室功能障碍之前给予皮质类固醇大大增加了 改善预后。不幸的是，心脏结节病的诊断极具挑战性， 从症状出现到确诊的时间平均为9个月。肌内膜活检是 诊断证实CS，但由于肉芽肿的局灶性性质， 手术是侵入性的。较新的成像方式，如心脏磁共振和18F- 氟脱氧葡萄糖-正电子发射断层扫描大大提高了检测心脏 病变然而，这两种成像方法都是昂贵的，具有较低的特异性，并且通常不兼容 植入的心脏器械在该患者人群中很常见，或者由于以下原因不能重复使用 电离辐射暴露。结节病患者常伴有高丙种球蛋白血症， 异常B细胞活化引起的循环免疫球蛋白水平。值得注意的是，最近的一项研究 证实了系统性结节病的免疫球蛋白G组分中存在自身抗原反应性 血清标本抗体，无论是病理性的还是其他的，都是免疫失调的血清学标志物。 针对特定疾病的抗体“特征”的应答和鉴定是一种有前途的新方法， 发展诊断学。在第一阶段的申请中，我们建议确定CS中存在的免疫特征， 在未来的工作中，我们将扩展到一种新的，易于使用的，非侵入性的，体外诊断检测， 检测心脏受累风险最高的患者。这样的测试最终将允许更早的 干预，降低CS相关的发病率和死亡率。