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.

摘要/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和 其特征是形成含有免疫细胞的非坏死性肉芽肿。 美国每年影响超过 25,000 人，总病例数为 150,000-200,000 例。 肉芽肿几乎可以在身体的任何器官中形成。心脏肉芽肿被归类为心脏结节病。 (CS)，可以作为系统性结节病的一部分发生，也可以作为临床诊断的孤立病症。 仅 5% 的结节病患者在尸检和检查时观察到多达 27% 的病例出现 CS 占结节病相关发病率和死亡率的大部分，临床最常见 表现为房室传导阻滞、心律失常、心力衰竭、心源性猝死。 早期识别 CS 至关重要，因为在心室功能障碍之前给予皮质类固醇会显着增加 不幸的是，心脏结节病的诊断极具挑战性，中位数为 从症状出现到诊断的时间平均为 9 个月，心内膜心肌活检是诊断的金标准。 CS 的诊断确认，但由于肉芽肿的局灶性和 较新的成像方式如心脏磁共振和 18F- 是侵入性的。 氟脱氧葡萄糖-正电子发射断层扫描大大提高了心脏疾病检测的灵敏度 然而，这两种成像方法成本高昂，特异性较低，并且通常不兼容。 植入的心脏装置在该患者群体中很常见，或者由于以下原因无法重复使用 结节病患者经常患有电离辐射，并伴有高丙种球蛋白血症。 值得注意的是，最近的一项研究发现，B 细胞激活异常会导致循环免疫球蛋白水平升高。 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 血清样本，无论是病理性的还是其他的，都是免疫失调的血清学标志。 对特定疾病的抗体“特征”的反应和识别是一种有前途的新方法 在此一期应用中，我们建议鉴定 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颖的、易于使用的、无创的体外诊断检测方法 检测出最有可能发生心脏受累的患者，这样的测试最终将有助于更早地进行检查。 干预并降低 CS 相关的发病率和死亡率。