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 结节病是一种未知病因的疾病，被认为是在暴露于抗原刺激和 以形成含有免疫细胞的非核肉芽肿的形成。全身性结节病 每年在美国影响25,000多人，总案件为150,000-200,000人。结节病 肉芽瘤几乎可以在人体的任何器官中形成。心脏中的肉芽瘤，分类为心脏结节病 （CS），可以作为全身性结节病的一部分或可能作为孤立状况发生。在临床上诊断 在尸检时审查的多达27％的病例中，只有5％的结节病患者观察到CS 占与结节病有关的大部分发病率和死亡率，最常见的临床 表现是心房障碍，心律不齐，心力衰竭和心脏猝死。 CS的早期鉴定至关重要，因为在心室功能障碍之前的皮质类固醇的给药很大 改善预后。不幸的是，心脏结节病的诊断非常具有挑战性，中位数 从症状发作到诊断时间为9个月的时间。心内膜活检是金标准 CS的诊断确认，但是由于颗粒和 程序是侵入性的。较新的成像方式，例如心脏磁共振和18F- 氟脱氧葡萄糖 - 稳定性发射断层扫描已大大提高了心脏检测的敏感性 病变。然而，两种成像方法都是昂贵的，均具有较低的特异性，并且通常不兼容 使用该患者人群中常见的植入心脏设备，或者由于无法重复使用 电离辐射暴露。结节病的患者经常患有高肿瘤性血症，增加 从异常B细胞激活中循环免疫球蛋白的水平。值得注意的是，最近的研究有 证明了全身性结节病的免疫球蛋白G部分中存在自身抗原反应性 血清标本。抗体（病理或其他方式）是免疫失调的血清学标记物 针对特定疾病的抗体“签名”的反应和鉴定是一种有希望的新方法 开发诊断。在此阶段I应用中，我们建议确定CS中存在的免疫签名 在以后的工作中，我们将扩展到一种新颖，易于使用的，无创的，体外诊断测定法 检测最有患心脏参与风险的患者。这样的测试最终将允许更早 干预并降低与CS相关的发病率和死亡率。