Immunoprofiling to develop a novel diagnostic array for cardiac sarcoidosis

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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.