Abstract
Introduction: Myocarditis is an inflammatory disease of the myocardium that results in injury to the cardiac myocytes. However, there is a lack of research focusing on its immune reaction. Also, most studies have been done through analysis of peripheral blood. Here, we aimed to identify proteome-based immunopathogenesis in patients with biopsy-proven myocarditis. Methods: Comparative proteomic analysis of right ventricle biopsy specimens was performed from six patients with myocarditis and four controls (normal endomyocardial biopsy specimens from one-year surveillance of heart transplant recipients) by tandem mass tag combined with liquid chromatography-mass spectrometry. Based on the results of protein expression, cell fractions were calculated using CIBERSORTx and Gene ontology (GO), and ingenuity pathway analysis was conducted to address immune features and related molecular mechanisms in myocarditis. Results: In total, 720 up-regulated proteins were screened. The top 10 GO terms in up-regulated proteins were mostly related to immune response. Also, the T follicular helper (Tfh) cells and plasma cell fractions were significantly increased in myocarditis. The ingenuity pathways analysis showed that the pathway for activation and immune response of immune cells included signaling of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) with other mediators including interferon regulatory factor (IRF) 1,5, 7 and signal transducer and activator of transcription 1 (STAT1). Conclusions: From mass spectrometry protein analysis, we revealed that Tfh cells and plasma cells play a major role in the development of immune response in myocarditis. Also, TNF-driven interferon response via STAT1 and IRFs can be the main pathways for B cell activation by Tfh cells. Further studies are necessary to validate whether these proteins correlate with the clinical characteristics or can be used as biomarkers for myocarditis.
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