Letter by Varricchi et al Regarding Article, "Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction".

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HomeCirculationVol. 144, No. 13Letter by Varricchi et al Regarding Article, “Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBLetter by Varricchi et al Regarding Article, “Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction” Gilda Varricchi, MD, PhD, Giuseppe Rengo, MD, PhD and Stephen J. Galli, MD, Hon PhD Gilda VarricchiGilda Varricchi https://orcid.org/0000-0002-9285-4657 Department of Translational Medical Sciences, Federico II University, Naples, Italy (G.V., G.R.). Center for Basic and Clinical Immunology Research (CISI), Federico II University Naples, Italy (G.V.). WAO Center of Excellence, Naples, Italy (G.V.). Institute of Experimental Endocrinology and Oncology IEOS, National Research Council (CNR), Naples, Italy (G.V.). Search for more papers by this author , Giuseppe RengoGiuseppe Rengo Department of Translational Medical Sciences, Federico II University, Naples, Italy (G.V., G.R.). Istituti Clinici Scientifici Maugeri SpA Società Benefit, Telese, Italy (G.R.). Search for more papers by this author and Stephen J. GalliStephen J. Galli Sean N. Parker Center for Allergy and Asthma Research, Stanford, CA (S.J.G). Department of Microbiology and Immunology, Stanford, CA (S.J.G). Department of Pathology, Stanford University School of Medicine, Stanford, CA (S.J.G). Search for more papers by this author Originally published27 Sep 2021https://doi.org/10.1161/CIRCULATIONAHA.121.055167Circulation. 2021;144:e214–e215To the Editor:In their article, Zhao et al1 presented evidence that the immunoglobulin E (IgE)-FcεR1 complex plays a causative role in cardiac remodeling and suggested that IgE-FcεR1 signaling in rat cardiomyocytes and cardiac fibroblasts plays a central role in the effects described. We offer an alternative interpretation of their fascinating results.In the Discussion, the authors correctly mention that “we cannot exclude additional contributions from other cardiac resident cells, such as smooth muscle cells, endothelial cells, and pericytes.” Unfortunately, they omitted cardiac mast cells from their list. It is well established that mast cells are present in human and rat cardiac tissue.2 The enzymatic procedure used by Zhao et al to dissociate cardiac tissue and to isolate primary neonatal rat fibroblasts and cardiomyocytes1 is essentially the same as that which some of us have used to isolate human heart mast cells. Accordingly, it is possible that their preparations of cardiomyocytes and fibroblasts also contained mast cells.This hypothesis might explain some of the results presented in Figure 1E, 1F, 1H, and 1I.1 For example, the apparent increase of FcεR1 in the heart tissue (Figure 1F) following transverse aortic constriction could be explained by increased density of cardiac mast cells, as has been demonstrated in patients with heart failure.2 Moreover, it has been shown that angiotensin II infusion can increase cardiac mast cell density.3 Mast cells can be easily identified by flow cytometry, immunohistochemistry, and electron microscopy. In particular, flow cytometry of FcεR1+ IgE+ cells, using specific markers for mast cells, cardiomyocytes, and fibroblasts, can readily distinguish these cells.The results of experiments administering a monoclonal antibody antihuman IgE (omalizumab)1 are of particular interest. However, the authors might have considered that the administration2 of this monoclonal antibody in humans can reduce the density of FcεR1 on human basophils and mast cells. In the experiments involving bone marrow transplantation (Figure 4), mice were subjected to x-ray irradiation,1 but there is evidence that mast cells are resistant to the cytotoxic effects of irradiation.4 If significant persistence of mast cells occurred despite the irradiation used in these experiments, the results could still be explained by differences in mast cells in the wild-type and FcεR1–/–knockout mice. The experiments presented in Figure 5A show by Western blot that mast cells and, to a lesser extent, neonatal cardiomyocytes and fibroblasts, express FcεR1. However, a small amount of contamination with cardiac mast cells could explain the latter results. The bioinformatic analysis showing that exogenous IgE altered the expression of a plethora of genes, mainly angiogenic (Figure 7C), in cardiomyocytes are of interest. In this setting, IgE could have activated contaminating cells, as previously shown,5 which in turn influenced cardiac gene expression. Human cardiac mast cells are a major source of angiogenic factors.In conclusion, the hypothesis presented by Zhao et al, that IgE contributes to cardiac fibrosis,1 is fascinating and of great interest. However, we think that the authors should have considered the possible contributions of cardiac mast cells in the interpretation of several of their results.Disclosures None.Footnoteshttps://www.ahajournals.org/journal/circ