Catalytic antibodies in arrhythmogenic cardiomyopathy patients cleave desmoglein 2 and N-cadherin and impair cardiomyocyte cohesion.

Autor: Yeruva S; Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstrasse 11, 80336, Munich, Germany., Stangner K; Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstrasse 11, 80336, Munich, Germany., Jungwirth A; Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstrasse 11, 80336, Munich, Germany., Hiermaier M; Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstrasse 11, 80336, Munich, Germany., Shoykhet M; Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstrasse 11, 80336, Munich, Germany.; Department of Otorhinolarynology, Technical University of Munich and University Hospital rechts der Isar, Ismaningerstrasse 22, 81675, Munich, Germany., Kugelmann D; Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstrasse 11, 80336, Munich, Germany., Hertl M; Department of Dermatology and Allergology, Philipps-University Marburg, 35037, Marburg, Germany., Egami S; Department of Dermatology, Keio University School of Medicine, Tokyo, Japan., Ishii N; Department of Dermatology, Kurume University School of Medicine, Kurume, Japan., Koga H; Department of Dermatology, Kurume University School of Medicine, Kurume, Japan., Hashimoto T; Department of Dermatology, Graduate School of Medicine, Osaka City Metropolitan University, Osaka, Japan., Weis M; Krankenhaus Neuwittelsbach, Fachklinik Für Innere Medizin, Munich, Germany., Beckmann BM; Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University Munich (LMU), Campus Großhadern, Munich, Germany.; Institute of Legal Medicine, University Hospital Frankfurt, Goethe University, Frankfurt, Germany., Biller R; ARVC-Selbsthilfe E.V, Patient Association, Munich, Germany., Schüttler D; Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University Munich (LMU), Campus Großhadern, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance (MHA), Partner Site Munich, Munich, Germany.; Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians University Munich (LMU), Munich, Germany.; Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICON), LMU Munich, Munich, Germany., Kääb S; Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University Munich (LMU), Campus Großhadern, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance (MHA), Partner Site Munich, Munich, Germany.; Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICON), LMU Munich, Munich, Germany.; Member of the European Reference Network for rare, low prevalance and complex diseases of the heart , ERN GUARD-Heart, Munich, Germany., Waschke J; Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstrasse 11, 80336, Munich, Germany. jens.waschke@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2023 Jul 14; Vol. 80 (8), pp. 203. Date of Electronic Publication: 2023 Jul 14.
DOI: 10.1007/s00018-023-04853-1
Abstrakt: Aims: Arrhythmogenic cardiomyopathy (AC) is a severe heart disease predisposing to ventricular arrhythmias and sudden cardiac death caused by mutations affecting intercalated disc (ICD) proteins and aggravated by physical exercise. Recently, autoantibodies targeting ICD proteins, including the desmosomal cadherin desmoglein 2 (DSG2), were reported in AC patients and were considered relevant for disease development and progression, particularly in patients without underlying pathogenic mutations. However, it is unclear at present whether these autoantibodies are pathogenic and by which mechanisms show specificity for DSG2 and thus can be used as a diagnostic tool.
Methods and Results: IgG fractions were purified from 15 AC patients and 4 healthy controls. Immunostainings dissociation assays, atomic force microscopy (AFM), Western blot analysis and Triton X-100 assays were performed utilizing human heart left ventricle tissue, HL-1 cells and murine cardiac slices. Immunostainings revealed that autoantibodies against ICD proteins are prevalent in AC and most autoantibody fractions have catalytic properties and cleave the ICD adhesion molecules DSG2 and N-cadherin, thereby reducing cadherin interactions as revealed by AFM. Furthermore, most of the AC-IgG fractions causing loss of cardiomyocyte cohesion activated p38MAPK, which is known to contribute to a loss of desmosomal adhesion in different cell types, including cardiomyocytes. In addition, p38MAPK inhibition rescued the loss of cardiomyocyte cohesion induced by AC-IgGs.
Conclusion: Our study demonstrates that catalytic autoantibodies play a pathogenic role by cleaving ICD cadherins and thereby reducing cardiomyocyte cohesion by a mechanism involving p38MAPK activation. Finally, we conclude that DSG2 cleavage by autoantibodies could be used as a diagnostic tool for AC.
(© 2023. The Author(s).)
Databáze: MEDLINE
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