An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis

Diptendu Chatterjee, Meena Fatah, Deniz Akdis, Danna A. Spears, Tamara T. Koopmann, Kirti Mittal, Muhammad A. Rafiq, Bruce M. Cattanach, Qili Zhao, Jeff S. Healey, Michael John Ackerman, Johan Martijn Bos, Yu Sun, Jason T. Maynes, Corinna Brunckhorst, Argelia Medeiros-Domingo, Firat Duru, Ardan M. Saguner, Robert M. Hamilton

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC. Methods and results: We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified anti-DSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified. Conclusion: Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.

Original languageEnglish (US)
Pages (from-to)3932-3944
Number of pages13
JournalEuropean Heart Journal
Volume39
Issue number44
DOIs
StatePublished - Nov 21 2018
Externally publishedYes

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Desmoglein 2
Arrhythmogenic Right Ventricular Dysplasia
Autoantibodies
Antibodies
Mutation
Desmosomal Cadherins
Desmocollins
Dogs
Desmosomes
Ventricular Premature Complexes
Gap Junctions
Cadherins
Autoimmunity
Genes
Cardiac Arrhythmias
Epitopes
Anti-Idiotypic Antibodies
Proteins
Biomarkers
Western Blotting

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Chatterjee, D., Fatah, M., Akdis, D., Spears, D. A., Koopmann, T. T., Mittal, K., ... Hamilton, R. M. (2018). An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis. European Heart Journal, 39(44), 3932-3944. https://doi.org/10.1093/eurheartj/ehy567

An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis. / Chatterjee, Diptendu; Fatah, Meena; Akdis, Deniz; Spears, Danna A.; Koopmann, Tamara T.; Mittal, Kirti; Rafiq, Muhammad A.; Cattanach, Bruce M.; Zhao, Qili; Healey, Jeff S.; Ackerman, Michael John; Bos, Johan Martijn; Sun, Yu; Maynes, Jason T.; Brunckhorst, Corinna; Medeiros-Domingo, Argelia; Duru, Firat; Saguner, Ardan M.; Hamilton, Robert M.

In: European Heart Journal, Vol. 39, No. 44, 21.11.2018, p. 3932-3944.

Research output: Contribution to journalArticle

Chatterjee, D, Fatah, M, Akdis, D, Spears, DA, Koopmann, TT, Mittal, K, Rafiq, MA, Cattanach, BM, Zhao, Q, Healey, JS, Ackerman, MJ, Bos, JM, Sun, Y, Maynes, JT, Brunckhorst, C, Medeiros-Domingo, A, Duru, F, Saguner, AM & Hamilton, RM 2018, 'An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis', European Heart Journal, vol. 39, no. 44, pp. 3932-3944. https://doi.org/10.1093/eurheartj/ehy567
Chatterjee, Diptendu ; Fatah, Meena ; Akdis, Deniz ; Spears, Danna A. ; Koopmann, Tamara T. ; Mittal, Kirti ; Rafiq, Muhammad A. ; Cattanach, Bruce M. ; Zhao, Qili ; Healey, Jeff S. ; Ackerman, Michael John ; Bos, Johan Martijn ; Sun, Yu ; Maynes, Jason T. ; Brunckhorst, Corinna ; Medeiros-Domingo, Argelia ; Duru, Firat ; Saguner, Ardan M. ; Hamilton, Robert M. / An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis. In: European Heart Journal. 2018 ; Vol. 39, No. 44. pp. 3932-3944.
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abstract = "Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC. Methods and results: We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified anti-DSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified. Conclusion: Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.",
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T1 - An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis

AU - Chatterjee, Diptendu

AU - Fatah, Meena

AU - Akdis, Deniz

AU - Spears, Danna A.

AU - Koopmann, Tamara T.

AU - Mittal, Kirti

AU - Rafiq, Muhammad A.

AU - Cattanach, Bruce M.

AU - Zhao, Qili

AU - Healey, Jeff S.

AU - Ackerman, Michael John

AU - Bos, Johan Martijn

AU - Sun, Yu

AU - Maynes, Jason T.

AU - Brunckhorst, Corinna

AU - Medeiros-Domingo, Argelia

AU - Duru, Firat

AU - Saguner, Ardan M.

AU - Hamilton, Robert M.

PY - 2018/11/21

Y1 - 2018/11/21

N2 - Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC. Methods and results: We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified anti-DSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified. Conclusion: Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.

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