TY - JOUR
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 J.
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.
N1 - Publisher Copyright:
© 2018 Oxford University Press.
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.
AB - 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.
KW - Arrhythmogenic right ventricular cardiomyopathy
KW - Autoantibody
KW - Biomarker
KW - Boxer dog
KW - Human desmoglein-2
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U2 - 10.1093/eurheartj/ehy567
DO - 10.1093/eurheartj/ehy567
M3 - Article
C2 - 30239670
AN - SCOPUS:85056803229
SN - 0195-668X
VL - 39
SP - 3932
EP - 3944
JO - European heart journal
JF - European heart journal
IS - 44
ER -