Doberman pinschers present autoimmunity associated with functional autoantibodies: A model to study the autoimmune background of human dilated cardiomyopathy

By | 23rd July 2019

PLoS One. 2019; 14(7): e0214263.
Published online 2019 Jul 5. doi: 10.1371/journal.pone.0214263
Gerhard Wess, Conceptualization, Project administration, Supervision,1 Gerd Wallukat, Formal analysis, Investigation, Methodology,2 Anna Fritscher, Investigation, Methodology,1 Niels-Peter Becker, Investigation, Writing – original draft,2 Katrin Wenzel, Investigation, Methodology,2 Johannes Müller, Conceptualization, Project administration, Supervision,2 and Ingolf Schimke, Conceptualization, Formal analysis, Project administration, Supervision, Writing – original draft2,*
Tomohiko Ai, Editor

Abstract

Background
Autoimmunity associated with autoantibodies against the β1-adrenergic receptor (β1-AAB) is increasingly accepted as the driver of human dilated cardiomyopathy (DCM). Unfortunately, there is a lack of animal models to extend the knowledge about β1-AAB autoimmunity in DCM and to develop appropriate treatment strategies.
Objectives
To introduce an animal model, we investigated the β1-AAB associated autoimmunity in Doberman Pinscher (DP) with dilated cardiomyopathy, which has similarities to human DCM.
Materials and methods
Eighty-seven DP with cardiomyopathy in terms of pathological ECG and echocardiography (DoCM) and 31 dogs (at enrollment) without DoCM (controls) were analyzed for serum activity of β1-AAB with a bioassay that records the chronotropic response of spontaneously beating cultured neonatal rat cardiomyocytes to the DP’s IgG. To locate the receptor binding site of β1-AAB and the autoantibody’s sensitivity to inhibition, competing experiments with related blockers were performed with the bioassay. In controls that developed DoCM during follow-up, β1-AAB were analyzed during progress.
Results
Fifty-nine (67.8%) DoCM dogs and 19 (61.3%) controls were β1-AAB positive. Of the controls that developed DoCM, 8 were β1-AAB positive (p = 0.044 vs. dogs remaining in the control group); their β1-AAB activity increased with the cardiomyopathy progress (p<0.02). To supplement DoCM group with the 9 animals which developed cardiomyopathy in the follow up, a more pronounced β1-AAB positivity became visible in the DoCM group (p = 0.066). Total and cardiac mortality were higher in β1-AAB positive DP (p = 0.002; p = 0037). The dogs’ β1-AAB recognized a specific epitope on the second extracellular receptor and were sensitive to inhibition by drugs already successfully tested to inhibit the corresponding human autoantibody. Conclusions Doberman Pinschers presented β1-AAB associated autoimmunity, similar as in the pathogenesis of human DCM. Consequently, DP could compensate the lack of animal models for the investigation of β1-AAB autoimmunity in human DCM.


Doberman pinschers present autoimmunity associated with functional autoantibodies: A model to study the autoimmune background of human dilated cardiomyopathy

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