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

ABSTRACT:

Background

Autoimmunity associated with autoantibodies against the ?1-adrenergic receptor (?1-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 ?1-AAB autoimmunity in DCM and to develop appropriate treatment strategies.

Objectives

To introduce an animal model, we investigated the ?1-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 ?1-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 ?1-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, ?1-AAB were analyzed during progress.

Results

Fifty-nine (67.8%) DoCM dogs and 19 (61.3%) controls were ?1-AAB positive. Of the controls that developed DoCM, 8 were ?1-AAB positive (p = 0.044 vs. dogs remaining in the control group); their ?1-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 ?1-AAB positivity became visible in the DoCM group (p = 0.066). Total and cardiac mortality were higher in ?1-AAB positive DP (p = 0.002; p = 0037). The dogs' ?1-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 ?1-AAB associated autoimmunity, similar as in the pathogenesis of human DCM. Consequently, DP could compensate the lack of animal models for the investigation of ?1-AAB autoimmunity in human DCM.

SUBMITTER: Wess G 

PROVIDER: S-EPMC6611557 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature