Diagnostic and therapeutic aspects of β1-adrenergic receptor autoantibodies in human heart disease

Abstract

Growing evidence indicates a cardio-pathogenic role of autoantibodies against β1-adrenergic receptors (β1AR). In particular autoantibodies stimulating β1AR-mediated cAMP-production (i.e. agonistic β1AR autoantibodies) play a paramount role in chronic heart failure. When induced by immunisation, such autoantibodies cause heart failure in rodents; when present in patients they negatively affect survival in heart failure. However, the true prevalence and clinical impact of agonistic β1AR autoantibodies in human heart disease are still unclear, as are the events triggering their production, and the inter-relationship between autoantibody level and disease activity. β1AR autoantibodies can be removed by extracorporeal absorption or neutralised by systemic administration of synthetic epitope mimics. Only patients bearing agonistic β1AR autoantibodies in their bloodstream will benefit from these approaches. Therefore, reliable detection of agonistic β1AR autoantibodies is a key pre-requisite for the future implementation of these strategies. β1AR autoantibodies impact on conformation and down-stream signalling of the receptor by binding a conformational epitope, which is poorly represented by synthetic mimics and readily destroyed by fixation. Consequently, β1AR autoantibodies can reliably be detected only by assays utilising the native β1AR as a test antigen. To provide a sufficient basis for diagnostic predictions or therapeutic decisions, one must also determine whether β1AR autoantibodies stimulate the receptor, which again requires native, cell-based reporter systems. Translation of these procedures into versatile diagnostic tests fitting the requirements of general health care is a challenge for future development. Here, we will review the state of diagnostic and therapeutic efforts in the field of β1AR-directed autoimmunity, thereby aiming to furnish a conceptual frame for the further development of novel, more reliable diagnostic tools and more specific antibody-targeted therapeutic concepts.

A standardised FACS assay based on native, receptor transfected cells for the clinical diagnosis and monitoring of β1-adrenergic receptor autoantibodies in human heart disease

“…Autoantibodies that bind to and activate β 1 AR play a pathophysiological role in various cardiovascular disorders [1,2]. In rats, agonistic β 1 AR-antibodies raised by immunisation cause cardiac dysfunction and chronic heart failure [3].…”

Questionable Validity of Peptide-Based ELISA Strategies in the Diagnostics of Cardiopathogenic Autoantibodies That Activate G-Protein-Coupled Receptors

“…By targeting a metastable, polymorphic conformational epitope, β 1 -AR aabs only poorly cross-react with linear peptide mimics or denatured versions of that target domain. Thus, measurements based on interactions with immobilised (linear) peptide homologues of the target domain are only poorly or not at all correlated with measurements based on interactions with native membrane-bound β 1 -AR [9,14,15,16]. Epidemiological studies using peptide-based immunoassays [17,18] differ significantly from studies employing native cell assays [15,19,20,21].…”

“…Thus, β 1 -AR aabs associated with ventricular arrhythmia and increased mortality in dilated cardiomyopathy [3], AII-R 1 aabs associated with pre-eclampsia [4] and renal allograft rejection [5], and α 1 -AR aabs associated with malignant or refractory hypertension [6,7,8] all activate their respective GPCR. Moreover, immunisation of rats with epitopes that are thought to be the target of functionally active GPCR aabs induces pathological phenotypes corresponding to dilated cardiomyopathy [9,10] or arterial hypertension [11], underscoring their pathogenic potential. Consequently, the assessment of circulating agonistic GPCR aabs levels in patients with cardiovascular diseases has been attempted for years.…”

“…Importantly, clinical correlations clearly indicate that the latter results are much more valid [15,16,22]. Therefore, peptide-based immunoassays can currently not be accepted as a scientifically or diagnostically valid tool for the detection of clinically relevant β 1 -AR aabs in humans [9,23,24]. That imponderability probably also applies to the diagnostic significance of aabs directed against AII-R 1 and/or other GPCR, which induce their pathogenic effects by receptor activation [4,5,6,7,8,21].…”

“…Consequently, the assessment of circulating agonistic GPCR aabs levels in patients with cardiovascular diseases has been attempted for years. However, to solve that diagnostic challenge no simple solution exists [9]. The receptor domain targeted by β 1 -AR aabs is predicted to form an extracellular α-helix [12,13].…”