Unmasking features of the auto-epitope essential for β(1)-adrenoceptor activation by autoantibodies in chronic heart failure

AIMS: Chronic heart failure (CHF) can be caused by autoantibodies stimulating the heart via binding to first and/or second extracellular loops of cardiac β(1)-adrenoceptors. Allosteric receptor activation depends on conformational features of the autoantibody binding site. Elucidating these features will pave the way for the development of specific diagnostics and therapeutics. Our aim was (i) to fine-map the conformational epitope within the second extracellular loop of the human β(1)-adrenoceptor (β(1) EC(II)) that is targeted by stimulating β(1)-receptor (auto)antibodies and (ii) to generate competitive cyclopeptide inhibitors of allosteric receptor activation, which faithfully conserve the conformational auto-epitope. METHODS AND RESULTS: Non-conserved amino acids within the β(1) ECII loop (compared with the amino acids constituting the ECII loop of the β(2)-adrenoceptor) were one by one replaced with alanine; potential intra-loop disulfide bridges were probed by cysteine-serine exchanges. Effects on antibody binding and allosteric receptor activation were assessed (i) by (auto)antibody neutralization using cyclopeptides mimicking β(1) ECII ± the above replacements, and (ii) by (auto)antibody stimulation of human β(1)-adrenoceptors bearing corresponding point mutations. With the use of stimulating β(1)-receptor (auto)antibodies raised in mice, rats, or rabbits and isolated from exemplary dilated cardiomyopathy patients, our series of experiments unmasked two features of the β(1) ECII loop essential for (auto)antibody binding and allosteric receptor activation: (i) the NDPK(211-214) motif and (ii) the intra-loop disulfide bond C(209)↔C(215). Of note, aberrant intra-loop disulfide bond C(209)↔C(216) almost fully disrupted the functional auto-epitope in cyclopeptides. CONCLUSIONS: The conformational auto-epitope targeted by cardio-pathogenic β(1)-receptor autoantibodies is faithfully conserved in cyclopeptide homologues of the β(1) EC(II) loop bearing the NDPK(211-214) motif and the C(209)↔C(215) bridge while lacking cysteine C(216). Such molecules provide promising tools for novel diagnostic and therapeutic approaches in β(1)-autoantibody-positive CHF

Is there a silver lining to the Zika virus epidemic in the Americas?

It is hard to find anything positive to say about an epidemic of an emerging virus that infects pregnant women, targets developing fetuses’ neural progenitor cells, and disrupts the sequence of neural development to cause a devastating syndrome resulting in lifelong disabilities. Infants with microcephaly became the faces of the Zika virus epidemic in the Americas, which affected almost all countries in the western hemisphere in 2014–17. By the end of 2017, Zika virus has nearly disappeared from the Americas as quickly as it emerged. Now that the dust is settling, what have the scientific and public health communities learned? Is there a silver lining to Zika’s devastation

The Impact of Maternal Depression and Parent–Child Interactions on Risk of Parasitic Infections in Early Childhood: A Prospective Cohort in Benin

Objectives: Maternal depression occurs in 13–20% of women from low-income countries, which is associated with negative child health outcomes, including diarrheal disease. However, few studies have investigated its impact on child risk of infectious disease. We studied the impacts of maternal depressive symptoms and parent–child interactions, independently, on the risk of Plasmodium falciparum malaria and soil-transmitted helminth infection in Beninese children. Methods: Our population included mothers and children enrolled in a clinical trial during pregnancy (MiPPAD) in Benin. The Edinburgh Postnatal Depression Scale (EPDS) assessed maternal depressive symptoms and the home observation measurement of the environment (HOME) assessed parent–child interactions. Blood and stool sample analyses diagnosed child malaria and helminth infection at 12, 18, and 24 months. Negative binomial and Poisson regression models with robust variance tested associations. Results: Of the 302 mother–child pairs, 39 (12.9%) mothers had depressive symptoms. Median number of malaria episodes per child was 3 (0–14) and 29.1% children had at least one helminth infection. Higher EPDS scores were associated with lower HOME scores; relative risk (RR) 0.97 (95% confidence interval (CI) 0.95, 0.99), particularly with lower acceptance, involvement, and variety subscales; RR 0.92 (95% CI 0.85, 0.99), RR 0.82 (95% CI 0.77, 0.88), RR 0.93 (95% CI 0.88, 0.99), respectively. However, neither exposure was associated with risk of parasitic infection in children. Conclusions for Practice: Maternal depressive symptoms are associated with poor parent–child interactions, particularly acceptance of behavior, involvement with children, and variety of interactions, but these exposures do not independently impact risk of parasitic infection in children

Modulation of beta1 adrenoceptor activity by domain-specific antibodies and heart failure-associated autoantibodies

OBJECTIVES: Our study attempted to gain further understanding of the allosteric effects of human autoantibodies on beta1-adrenergic receptor (beta1-AR) function. BACKGROUND: Recently, we reported on the existence of activating anti-beta1-AR antibodies in patients with dilated cardiomyopathy (DCM 26% prevalence) or ischemic cardiomyopathy (ICM, 10% prevalence); however, their functional effects have not yet been thoroughly characterized. METHODS: In this study we detected functionally active receptor-antibodies in 8 out of 30 DCM patients. Their immunological and functional properties were analyzed using both synthetic receptor-peptides and intact recombinant human beta1-AR, and were compared with those of heterologous antibodies to selected beta1-AR domains generated in rabbits and mice RESULTS: Rabbit, mouse, and human anti-beta1-AR against the second extracellular domain preferentially bound to a native receptor conformation and impaired radioligand binding to the receptor. However, their functional effects differed considerably: Rabbit and mouse antibodies decreased both basal and agonist-stimulated cAMP production, whereas the patient antibodies (n = 8) increased basal, and six of them also increased agonist-stimulated receptor activity (i.e., acted as receptor-sensitizing agents). Two out of eight human anti-beta1-AR increased basal but decreased agonist-stimulated receptor activity (i.e., acted as partial agonists). CONCLUSIONS: Antibodies against the same small beta1-AR domain can have very divergent allosteric effects, ranging from inhibitory to agonist-promoting activities. Activating autoantibodies were associated with severe cardiac dysfunction and thus might be involved in the development and/or course of human cardiomyopathy