Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Ghrelin-Reactive autoantibodies are elevated in children with Prader-Willi Syndrome compared to unaffected controls (#26)

Gabrielle Crisp 1 , Ohn Nyunt 2 , Inge Seim 1 , Lisa Chopin 1 , Mark Harris 3 , Penny Jeffery 1
  1. Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
  2. Royal North Shore Hospital, Sydney, New South Wales, Australia
  3. Lady Cilento Children's Hospital, Brisbane, Queensland, Australia

Background: Prader-Willi Syndrome (PWS) is a genetic disorder characterised by developmental and growth abnormalities, insatiable appetite, and excessive eating (hyperphagia). This hyperphagia is thought to be driven by supraphysiological levels of the appetite-stimulating peptide hormone ghrelin. However, the underlying causes of hyperghrelinaemia in PWS are currently unknown. Recently, ghrelin-reactive autoantibodies (subclass IgG) were identified in non-genetic obesity.  These autoantibodies reversibly bind to circulating ghrelin and act as carrier proteins - protecting ghrelin from degradation, thereby potentiating its orexigenic effects.

Aims: 1: to measure ghrelin-reactive autoantibodies in children with PWS; 2: investigate whether inactive ghrelin isoform, unacylated ghrelin (UAG), can outcompete ghrelin to sequester ghrelin-reactive autoantibodies ex vivo and 3: determine the ghrelin-reactive autoantibody binding regions of the ghrelin peptide using epitope mapping.

Methods: Ghrelin and levels of ghrelin-reactive autoantibodies were measured in plasma collected from 16 children with PWS and 16 unaffected controls using ELISA. To test the specificity of the ELISA, and to determine if the autoantibodies complex with UAG, the samples were also pre-absorbed with exogenous ghrelin or UAG (10-6 M) prior to being subjected to separate ELISAs. Linear epitope mapping was performed with fasted plasma samples from all participants.

Results: Children with PWS display hyperghrelinaemia and significantly higher levels of plasma ghrelin-reactive autoantibodies than controls (P<0.0001, t test). Pre-absorption with exogenous ghrelin and UAG significantly reduced the level of ghrelin-reactive autoantibodies detected in both cohorts (P<0.001, paired t test), suggesting that the autoantibodies complex with both isoforms of ghrelin. The autoantibodies from PWS patients bound to several unique epitopes of the ghrelin peptide compared to controls (P<0.0001, t test).

Conclusions: Increased levels of ghrelin-reactive autoantibodies in children with PWS may contribute to the hyperghrelinaemia and hyperphagia that characterises the syndrome. Targeting these autoantibodies and their unique epitopes may provide a future therapeutic avenue for this incurable disorder.