ESPE Abstracts (2016) 86 FC6.1

ESPE2016 Free Communications Syndromes: Mechanisms and Management (6 abstracts)

Ghrelin-Reactive Autoantibodies are Elevated in Children with Prader-Willi Syndrome Compared to Unaffected Sibling Controls

Gabrielle Crisp a , Ohn Nyunt b , Yassmin Musthaffa c , Inge Seim a , Lisa Chopin a , Mark Harris c & Penny Jeffery a

aGhrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, Brisbane, Queensland, Australia; bRoyal North Shore Hospital, NSW, Australia; cLady Cilento Children’s Hospital, Brisbane, Queensland, Australia

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

Objectives: This project aimed to measure ghrelin-reactive autoantibodies in children with PWS. We hypothesised that patients possess higher levels of ghrelin-reactive autoantibodies compared to their unaffected sibling controls. We also tested whether the inactive ghrelin isoform, unacylated ghrelin (UAG), outcompetes ghrelin and sequesters autoantibodies ex vivo.

Methods: Blood samples were taken from patients and controls after an overnight fast and 10, 20, 30, 60 and 120 minutes after a standardised mixed meal. Plasma was extracted and ghrelin-reactive autoantibodies were measured using ELISA. To test specificity of the ELISA and to determine if the autoantibodies bind to UAG, the samples were also pre-absorbed with exogenous ghrelin and UAG (10−6 M) prior to being subjected to separate ELISAs.

Results: We have demonstrated that children with PWS have significantly higher levels of plasma ghrelin-reactive autoantibodies compared to controls after an overnight fast (P<0.0001, unpaired t test). Food intake did not affect autoantibody levels in patients or controls. Both ghrelin and UAG pre-absorbed controls showed significant reduction of ghrelin-reactive autoantibody detection in the PWS and control groups (P<0.001, unpaired t test), suggesting that the autoantibodies complex with both isoforms.

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

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