Altered endotoxin responsiveness in healthy children with Down syndrome

Dean Huggard,Fiona Mcgrane,Edna Roche,Joanne Balfe,Niamh Lagan,Eleanor J Molloy,Ana Moreno,Ashanty M Melo,Orla Franklin,Timothy Ronan Leahy,Derek G Doherty

doi:10.1186/s12865-018-0270-z

Abstract

BackgroundDown syndrome (DS) is the most common syndromic immunodeficiency with an increased risk of infection, mortality from sepsis, and autoinflammation. Innate immune function is altered in DS and therefore we examined responses in CD11b and Toll like receptor 4 (TLR-4), which are important immune cell surface markers upregulated in response to Lipopolysaccharide (LPS) endotoxin, and the immunomodulator melatonin. Neutrophil and monocyte responses to LPS and melatonin in children with Down syndrome (DS) who were clinically stable were compared to age-matched controls. Whole blood was incubated with LPS and melatonin and the relative expression of CD11b and TLR-4 evaluated by flow cytometry.ResultsChildren with DS had an increased response to LPS in neutrophils and intermediate monocytes, while also having elevated TLR-4 expression on non-classical monocytes compared to controls at baseline. Melatonin reduced CD11b expression on neutrophils, total monocytes, both classical and intermediate sub-types, in children with DS and controls.ConclusionMelatonin could represent a useful clinical adjunct in the treatment of sepsis as an immunomodulator. Children with DS had increased LPS responses which may contribute to the more adverse outcomes seen in sepsis.

Highlights

Down syndrome (DS) is the most common syndromic immunodeficiency with an increased risk of infection, mortality from sepsis, and autoinflammation
Effects of LPS endotoxin on CD11b expression Neutrophil baseline CD11b expression in children with DS was significantly lower compared with controls (p = 0.045)
We demonstrated that melatonin has an anti-inflammatory influence on innate immune function by reducing CD11b expression on neutrophils and total monocytes in children with DS and controls, thereby inhibiting neutrophil and monocyte activation and migration

Summary

Introduction

Down syndrome (DS) is the most common syndromic immunodeficiency with an increased risk of infection, mortality from sepsis, and autoinflammation. Innate immune function is altered in DS and we examined responses in CD11b and Toll like receptor 4 (TLR-4), which are important immune cell surface markers upregulated in response to Lipopolysaccharide (LPS) endotoxin, and the immunomodulator melatonin. Co-morbidities associated with DS include developmental disability, congenital heart disease (CHD), gastrointestinal tract anomalies, and an increased risk of haematological malignancy [3]. It is the most common genetic syndrome associated with abnormal immune function and immune defects [4]. Mortality from sepsis is 30% greater in patients with DS in comparison to children without DS who had sepsis [16]

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