Characterisation of innate immune responses in children with Down syndrome

Abstract

Introduction: Down syndrome (DS) is associated with increased incidence of infections in childhood, higher mortality from sepsis, and other inflammatory conditions such as arthropathy, thyroid and coeliac disease. Several immunodeficiencies have already been described in DS, however we evaluated novel aspects of their immune system; neutrophil and monocyte function, genes involved in Toll like receptor (TLR) pathway signalling, a broad panel of pro-and anti-inflammatory cytokines, and characterisation of the NLRP3 inflammasome. Furthermore, the clinical significance of immune screening and the latest evidence around vaccination in DS was evaluated.

Methods: Children with DS and age matched controls were recruited to examine neutrophil and monocyte cell surface markers CD11b, TLR2 and TLR4 by flow cytometry. Enzyme linked immunosorbent assay (ELISA) was utilised to evaluate an extensive panel of inflammatory cytokines, and quantitative polymerase chain reaction (qPCR) to quantify fold change in expression of key genes involved in TLR signalling and the inflammasome. All experiments featured immunomodulation with pro- (LPS, Pam3Csk4) and anti-inflammatory (Melatonin, Sparstolonin B (SsnB)) stimuli.

Results: Children with DS displayed further dysregulation of their immune system and inflammatory response: neutrophil endotoxin hyperresponsiveness, increased TLR2 expression on neutrophils and monocytes with abnormal TLR signalling; and further evidence of excess circulating inflammatory cytokines. Melatonin and SsnB were effective at abrogating the inflammatory response. Both the white cell (WCC) and neutrophil count were associated with poor respiratory outcome. Children with DS are at increased risk from vaccine preventable diseases like, respiratory syncytial virus (RSV), influenza, and pneumococcus.

Conclusion: Children with DS have a complex and profound immune dysregulation which contributes to respiratory morbidity, mortality from sepsis and autoimmunity. Melatonin and SsnB may have potential therapeutic benefit as immunomodulators. The WCC and neutrophils may be used as biomarkers to help predict prognosis and allow timely intervention for high risk individuals. Tailored vaccination programmes should be endorsed and administered for all children with DS.