Altered endotoxin responsiveness in healthy children with Down syndrome

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.

Immune Dysregulation in Children With Down Syndrome

“…Non-classical monocyte have been implicated in various disease states such as cancer, sepsis and chronic inflammation (51). We reported significantly elevated TLR-4 on non-classical monocytes in children with DS vs. controls (43), and greater TLR-2 expression on intermediate and non-classical sub-types (52). This portrays a pro-inflammatory phenotype of monocyte subpopulations in DS.…”

“…In adults with DS and periodontal disease compared to controls without periodontitis, there was no difference in the expression of TLR2 or TLR4 single nucleotide polymorphisms (SNPs) (86). We reported an increase in TLR4 expression on non-classical (CD14dim/CD16+) monocytes at baseline in children with DS vs. controls, highlighting an increase in pro-inflammatory phenotype in this cohort (43).…”

“…Novo et al (42) found no significant differences in CD11b expression on neutrophils in children with DS (n = 12, age 8-16 years) vs. controls (42). However, we reported a significant decrease in neutrophil CD11b at baseline in children with DS (n = 23, mean age 8.67 years) compared to controls (n = 21, age 7.4 years), and a significantly greater rise in CD11b post lipopolysaccharide (LPS; endotoxin) stimulation in the DS cohort vs. controls (43). This endotoxin hyperresponsiveness in neutrophils in DS which may lead to deleterious inflammatory consequences.…”

“…The intermediate monocyte has multi functionality in phagocytosis and antigen presentation, but also in cytokine production such as Interleukin (IL)-10, increased Toll like receptor (TLR) cell surface expression and increased numbers in acute inflammation. We reported the highest baseline TLR4 (and TLR2) expression on intermediate monocytes in both children with DS and controls (43). The nonclassical monocyte is pro-inflammatory and is the chief producer of pro-inflammatory cytokines IL-1β and Tumor Necrosis Factor (TNF-α) its numbers increase in both acute and chronic disease (47,48).…”

Multiorgan involvement and management in children with Down syndrome

“…4 The increased susceptibility to infections has been associated with atypical immune function in conjunction with various non-immune related medical and anatomical comorbidities. 2,5 The prevalence of leukaemia is estimated to be up to 15-20 times more frequent in children with DS and although leukaemia treatment is improving, it is still a major cause of mortality in children with DS. 6,7 The life expectancy of people with Down syndrome increased dramatically between 1960 and 2007, from 10 to 47 years old.…”