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    Altered Toll like receptor signalling in children with Down syndrome


    Dr. Dean Huggard is funded by the NCRC Clinical Research Fellowship scheme to undertake a PhD under the supervision of Prof. Eleanor Molloy and Dr. Derek Doherty (Trinity College Dublin).  In his PhD, Dean is working on the DINOSAUR study (Down syndrome and ImmuNOdeficiency and Systemic And mUltiorgan Responses) which aims to increase our understanding of the causes of altered immune responses in children with Down Syndrome. Dean recently published a paper titled “Altered Toll-Like Receptor Signalling in Children with Down Syndrome” in the journal “Mediators of Inflammation”(Pubmed). Read Dean’s plain English summary of the paper below.

    Children with Down syndrome (a genetic disorder caused by the presence of an extra chromosome 21) are more prone to developing infections and autoimmune conditions such as arthritis. This is thought to be caused by changes in how the immune system of children with Down Syndrome works. Previous research studies have shown that children with Down Syndrome have lower numbers of certain types of white blood cells (e.g. T-cells and B-cells), altered levels of cytokines (signalling proteins released by immune cells), and poorer responses to vaccination (e.g. a lower number of antibody-producing memory B cells following vaccination).

    In our research group, we are interested in Toll like receptors (TLRs), a family of proteins expressed by many types of white blood cell. TLRs play an important role in our immune response to infectious agents due to their ability to detect and bind molecules derived from microorganisms such as bacteria, fungi, and viruses. When these molecules bind to TLRs on white blood cells, this causes a series of signalling events that help to fight the infection (e.g. the production of cytokines).

    In our study, we compared the levels and activity of Toll like receptor 2 (TLR2) in children with and without Down Syndrome. We did this by measuring the levels of TLR2 on the surface of white blood cells (monocytes and neutrophils), measuring the gene expression of proteins involved in TLR2 signalling events within white blood cells, and by measuring cytokine levels in serum (the liquid part of clotted blood samples). All measurements were made in the presence and absence of molecules that bind to and activate TLR2 (e.g. Pam3CSK3). This is an important area of research as changes in TLR2 expression and activity are associated with an increased risk of bacterial infections and poorer outcomes in cases of sepsis (an exaggerated immune response to infection that can cause organ damage and death).

    We found that children with Down Syndrome had increased levels of the TLR2 on the surface of their white blood cells compared to children without Down Syndrome. Altered levels of TLR2 associated signalling molecules were also found in children with Down Syndrome. In addition, we found that an agent that can block TLR2/TLR4 receptors (Sparstolonin B) was effective at decreasing TLR2 levels on white blood cells and decreasing the effects of TLR2 signalling (cytokine production) in children with Down Syndrome.

    This study is the first to highlight altered TLR signalling in children with Down syndrome which may contribute to why they are more prone to infections and autoimmune conditions. The TLR2/TLR4 blocker Sparstolonin B could be of potential clinical benefit due to its ability to regulate TLR2 expression and activity.


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