Davidson et al (2004) Primary immunodeficiency to pneumococcal infection due to a defect in toll-like receptor signalling. J. Paed. 144;512-518

Primary immunodeficiency to pneumococcal infection due to a defect in toll-like receptor signalling.

Davidson, D. J.*, Currie, A. J.*, Reid, G. S. D., Bharya, S., MacDonald, K. L., Devon, R. S., and Speert, D. P.
* denotes equal contribution
J. Paed. (2004) 144;512-518    PubMed
Davidson supported by funding from: Wellcome Trust/ CCFF

OBJECTIVE:The role of human Toll-like receptors (TLRs) in initiating protective immune responses in vivo is not well understood. We investigated the role of TLR signaling in defense against infection in a 3-year-old boy with a severe defect resulting in recurrent Streptococcus pneumoniae bacteremia.
METHODS:After classic immunodeficiencies were ruled out, the patient’s mononuclear cells, macrophages, and dendritic cells (DCs) were studied. TLR signaling responses to a range of TLR- and interleukin-1 receptor (IL-1R)-specific agonists were investigated pre- and posttranscriptionally by measuring NF-kappaB translocation and cytokine mRNA and protein expression.
RESULTS:The patient’s monocytic cells were profoundly deficient in cytokine production in response to a range of microbial-derived TLR agonists and to recombinant IL-1beta or IL-18. Lipopolysaccharide (LPS)-induced translocation of NF-kappaB p50 and p65 and the kinetics of LPS-induced cytokine mRNA transcription were normal except for IL-6 and IL-12p40, which were poorly transcribed. Despite deficient responses to TLR agonists by the patient’s DCs and B cells, CD40L responses were normal.
CONCLUSIONS:We describe a patient with deficient TLR-mediated cytokine production with intact interleukin receptor-associated kinase (IRAK)-4 expression, NF-kappaB translocation, and enhanced susceptibility to infection. This patient demonstrates that TLR signaling, in the presence of intact antibody responses, may be a nonredundant requirement for defense against pyogenic infections. PMID:15069402
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