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Primary Immunodeficiency to pneumococcal infection due to a defect in Toll-like receptor signaling

2004; Elsevier BV; Volume: 144; Issue: 4 Linguagem: Inglês

10.1016/j.jpeds.2003.10.034

1097-6833

Andrew Currie, Donald J. Davidson, Gregor S. D. Reid, Simi Bharya, Kelly L. MacDonald, Rebecca S. Devon, David P. Speert,

NF-κB Signaling Pathways

Abstract 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-κB 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-1β or IL-18. Lipopolysaccharide (LPS)-induced translocation of NF-κB 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-κB 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.