Title: Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity
Authors: Ku, Cheng-Lung ×
von Bernuth, Horst
Picard, Capucine
Zhang, Shen-Ying
Chang, Huey-Hsuan
Yang, Kun
Chrabieh, Maya
Issekutz, Andrew C
Cunningham, Coleen K
Gallin, John
Holland, Steven M
Roifman, Chaim
Ehl, Stephan
Smart, Joanne
Tang, Mimi
Barrat, Franck J
Levy, Ofer
McDonald, Douglas
Day-Good, Noorbibi K
Miller, Richard
Takada, Hidetoshi
Hara, Toshiro
Al-Hajjar, Sami
Al-Ghonaium, Abdulaziz
Speert, David
Sanlaville, Damien
Li, Xiaoxia
Geissmann, Frédéric
Vivier, Eric
Maródi, László
Garty, Ben-Zion
Chapel, Helen
Rodriguez-Gallego, Carlos
Bossuyt, Xavier
Abel, Laurent
Puel, Anne
Casanova, Jean-Laurent #
Issue Date: Oct-2007
Publisher: Rockefeller Institute for Medical Research
Series Title: Journal of Experimental Medicine vol:204 issue:10 pages:2407-2422
Abstract: Human interleukin (IL) 1 receptor-associated kinase 4 (IRAK-4) deficiency is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3- and TLR4-interferon (IFN)-alpha/beta pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells [MDDCs], myeloid DCs [MDCs], and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK-4-dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4-dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.
ISSN: 0022-1007
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Clinical Bacteriology and Mycology
Experimental Laboratory Immunology
× corresponding author
# (joint) last author

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