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Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity.
Ku, Cheng-Lung 1, 2; von Bernuth, Horst 1, 2, 3; Picard, Capucine 1, 2, 19; Zhang, Shen-Ying 1, 2; Chang, Huey-Hsuan 1, 2; Yang, Kun 1, 2; Chrabieh, Maya 1, 2; Issekutz, Andrew C. 4; Cunningham, Coleen K. 5; Gallin, John 6; Holland, Steven M. 6; Roifman, Chaim 7; Ehl, Stephan 8; Smart, Joanne 9; Tang, Mimi 9; Barrat, Franck J. 10; Levy, Ofer 11, 13; McDonald, Douglas 12, 13; Day-Good, Noorbibi K. 14; Miller, Richard 15; Takada, Hidetoshi 16; Hara, Toshiro 16; Al-Hajjar, Sami 17; Al-Ghonaium, Abdulaziz 17; Speert, David 18; Sanlaville, Damien 20; Li, Xiaoxia 22; Geissmann, Frederic 2, 23; Vivier, Eric 24; Marodi, Laszlo 25; Garty, Ben-Zion 26; Chapel, Helen 27; Rodriguez-Gallego, Carlos 28; Bossuyt, Xavier 29; Abel, Laurent 1, 2; Puel, Anne 1, 2; Casanova, Jean-Laurent 1, 2, 21
[Article] Journal of Experimental Medicine. 204(10):2407-2422, October 1, 2007.

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: 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)-a/b 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.