title: Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity.
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.
authors: Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France.
authors: Cheng-Lung
authors: CL
authors: Ku
authors: Horst
authors: H
authors: von Bernuth
authors: Capucine
authors: C
authors: Picard
authors: Shen-Ying
authors: SY
authors: Zhang
authors: Huey-Hsuan
authors: HH
authors: Chang
authors: Kun
authors: K
authors: Yang
authors: Maya
authors: M
authors: Chrabieh
authors: Andrew C
authors: AC
authors: Issekutz
authors: Coleen K
authors: CK
authors: Cunningham
authors: John
authors: J
authors: Gallin
authors: Steven M
authors: SM
authors: Holland
authors: Chaim
authors: C
authors: Roifman
authors: Stephan
authors: S
authors: Ehl
authors: Joanne
authors: J
authors: Smart
authors: Mimi
authors: M
authors: Tang
authors: Franck J
authors: FJ
authors: Barrat
authors: Ofer
authors: O
authors: Levy
authors: Douglas
authors: D
authors: McDonald
authors: Noorbibi K
authors: NK
authors: Day-Good
authors: Richard
authors: R
authors: Miller
authors: Hidetoshi
authors: H
authors: Takada
authors: Toshiro
authors: T
authors: Hara
authors: Sami
authors: S
authors: Al-Hajjar
authors: Abdulaziz
authors: A
authors: Al-Ghonaium
authors: David
authors: D
authors: Speert
authors: Damien
authors: D
authors: Sanlaville
authors: Xiaoxia
authors: X
authors: Li
authors: Frédéric
authors: F
authors: Geissmann
authors: Eric
authors: E
authors: Vivier
authors: László
authors: L
authors: Maródi
authors: Ben-Zion
authors: BZ
authors: Garty
authors: Helen
authors: H
authors: Chapel
authors: Carlos
authors: C
authors: Rodriguez-Gallego
authors: Xavier
authors: X
authors: Bossuyt
authors: Laurent
authors: L
authors: Abel
authors: Anne
authors: A
authors: Puel
authors: Jean-Laurent
authors: JL
authors: Casanova
mesh_terms: D000293:Adolescent; D000328:Adult; D001424:Bacterial Infections / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D010375:Pedigree; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases