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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.

SUBMITTER: Ku CL

PROVIDER: S-EPMC2118442 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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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 CL von Bernuth Horst H Picard Capucine C Zhang Shen-Ying SY Chang Huey-Hsuan HH Yang Kun K Chrabieh Maya M Issekutz Andrew C AC Cunningham Coleen K CK Gallin John J Holland Steven M SM Roifman Chaim C Ehl Stephan S Smart Joanne J Tang Mimi M Barrat Franck J FJ Levy Ofer O McDonald Douglas D Day-Good Noorbibi K NK Miller Richard R Takada Hidetoshi H Hara Toshiro T Al-Hajjar Sami S Al-Ghonaium Abdulaziz A Speert David D Sanlaville Damien D Li Xiaoxia X Geissmann Frédéric F Vivier Eric E Maródi László L Garty Ben-Zion BZ Chapel Helen H Rodriguez-Gallego Carlos C Bossuyt Xavier X Abel Laurent L Puel Anne A Casanova Jean-Laurent JL

The Journal of experimental medicine 20070924 10

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 blo ...[more]

PMID: 17893200

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Dataset Information

Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity.

Publications

Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity.

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