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

Cheng Lung Ku, Horst Von Bernuth, Capucine Picard, Shen Ying Zhang, Huey Hsuan Chang, Kun Yang, Maya Chrabieh, Andrew C. Issekutz, Coleen K. Cunningham, John Gallin, Steven M. Holland, Chaim Roifman, Stephan Ehl, Joanne Smart, Mimi Tang, Franck J. Barrat, Ofer Levy, Douglas McDonald, Noorbibi K. Day-Good, Richard MillerHidetoshi Takada, Toshiro Hara, Sami Al-Hajjar, Abdulaziz Al-Ghonaium, David Speert, Damien Sanlaville, Xiaoxia Li, Frédéric Geissmann, Eric Vivier, L. Máródi, Ben Zion Garty, Helen Chapel, Carlos Rodriguez-Gallego, Xavier Bossuyt, Laurent Abel, Anne Puel, Jean Laurent Casanova

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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)-α/β 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. JEM

Original languageEnglish
Pages (from-to)2407-2422
Number of pages16
JournalJournal of Experimental Medicine
Volume204
Issue number10
DOIs
Publication statusPublished - Oct 1 2007

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Interleukin-1 Receptor-Associated Kinases
Bacterial Infections
Immunity
Toll-Like Receptors
Monocytes
Interleukins
Dendritic Cells
Infection
Toll-Like Receptor 3
Cytokines
Bacteria
Cell Lineage
Streptococcus pneumoniae
Granulocytes
Natural Killer Cells
Interferons
Lipopolysaccharides
Blood Cells
Leukocytes
B-Lymphocytes

ASJC Scopus subject areas

  • Immunology

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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; 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; Máródi, L.; Garty, Ben Zion; Chapel, Helen; Rodriguez-Gallego, Carlos; Bossuyt, Xavier; Abel, Laurent; Puel, Anne; Casanova, Jean Laurent.

In: Journal of Experimental Medicine, Vol. 204, No. 10, 01.10.2007, p. 2407-2422.

Research output: Contribution to journalArticle

Ku, CL, Von Bernuth, H, Picard, C, Zhang, SY, Chang, HH, Yang, K, Chrabieh, M, Issekutz, AC, Cunningham, CK, Gallin, J, Holland, SM, Roifman, C, Ehl, S, Smart, J, Tang, M, Barrat, FJ, Levy, O, McDonald, D, Day-Good, NK, Miller, R, Takada, H, Hara, T, Al-Hajjar, S, Al-Ghonaium, A, Speert, D, Sanlaville, D, Li, X, Geissmann, F, Vivier, E, Máródi, L, Garty, BZ, Chapel, H, Rodriguez-Gallego, C, Bossuyt, X, Abel, L, Puel, A & Casanova, JL 2007, 'Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity', Journal of Experimental Medicine, vol. 204, no. 10, pp. 2407-2422. https://doi.org/10.1084/jem.20070628
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 ; Máródi, L. ; Garty, Ben Zion ; Chapel, Helen ; Rodriguez-Gallego, Carlos ; Bossuyt, Xavier ; Abel, Laurent ; Puel, Anne ; Casanova, Jean Laurent. / Selective predisposition to bacterial infections in IRAK-4-deficient children : IRAK-4-dependent TLRs are otherwise redundant in protective immunity. In: Journal of Experimental Medicine. 2007 ; Vol. 204, No. 10. pp. 2407-2422.
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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)-α/β 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. JEM",
author = "Ku, {Cheng Lung} and {Von Bernuth}, Horst and Capucine Picard and Zhang, {Shen Ying} and Chang, {Huey Hsuan} and Kun Yang and Maya Chrabieh and Issekutz, {Andrew C.} and Cunningham, {Coleen K.} and John Gallin and Holland, {Steven M.} and Chaim Roifman and Stephan Ehl and Joanne Smart and Mimi Tang and Barrat, {Franck J.} and Ofer Levy and Douglas McDonald and Day-Good, {Noorbibi K.} and Richard Miller and Hidetoshi Takada and Toshiro Hara and Sami Al-Hajjar and Abdulaziz Al-Ghonaium and David Speert and Damien Sanlaville and Xiaoxia Li and Fr{\'e}d{\'e}ric Geissmann and Eric Vivier and L. M{\'a}r{\'o}di and Garty, {Ben Zion} and Helen Chapel and Carlos Rodriguez-Gallego and Xavier Bossuyt and Laurent Abel and Anne Puel and Casanova, {Jean Laurent}",
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T1 - Selective predisposition to bacterial infections in IRAK-4-deficient children

T2 - IRAK-4-dependent TLRs are otherwise redundant in protective immunity

AU - Ku, Cheng Lung

AU - Von Bernuth, Horst

AU - Picard, Capucine

AU - Zhang, Shen Ying

AU - Chang, Huey Hsuan

AU - Yang, Kun

AU - Chrabieh, Maya

AU - Issekutz, Andrew C.

AU - Cunningham, Coleen K.

AU - Gallin, John

AU - Holland, Steven M.

AU - Roifman, Chaim

AU - Ehl, Stephan

AU - Smart, Joanne

AU - Tang, Mimi

AU - Barrat, Franck J.

AU - Levy, Ofer

AU - McDonald, Douglas

AU - Day-Good, Noorbibi K.

AU - Miller, Richard

AU - Takada, Hidetoshi

AU - Hara, Toshiro

AU - Al-Hajjar, Sami

AU - Al-Ghonaium, Abdulaziz

AU - Speert, David

AU - Sanlaville, Damien

AU - Li, Xiaoxia

AU - Geissmann, Frédéric

AU - Vivier, Eric

AU - Máródi, L.

AU - Garty, Ben Zion

AU - Chapel, Helen

AU - Rodriguez-Gallego, Carlos

AU - Bossuyt, Xavier

AU - Abel, Laurent

AU - Puel, Anne

AU - Casanova, Jean Laurent

PY - 2007/10/1

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N2 - 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)-α/β 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. JEM

AB - 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)-α/β 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. JEM

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