TY - JOUR
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 - Maródi, László
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
Y1 - 2007/10/1
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
UR - http://www.scopus.com/inward/record.url?scp=34948904198&partnerID=8YFLogxK
U2 - 10.1084/jem.20070628
DO - 10.1084/jem.20070628
M3 - 文章
C2 - 17893200
AN - SCOPUS:34948904198
SN - 0022-1007
VL - 204
SP - 2407
EP - 2422
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -