Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity.
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.
Ku
Cheng-Lung
CL
Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France.
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
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*
D016207:Cytokines; D051193:Toll-Like Receptors; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases