The Journal of Experimental Medicine
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Published 18 August 2003. doi:10.1084/jem.20030701
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© Rockefeller University Press, 0022-1007/2003/8/521 $5.00
The Journal of Experimental Medicine, Volume 198, Number 4, 521-531

Distinct Mutations in IRAK-4 Confer Hyporesponsiveness to Lipopolysaccharide and Interleukin-1 in a Patient with Recurrent Bacterial Infections

Andrei E. Medvedev1,5, Arnd Lentschat1,5, Douglas B. Kuhns2, Jorge C.G. Blanco5, Cindy Salkowski5, Shuling Zhang5, Moshe Arditi3, John I. Gallin4 and Stefanie N. Vogel1,5

1 Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, MD 21201
2 Clinical Services Program, Science Applications International Corporation Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702
3 Division of Pediatric Infectious Diseases, Cedar-Sinai Medical Center, Los Angeles, CA 90048
4 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
5 Uniformed Services University of the Health Sciences, Bethesda, MD 20814

Address correspondence to Stefanie N. Vogel, Dept. of Microbiology and Immunology, University of Maryland, Baltimore, 655 W. Baltimore St., Rm. 13-009, Baltimore, MD 20101. Phone: (410) 706-4838; Fax: (410) 706-8607; email: svogel{at}som.umaryland.edu

We identified previously a patient with recurrent bacterial infections who failed to respond to gram-negative LPS in vivo, and whose leukocytes were profoundly hyporesponsive to LPS and IL-1 in vitro. We now demonstrate that this patient also exhibits deficient responses in a skin blister model of aseptic inflammation. A lack of IL-18 responsiveness, coupled with diminished LPS and/or IL-1–induced nuclear factor–{kappa}B and activator protein-1 translocation, p38 phosphorylation, gene expression, and dysregulated IL-1R–associated kinase (IRAK)–1 activity in vitro support the hypothesis that the defect lies within the signaling pathway common to toll-like receptor 4, IL-1R, and IL-18R. This patient expresses a "compound heterozygous" genotype, with a point mutation (C877T in cDNA) and a two-nucleotide, AC deletion (620–621del in cDNA) encoded by distinct alleles of the IRAK-4 gene (GenBank/EMBL/DDBJ accession nos. AF445802 and AY186092). Both mutations encode proteins with an intact death domain, but a truncated kinase domain, thereby precluding expression of full-length IRAK-4 (i.e., a recessive phenotype). When overexpressed in HEK293T cells, neither truncated form augmented endogenous IRAK-1 kinase activity, and both inhibited endogenous IRAK-1 activity modestly. Thus, IRAK-4 is pivotal in the development of a normal inflammatory response initiated by bacterial or nonbacterial insults.

Key Words: immunodeficiency • TLR4 • IL-1R • inflammation • signal transduction


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