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Impaired Priming and Activation of the Neutrophil NADPH Oxidase in Patients with IRAK4 or NEMO Deficiency¹

Anjali Singh^*, Kol A. Zarember^*, Douglas B. Kuhns and John I. Gallin^2,*

^* Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, and Clinical Services Program, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702

The NADPH oxidase (NOX), an oligomeric enzyme, plays a key role in polymorphonuclear neutrophil (PMN)-mediated host defense by producing cytotoxic superoxide anion (O₂). Whereas in vitro and biochemical studies have examined the assembly and activation of this important host immune defense system, few studies have examined the function of NOX in human patients with primary immunodeficiency other than chronic granulomatous disease. We studied the activation of NOX in PMN from patients with two distinct immunodeficiencies, IL-1R-associated kinase (IRAK)4 deficiency and NF-B essential modulator (NEMO or IB kinase ) deficiency. We observed impaired O₂ generation by LPS-treated and fMLP-activated IRAK4-deficient PMN that correlated with decreased phosphorylation of p47^phox and subnormal translocation of p47^phox, p67^phox, Rac2, and gp91^phox/Nox2 to the membranes indicating that TLR4 signaling to the NOX activation pathway requires IRAK4. NEMO-deficient PMN generated significantly less O₂ in response to LPS-primed fMLP and translocated less p67^phox than normal PMN, although p47^phox and Rac2 translocation were normal. Generally, responses of NEMO-deficient cells were intermediate between IRAK4-deficient cells and normal cells. Decreased LPS- and fMLP-induced phosphorylation of p38 MAPK in both IRAK4- and NEMO-deficient PMN implicates additional signal transduction pathways in regulating PMN activation by LPS and fMLP. Decreased activation of NOX may contribute to the increased risk of infection seen in patients with IRAK4 and NEMO deficiency.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the National Institutes of Health Clinical Center.

² Address correspondence and reprint requests to Dr. John I. Gallin, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Room 6-2551, MSC 1504, Bethesda, MD 20892-1504. E-mail address: jgallin{at}cc.nih.gov

³ Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; IRAK, IL-1R-associated kinase; NEMO, NF-B essential modulator; NOX, NADPH oxidase; MF, membrane fraction.

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				P. R. Errante, C. Prando, J. Bustamante, W. C. Aragao Filho, P. V. S. Pereira, J. Rehder, J. L. Casanova, P. Newburger, and A. C. Neto Comment on "Impaired Priming and Activation of the Neutrophil NADPH Oxidase in Patients with IRAK4 or NEMO Deficiency" J. Immunol., September 15, 2009; 183(6): 3559 - 3559. [Full Text] [PDF]