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Blood, 1 October 2004, Vol. 104, No. 7, pp. 2095-2101. Prepublished online as a Blood First Edition Paper on June 3, 2004; DOI 10.1182/blood-2004-02-0584. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: 2004-02-0584v1 104/7/2095    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fieschi, C. Articles by Casanova, J.-L. Search for Related Content PubMed PubMed Citation Articles by Fieschi, C. Articles by Casanova, J.-L. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY A novel form of complete IL-12/IL-23 receptor 1 deficiency with cell surface-expressed nonfunctional receptors Claire Fieschi, Marita Bosticardo, Ludovic de Beaucoudrey, Stéphanie Boisson-Dupuis, Jacqueline Feinberg, Orchidée Filipe Santos, Jacinta Bustamante, Jacov Levy, Fabio Candotti, and Jean-Laurent Casanova From the Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes (Institut National de la Santé et de la Recherche Médicale [INSERM] U550), France, EU; Necker Medical School, Paris, France, EU; Disorders of Immunity Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; Division of Pediatrics, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; and Pediatric Immunology and Hematology Unit, Necker Hospital, Paris, France, EU. Complete interleukin-12/interleukin-23 receptor 1 (IL-12R1) deficiency is the most frequent known genetic etiology of the syndrome of Mendelian susceptibility to mycobacterial disease. The patients described to date lack IL-12R1 at the surface of their natural killer (NK) and T cells due to IL12RB1 mutations, which either interrupt the open reading frame or disrupt protein folding. We describe a patient with a large in-frame deletion of 12165 nucleotides (nt) in IL12RB1, encompassing exons 8 to 13 and resulting in the surface expression of nonfunctional IL-12R1. These 6 exons encode the proximal NH2-terminal half of the extracellular domain downstream from the cytokine-binding domain. Five of 6 monoclonal anti-IL-12R1 antibodies tested recognized the internally truncated chain on the cell surface. However, IL-12 and IL-23 did not bind normally to the patient's IL-12R1-containing respective heterodimeric receptors. As a result, signal transducer and activator of transcription-4 (STAT4) was not phosphorylated and interferon- (IFN-) production was not induced in the patient's cells upon stimulation with even high doses of IL-12 or IL-23. The functional defect was completely rescued by retrovirus-mediated IL-12R1 gene transfer. Thus, the detection of IL-12R1 on the cell surface does not exclude the possibility of complete IL-12R1 deficiency in patients with mycobacteriosis or salmonellosis. Paradoxically, the largest IL12RB1 mutation detected is associated with the cell surface expression of nonfunctional IL-12R1, defining a novel genetic form of IL-12R1 deficiency. (Blood. 2004;104:2095-2101) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S Y Patel, R Doffinger, G Barcenas-Morales, and D S Kumararatne Genetically determined susceptibility to mycobacterial infection J. Clin. Pathol., September 1, 2008; 61(9): 1006 - 1012. [Abstract] [Full Text] [PDF] S. A. Khader, S. Partida-Sanchez, G. Bell, D. M. Jelley-Gibbs, S. Swain, J. E. Pearl, N. Ghilardi, F. J. deSauvage, F. E. Lund, and A. M. Cooper Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection J. Exp. Med., July 10, 2006; 203(7): 1805 - 1815. [Abstract] [Full Text] [PDF] O. Filipe-Santos, J. Bustamante, M. H. Haverkamp, E. Vinolo, C.-L. Ku, A. Puel, D. M. Frucht, K. Christel, H. von Bernuth, E. Jouanguy, et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production J. Exp. Med., July 10, 2006; 203(7): 1745 - 1759. [Abstract] [Full Text] [PDF] A. Chapgier, R. F. Wynn, E. Jouanguy, O. Filipe-Santos, S. Zhang, J. Feinberg, K. Hawkins, J.-L. Casanova, and P. D. Arkwright Human Complete Stat-1 Deficiency Is Associated with Defective Type I and II IFN Responses In Vitro but Immunity to Some Low Virulence Viruses In Vivo. J. Immunol., April 15, 2006; 176(8): 5078 - 5083. [Abstract] [Full Text] [PDF]

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