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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 23, 2004 Accepted May 3, 2004 A novel form of complete IL-12/IL-23 receptor 1-deficiency with cell surface-expressed non-functional receptors Claire FIESCHI, Marita BOSTICARDO, Ludovic DE BEAUCOUDREY, Stephanie BOISSON-DUPUIS, Jacqueline FEINBERG, Orchidee FILIPE SANTOS, Jacinta BUSTAMANTE, Jacov LEVY, Fabio CANDOTTI, and Jean-Laurent CASANOVA* INSERM U550, Necker Medical School, Paris, France Disorders of Immunity Section, NIH, Bethesda, MD, USA Division of Pediatrics, Ben Gourion University, Beer Sheva, Israel INSERM U550, Necker Medical School, Paris, France; Pediatric Immunology and hematology Unit, Necker Hospital, Paris, France * Corresponding author; email: casanova{at}necker.fr. 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 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 12,165 nucleotides in IL12RB1, encompassing exons 8 to 13 and resulting in the surface expression of non-functional IL-12R1. These six exons encode the proximal NH2-terminal half of the extracellular domain downstream from the cytokine binding domain. Five of six 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, STAT-4 was not phosphorylated and 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 non-functional IL-12R1, defining a novel genetic form of IL-12R1 deficiency. 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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