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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.
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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)
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