A novel form of complete IL-12/IL-23 receptor beta1 deficiency with cell surface-expressed nonfunctional receptors.

Abstract:

:Complete interleukin-12/interleukin-23 receptor beta1 (IL-12Rbeta1) deficiency is the most frequent known genetic etiology of the syndrome of Mendelian susceptibility to mycobacterial disease. The patients described to date lack IL-12Rbeta1 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-12Rbeta1. 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-12Rbeta1 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-12Rbeta1-containing respective heterodimeric receptors. As a result, signal transducer and activator of transcription-4 (STAT4) was not phosphorylated and interferon-gamma (IFN-gamma) 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-12Rbeta1 gene transfer. Thus, the detection of IL-12Rbeta1 on the cell surface does not exclude the possibility of complete IL-12Rbeta1 deficiency in patients with mycobacteriosis or salmonellosis. Paradoxically, the largest IL12RB1 mutation detected is associated with the cell surface expression of nonfunctional IL-12Rbeta1, defining a novel genetic form of IL-12Rbeta1 deficiency.

journal_name

Blood

journal_title

Blood

authors

Fieschi C,Bosticardo M,de Beaucoudrey L,Boisson-Dupuis S,Feinberg J,Santos OF,Bustamante J,Levy J,Candotti F,Casanova JL

doi

10.1182/blood-2004-02-0584

subject

Has Abstract

pub_date

2004-10-01 00:00:00

pages

2095-101

issue

7

eissn

0006-4971

issn

1528-0020

pii

2004-02-0584

journal_volume

104

pub_type

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