A novel form of complete IL-12/IL-23 receptor β1 deficiency with cell surface-expressed nonfunctional receptors

摘要: Complete interleukin-12/interleukin-23 receptor β1 (IL-12Rβ1) deficiency is the most frequent known genetic etiology of syndrome Mendelian susceptibility to mycobacterial disease. The patients described date lack IL-12Rβ1 at surface their natural killer (NK) and T cells due IL12RB1 mutations, which either interrupt open reading frame or disrupt protein folding. We describe a patient with large in-frame deletion 12165 nucleotides (nt) in IL12RB1, encompassing exons 8 13 resulting expression nonfunctional IL-12Rβ1. These 6 encode proximal NH2-terminal half extracellular domain downstream from cytokine-binding domain. Five monoclonal anti-IL-12Rβ1 antibodies tested recognized internally truncated chain on cell surface. However, IL-12 IL-23 did not bind normally patient's IL-12Rβ1-containing respective heterodimeric receptors. As result, signal transducer activator transcription-4 (STAT4) was phosphorylated interferon-γ (IFN-γ) production induced upon stimulation even high doses IL-23. functional defect completely rescued by retrovirus-mediated gene transfer. Thus, detection does exclude possibility complete mycobacteriosis salmonellosis. Paradoxically, largest mutation detected associated IL-12Rβ1, defining novel form deficiency. (Blood. 2004;104:2095-2101)