Severe Mycobacterium bovis BCG infections in a large series of novel IL-12 receptor beta1 deficient patients and evidence for the existence of partial IL-12 receptor beta1 deficiency.

Cell mediated immunity plays a critical role in human host defence against intracellular bacteria. In patients with unusual, severe infections caused by poorly pathogenic species of mycobacteria and salmonellae, genetic deficiencies have been identified in key genes in the type-1 cytokine pathway, especially in IFNGR1 and IL12RB1. Here, we analyzed 11 patients originating from Turkey and suffering from unusual Mycobacterium bovis Bacille Calmette-Guerin infections following vaccination, and found that most patients (n=8) are deficient in IL-12Rbeta1 expression and function. No defects were found in patients' IFN-gammaR or IL-18R. In addition, a first patient suffering from partial IL-12Rbeta1 deficiency is described. This patient presented with an intermediate cellular and immunological phenotype: a consistent, low response to IL-12 was found, which could be further augmented by IL-18. Despite a lack of cell surface IL-12Rbeta1 expression, normal levels of intracellular IL-12Rbeta1 protein were detectable, which was not seen in the other, completely IL-12Rbeta1 deficient patients examined. Moreover, this patient had a relatively mild clinical phenotype and was the only individual with a single homozygous amino acid substitution in IL-12Rbeta1 (C198R). Collectively, our findings indicate that idiopathic, unusually severe infections due to M. bovis BCG can be caused by complete as well as partial IL-12Rbeta1 deficiency.