Severe Mycobacterium bovis BCG infections in a large series of novel IL–12 receptor β1 deficient patients and evidence for the existence of partial IL–12 receptor β1 deficiency

Abstract

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‐12Rβ1 expression and function. No defects were found in patients' IFN‐γR or IL‐18R. In addition, a first patient suffering from partial IL‐12Rβ1 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‐12Rβ1 expression, normal levels of intracellular IL‐12Rβ1 protein were detectable, which was not seen in the other, completely IL‐12Rβ1 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‐12Rβ1 (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‐12Rβ1 deficiency.

A novel form of complete IL-12/IL-23 receptor 1 deficiency with cell surface-expressed nonfunctional receptors

“…The 700 ϩ 362_1619-944 del IL12RB1 allele therefore encodes a detectable surface-expressed IL-12R␤1 chain in our patient. Remarkably, none of the other 53 patients with IL-12R␤1 deficiency described to date [17][18][19][20][21][22][23][24][25][26]28 were found to express detectable levels of these receptors at the cell surface. In contrast, IL-12R␤1 was present in large amounts at the cell surface in P and was detected with 5 of the 6 mAbs tested, including 2 of the 3 commercially available mAbs.…”

“…[15][16][17] Null recessive IL12RB1 mutations have been identified in 54 other patients with IL-12 and IL-23 receptor ␤1 chain deficiency. [17][18][19][20][21][22][23][24][25][26][27][28] Patients with IL-12 p40 and IL-12R␤1 deficiency share a number of common clinical characteristics: low penetrance of genetic susceptibility to mycobacteriosis and salmonellosis; high proportion of extraintestinal salmonellosis among symptomatic patients; broad resistance to other microorganisms; and a favorable clinical outcome. 29,30 From a molecular point of view, 53 of 54 known patients with complete IL-12R␤1 deficiency [17][18][19][20][21][22][23][24][25][26]28 have no detectable IL-12R␤1 on the cell surface, due to mutations that either interrupt the open reading frame (ORF) (nonsense and frameshift mutations) or disrupt folding of the protein (missense mutations).…”

“…5 Complete recessive STAT-1 deficiency is a related but distinct disorder involving susceptibility to both mycobacteria and viruses, due to the impairment of IFN-␥-and IFN-␣/␤-mediated immunity. 14 From [17][18][19][20][21][22][23][24][25][26]28 have no detectable IL-12R␤1 on the cell surface, due to mutations that either interrupt the open reading frame (ORF) (nonsense and frameshift mutations) or disrupt folding of the protein (missense mutations). We report here the molecular investigation of a patient with complete IL-12R␤1 deficiency despite the presence of IL-12R␤1 at the cell surface.…”

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

“…IL12RB1 is also transcribed by pleural cells of patients with active TB (12,13), and encodes the protein IL12R␤1, a type I transmembrane receptor that binds the IL12p40-subunit of IL-12, IL-23, and IL-12(p40) 2 (14)(15)(16). Reflecting the importance of IL12RB1 expression, IL12RB1 null individuals are susceptible to disseminated forms of disease caused by the M. tuberculosis complex (7,17,18), as well as nontuberculous mycobacteria (19)(20)(21). Given the importance of IL12RB1 and IL-12-family members to limiting M. tuberculosis activity, several promising, experimental vaccine strategies that specifically target these cytokine pathways are being developed (22,23).…”

Immunity towards tuberculosis infection: A review

“…Similarly, the receptor for IL-23 consists of a subunit IL-12R 1, in a complex with a member recently identified as the homopoietin receiving family. IL-12 and IL-23 have similar functions, although are non-identical-including in the stimulation of IFN- production Lichtenauer -Kaligis et al, 2003). IL12 is a heterodimeric cytokine composed of two subunits, p35 and p40, which are encoded by the IL12A and IL12B genes, respectively.…”