Interleukin 12 receptor deficiency in a child with recurrent bronchopneumonia and very high IgE levels

Abstract

Interleukin-12 (IL-12) is involved in cellular immune responses against intracellular pathogens by promoting the generation of T naive in T helper 1 (Th1) cells and by increasing interferon-gamma (IFN-gamma) production from T and natural killer (NK) cells. A defective induction of a Th1 response may lead to a higher risk of infections, and, in particular, infections due to typical and atypical Mycobacteria. We report on the case of a girl with suffering from recurrent bronchopneumonia associated with very high serum IgE levels, who exhibited a profound impairment of the Th1 generation associated with a novel mutation in the exon 5 of the IL-12R β1 gene (R156H). Our data suggest that in children with severe and recurrent infections, even in the absence of a mycobacterial infection, functional and/or genetic alterations of the molecular mechanisms governing Th1/Th2 homeostasis might be responsible for an atypical immunodeficiency and, therefore, should be investigated in these patients.

The role of IL-12/23 in T cell–related chronic inflammation: implications of immunodeficiency and therapeutic blockade

“…Heterozygous carriers appear to be clinically healthy with normal IL-12 signalling and IFNγ production. Another report documents an 8-year old girl with recurrent bronchopneumonia (due to Haemophilus on one occasion) associated with very high IgE levels (31). She was found to have a complete absence of the IL-12Rβ2 chain due to a novel mutation.…”

Regulation of Natural Killer Cell Function by STAT3

“…There is also evidence that IL-12 and IL-23 cross inhibit each other during an inflammatory response ( 152 , 153 ). Interleukin-12 is a critical cytokine that induces the maturation and functional activation of NK cells; it has been shown that NK cell differentiation and effector function are defective in IL-12- and IL-12 receptor-deficient mice, and patients with IL-12/IL-12R mutations are immunodeficient ( 154 – 158 ). In the context of an antitumor immune response, administration of recombinant IL-12 has antitumor effects, and IL-12 knockout mice were found to be more susceptible to ultraviolet light (UV)-induced tumors and skin papillomas ( 159 ).…”

The R156H variation in IL-12Rβ1 is not a mutation

“…We have read with interest the article by Loredana Palamaro et al [1] about a child with recurrent bronchopneumonia and very high IgE levels in which a mutation was found in the IL12RB1 gene that encodes the IL-12Rβ1 chain of both the IL-12 and IL-23 receptor.…”

“…No functional immunological analyses to determine whether the IL-12/IFN-γ pathway was affected were performed in the child [1]. The only experiment performed that, at best, provided circumstantial evidence that the IL12RB1 gene might be affected is the absence of an IL12RB2 transcript in PBMCs from the patient stimulated, not with a relevant stimulus such as IL-12 or IL-23, but with a mitogen.…”

“…Subsequent sequencing of the IL12RB1 transcript revealed a heterozygous variation, 531G>A, which leads to the amino acid substitution R156H. The variation was not found in 100 chromosomes of unrelated individuals, after which it was concluded that this must be a mutation [1]. …”