Interleukin 12 receptor deficiency in a child with recurrent bronchopneumonia and very high IgE levels
© Palamaro et al.; licensee BioMed Central Ltd. 2012
Received: 1 September 2012
Accepted: 14 September 2012
Published: 19 September 2012
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.
KeywordsImmunodeficiency IL-12/IL-12 receptor Recurrent pneumonia
Primary congenital immunodeficiencies encompass a wide spectrum of distinct clinical entities, which differ in either pathogenetic mechanism or clinical features. Recently, several novel syndromes with unusual phenotypes have been described [1, 2]. However, in a number of patients suffering from severe and sometimes life-threatening infections, in which an immunological disorder is suspected, the underlying genetic defect responsible for the immunodeficiency still remains to be elucidated . Recently, a higher susceptibility to intracellular pathogens and, in particular, atypical mycobacterial and salmonella infections has been described in patients with genetic alterations of the IL-12 receptor (IL-12R) [4–9]. IL-12 stimulates 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. Induction of a Th1 response and cell cycle progression mostly relies on the expression of a high affinity IL-12R, consisting of β1 and β2 chains [10–15]. A few genetic alterations of β1 chain have already been reported in patients suffering of mycobacterial infections [5, 6].
Specific antibody responses
German measles virus
Proliferative response to mitogens stimulation
Patient (mean ± SE)
Control (mean ± SE)
PMA + iono
22458 ± 11013
32159 ± 27858
800 ± 68
29500 ± 3000
The patient’s family history was notable for the presence of allergic disorders in both lineages. In particular, her mother and grandmother had a history of allergic rhinitis, while her father had urticaria. A maternal aunt died at 2 years of age by whooping-cough and a maternal uncle died at 16 months by a severe not better specified respiratory infection. A paternal aunt and her daughter had a history of allergic rhinitis.
The case here reported indicates that alterations of the induction of a proper Th1 response may be associated with an atypical immunodeficiency characterized by high susceptibility to infections. The functional response of lymphocytes to IL-12 depends on the expression of a high affinity IL-12 receptor on Th1 and NK cells. The high affinity receptor for IL-12 consists of two subunits, β1 and β2, closely related to the cytokine receptor glycoprotein (gp) 130 [11, 17]. The complete IL-12R is thought to be associated with the development, being expressed on human naive T cells during differentiation to Th1 but not to Th2. Therefore, the expression of these molecules is generally considered as a marker of Th1 dominated response [11–13, 16]. Th1 cells produce IFN-gamma and IL-2 and, predominantly, promote cell mediate immune responses against intracellular pathogens [18, 19]. In a previous study, we provided evidence of altered IL-12/IL-12R signaling in patients with very high IgE levels, suggestive of an impaired Th1 induction . A defective induction of a Th1 response in patients may lead to a higher risk of infections, thus worsening the overall outcome of patients with very high IgE levels. In the case herein described a genetic alteration of the IL-12R β1 has been found in heterozygosity. Whether this alteration is really responsible for the phenotype remains to be definitively demonstrated with further molecular and functional studies. However, it should be noted that patients with homozygous alterations of the same gene have already been reported, being affected with a more severe clinical phenotype and selective susceptibility to mycobacterial infections [5, 6]. Based on this clinical observation, we suggest that a better understanding of the molecular mechanisms governing Th1/Th2 homeostasis may help recognize novel clinical phenotypes of atypical immunodeficiencies.
Written informed consent was obtained from the parents of the patient for publication of this Case report and any accompanying images.
T helper 1
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