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
- Palamaro L, Vigliano I, Giardino G, Cirillo E, Aloj G, Romano R, Pignata C: SCID-like phenotype associated with an inhibitory autoreactive immunoglobulin. J Investig Allergol Clin Immunol. 2012, 22: 67-70.PubMed
- De Vries E, Alvarez Cardona A, Abdul Latiff AH, Badolato R, Brodszki N, Cant AJ, Carbone J, Casper JT, Ciznar P, Cochino AV, Conley ME, Derfalvi B, Driessen GJ, Elfeky R, Espanol T, Glimour K, Gueseva MN, Haverkamp MH, Helminen M, Honig M, Kanariou MG, Kirschfink M, Klein C, Kuijpers TW, Kutukculer N, Martire B, Meyts I, Niehues T, Pignata C, Reda SM, Renner ED, Rezaei N, Rizzi M, Sampalo Lainz MA, Sargur RB, Sediva A, Seidel MG, Seneviratne SL, Soler-Palacin P, Tommasini A, Warnatz K: Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol. 2012, 167: 108-119. 10.1111/j.1365-2249.2011.04461.x.PubMed CentralView ArticlePubMed
- Aloj G, Giardino G, Valentino L, Maio F, Gallo V, Esposito T, Naddei R, Cirillo E, Pignata C: Severe combined immunodeficiences: new and old scenarios. Int Rev Immunol. 2012, 31: 43-65. 10.3109/08830185.2011.644607.View ArticlePubMed
- Aytekin C, Dogu F, Tuygun N, Tanir G, Guloglu D, Boisson-Dupuis S, Bustamante J, Feinberg J, Casanova JL, Ikinciogullari A: Bacille Calmette-Guèrin lymphadenitis and recurrent oral candidiasis in an infant with a new mutation leading to interleukin-12 receptor beta-1 deficiency. J Invest Allergol Clin Immunol. 2011, 21: 401-404.
- Pedraza-Sanchez S, Herrera-Barrios MT, Aldana-Vergara R, Neumann-Ordoez M, Gonzalez-Hernandez Y, Sada-Dìaz E, de Beaucoudrey L, Casanova JL, Torres-Rojas M: Bacille Calmette-Guèrin infection and disease with fatal outcome associated with a point mutation in the interleukin-12/interleukin-23 receptor beta-1 chain in two Mexican families. Int J Infect Dis. 2010, 14: e256-e260.View ArticlePubMed
- Shah P, El-Maaytah M, Jerjes W, Upile T, Ayliffe P: Interleukin 12 receptor beta1 chain deficiency in a child with disseminated tuberculosis: a case report. J Oral Maxillofac Surg. 2010, 68: 909-911. 10.1016/j.joms.2009.04.116.View ArticlePubMed
- Granados EL, Porpiglia AS, Hogan MB, Matamoros N, Krasovec S, Pignata C, Smith CIE, Hammarstrom L, Bjorkander J, Belohradsky BH, Fontan Casariego G, Garcia Rodriguez MC, Conley ME: Clinical and molecular analysis of patients with defects in micro heavy chain gene. J Clin Invest. 2002, 110: 1029-1035.View Article
- Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, Drysdale P, Jouanguy E, Doffinger R, Bernaudin F, Jeppsson O, Gollob JA, Meinl E, Segal AW, Fischer A, Kumararatne D, Casanova JL: Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science. 1998, 280: 1432-1435. 10.1126/science.280.5368.1432.View ArticlePubMed
- Sakai T, Matsuoka M, Aoki M, Nosaka K, Mitsuya H: Missense mutation of the interleukin-12 receptor beta1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection. Blood. 2001, 97: 2688-2694. 10.1182/blood.V97.9.2688.View ArticlePubMed
- Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, Gately MK, Gubler U: A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits. Proc Natl Acad Sci USA. 1996, 93: 14002-14007. 10.1073/pnas.93.24.14002.PubMed CentralView ArticlePubMed
- Rogge L, Barberis-Maino L, Biffi M, Passini N, Presky DH, Gubler U, Sinigaglia F: Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med. 1997, 185: 825-831. 10.1084/jem.185.5.825.PubMed CentralView ArticlePubMed
- Szabo SJ, Dighe AS, Gubler U, Murphy KM: Regulation of the interleukin (IL) -12RB2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med. 1997, 185: 817-824. 10.1084/jem.185.5.817.PubMed CentralView ArticlePubMed
- Gately MK, Renzetti LM, Magram J, Stern AS, Adorini L, Gubler U, Presky DH: The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol. 1998, 16: 495-521. 10.1146/annurev.immunol.16.1.495.View ArticlePubMed
- Amorosi S, Russo I, Amodio G, Garbi C, Vitiello L, Palamaro L, Adriani M, Vigliano I, Pignata C: The cellular amount of the common γ-chain influences spontaneous or induced cell proliferation. J Immunol. 2009, 182: 3304-3309. 10.4049/jimmunol.0802400.View ArticlePubMed
- Vigliano I, Palamaro L, Bianchino G, Fusco A, Vitiello L, Grieco V, Romano R, Salvatore M, Pignata C: Role of the common g chain in cell cycle progression of human malignant cell lines. Int Immunol. 2012, 24: 159-167. 10.1093/intimm/dxr114.View ArticlePubMed
- Montella S, Maglione M, Bruzzese D, Mollica C, Pignata C, Aloj G, Manna A, Esposito A, Mirra V, Santamaria F: Magnetic resonance imaging is an accurate and reliable method to evaluate non-cystic fibrosis paediatric lung disease. Respirology. 2012, 17: 87-91. 10.1111/j.1440-1843.2011.02067.x.View ArticlePubMed
- Presky DH, Minetti LJ, Gillessen S, Wilkinson VL, Wu CY, Gubler U, Chizzonite R, Gately MK: Analysis of the multiple interactions between IL-12 and the high affinity IL-12 receptor complex. J Immunol. 1998, 160: 2174-2179.PubMed
- Santoni D, Pedicini M, Castiglione F: Implementation of a regulatory gene network to simulate the TH1/2 differentiation in an agent-based model of hypersensitivity reactions. Bioinformatics. 2008, 24: 1374-1380. 10.1093/bioinformatics/btn135.View ArticlePubMed
- Finkelman FD, Vercelli D: Advances in asthma, allergy mechanisms, and genetics in 2006. J Allergy Clin Immunol. 2007, 120: 544-550. 10.1016/j.jaci.2007.05.025.View ArticlePubMed
- Fusco A, Vigliano I, Palamaro L, Cirillo E, Aloj G, Piscopo G, Giardino G, Pignata C: Altered signaling through IL-12 receptor in children with very high serum IgE levels. Cell Immunol. 2010, 265: 74-79. 10.1016/j.cellimm.2010.07.005.View ArticlePubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.