Abstract
In the last decade, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) deficiency, the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), has been diagnosed in a few children and adults with severe tuberculosis in Iran. Here, we report three cases referred to the Immunology, Asthma and Allergy ward at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) at Masih Daneshvari Hospital from 2012 to 2017 with Mycobacterium tuberculosis and non-tuberculous mycobacteria infections due to defects in IL-12Rβ1 but with different clinical manifestations. All three were homozygous for either an IL-12Rβ1 missense or nonsense mutation that caused the IL-12Rβ1 protein not to be expressed on the cell membrane and completely abolished the cellular response to recombinant IL-12. Our findings suggest that the presence of IL-12Rβ1 deficiency should be determined in children with mycobacterial infections at least in countries with a high prevalence of parental consanguinity and in areas endemic for TB like Iran.
Highlights
Natural human immunity to intracellular pathogens, including opportunistic or low-virulence mycobacteria such as Bacillus Calmette-Guérin (BCG; an attenuated Mycobacterium bovis strain) vaccines, non-tuberculous mycobacteria (NTM) and non-typhoid Salmonella, and/or Mycobacterium tuberculosis (MTB), relies on the functional integrity of the interleukin (IL)10 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia11 Nutricia Research Centre for Specialized Nutrition, Utrecht, The NetherlandsImmunogenetics (2018) 70:373–37912/23-interferon (IFN)-γ axis enabling cross-talk between macrophages and T-lymphocytes/NK cells (Lee et al 2011; Mortaz et al 2015; Prando et al 2013)
Mendelian susceptibility to mycobacterial disease (MSMD)-causing mutations have been identified in eight autosomal genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8, ISG15, and TYK2) and two X-linked genes (IKBKG and CYBB) (Bogunovic et al 2012; Bustamante et al 2011; Filipe-Santos et al 2006; Hambleton et al 2011; Haverkamp et al 2014; Prando et al 2013) resulting in impaired IFN-γ-mediated immunity (Casanova and Abel 2002; de Beaucoudrey et al 2010)
Clinical TB has been described in a number of patients with IL-12/ IL-23/IFN-γ system defects (Ottenhoff et al 2005) and may result from autosomal recessive IL-12Rβ1 deficiency, in at least some children (Boisson-Dupuis et al 2011)
Summary
Natural human immunity to intracellular pathogens, including opportunistic or low-virulence mycobacteria such as Bacillus Calmette-Guérin (BCG; an attenuated Mycobacterium bovis strain) vaccines, non-tuberculous mycobacteria (NTM) and non-typhoid Salmonella, and/or Mycobacterium tuberculosis (MTB), relies on the functional integrity of the interleukin (IL). The patient was diagnosed with BCG-osis and treated with anti-TB drugs (rifampin, isoniazid, cycloserin, IFN-γ and, ethambutol), but despite this treatment, the patient was re-admitted to the hospital at the age of 7 months complaining of respiratory distress due to isoniazid use. The blood culture was positive for Kingella species and blood tests revealed the following results: WBC 7.05 × 103/μl (Neu 72.3%; Lymph 10.1%; Mono 11.9%; Eos 5.4%; Baso 0.3%), Hb 12.4 g/dl, and PLT 241 × 103/μl and the CD4/CD8 ratio was decreased compared to control levels (9/40). Functional analysis revealed possible defects in the IL-12Rβ1 (Table 2; patient 3) and genetic testing revealed the homozygous IL12RB1 mutation c.517C>T in exon 5 (Fig. 3e) This variation leads to an R173W amino acid change. The capsule is iso-intense (green arrow) and the vasogenic edema surrounding the lesion (blue arrow) is hyper-intense. d Pedigree of patient 3. e Sequencing analysis by dideoxy-nucleotide termination method demonstrated a mutation in exon 5 of the IL12RB1 gene using forward (left panel) and reverse (right panel) sequencing
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