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Chinese Patients with Defective IL-12/23-Interferon-γ Circuit in Taiwan: Partial Dominant Interferon-γ Receptor 1 Mutation Presenting as Cutaneous Granuloma and IL-12 Receptor β1 Mutation as Pneumatocele

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Abstract

Background

IL-12/23-interferon-γ circuit enhances reactive oxygen species (ROS) synthesis in macrophage to attack intracellular pathogens such as mycobacteria and salmonella. Defective ROS in patients with chronic granulomatous disease (CGD) have increased susceptibility to these pathogens. However, patients with defective IL-12/23-interferon-γ circuit rather than CGD are not recognized in Taiwan, endemic for tuberculosis and salmonella.

Aim

The purpose of this study was to identify Taiwanese patients with defective IL-12/23-IFN-γ circuit.

Patients and Methods

In a long-term molecular study of primary immunodeficiency diseases (PIDD), the tentative CGD patients presenting with Bacille Calmette–Guerin (BCG)-induced infection, refractory atypical mycobacterial cutaneous granuloma and osteomyelitis, recurrent salmonella sepsis, and pneumatocele were studied for the IL-12/23-IFN-γ circuit. ROS was first measured to exclude CGD. Candidate genes of IL12RB1, IFNRG1, IL12p40, IFNRG2, signal transducer and activator of transcription-1, and NF-κB essential modulator and their encoding protein expressions were analyzed.

Results

Of the 175 Taiwanese PIDD patients during a 28-year period, three patients from two unrelated families were identified with the hotspot INFRG1 deletion mutation (818del4) and had CGD features, presenting as cutaneous granuloma, and multiple osteomyelitis infected by non-tuberculosis mycobacteria, Mycobacteria avium complex and Mycobacterium scrofulaceum. Another with mis-sense IL12RB1 mutation (Arg211Pro) was noted as recurrent Salmonella enteritidis D sepsis and pneumatocele.

Conclusion

Patients with defective IL-12/23-IFN-γ circuit may resemble or overlap CGD manifestations of refractory cutaneous atypical mycobacterial granuloma and salmonella pneumatocele.

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Abbreviations

BCG:

Bacille Calmette–Guerin

CMC:

chronic mucocutaneous candidiasis

PBMCs:

peripheral blood mononuclear cells

PIDD:

primary immunodeficiency diseases

ROS:

reactive oxygen species

SCID:

severe combined immunodeficiency

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Acknowledgments

The authors wish to thank all of the patients and their families for their kind cooperation, as well as their physicians for the referrals. They also thank Yi-Chen Wang, Hsiu-Li Chou, and Hsiu-Shan Hsiao for their technical assistance. This study was supported by Chang-Gung Medical Research Progress Grant CMRPG 450061 and National Science Council Grants NSC96-2314-B-182A-053-MY2 and NMRPG466062.

Conflict of interest statement

All of the authors declare no conflict of interest.

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Authors and Affiliations

  1. Primary Immunodeficiency Care And Research (PICAR) Institute, Chang Gung Memory and Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Wen-I Lee, Jing-Long Huang & Tang-Her Jaing

  2. Department of Pediatric Allergy, Immunology and Rheumatology, Chang Gung Memory and Children’s Hospital, Chang Gung University College of Medicine, Pediatric Office 12 L, #5 Fu-Shing Street, Kwei-Shan, Taoyuan, Taiwan

    Wen-I Lee & Jing-Long Huang

  3. Department of Pediatric Infection, Chang Gung Memory and Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Tzou-Yien Lin & Cheng-Hsun Chiu

  4. Department of Pathology, Chang Gung Memory and Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Chuen Hsueh

  5. Department of Medical Imaging and Intervention, Chang Gung Memory and Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Alex M. Wong

  6. Department of Pediatric Neurology, Chang Gung Memory and Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Meng-Ying Hsieh

  7. Graduate Institute of Medical Clinics, Chang Gung Memory and Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Meng-Ying Hsieh

  8. Department of Pediatric Hematology and Oncology, Chang Gung Memory and Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Tang-Her Jaing

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  1. Wen-I Lee
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Correspondence to Wen-I Lee.

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Lee, WI., Huang, JL., Lin, TY. et al. Chinese Patients with Defective IL-12/23-Interferon-γ Circuit in Taiwan: Partial Dominant Interferon-γ Receptor 1 Mutation Presenting as Cutaneous Granuloma and IL-12 Receptor β1 Mutation as Pneumatocele. J Clin Immunol 29, 238–245 (2009). https://doi.org/10.1007/s10875-008-9253-9

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  • DOI: https://doi.org/10.1007/s10875-008-9253-9

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