Chinese patients with defective IL-12/23-interferon-gamma circuit in Taiwan: partial dominant interferon-gamma receptor 1 mutation presenting as cutaneous granuloma and IL-12 receptor beta1 mutation as pneumatocele.
BACKGROUND
IL-12/23-interferon-gamma 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-gamma circuit rather than CGD are not recognized in Taiwan, endemic for tuberculosis and salmonella.


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


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-gamma circuit. ROS was first measured to exclude CGD. Candidate genes of IL12RB1, IFNRG1, IL12p40, IFNRG2, signal transducer and activator of transcription-1, and NF-kappaB 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.


CONCLUSIONS
Patients with defective IL-12/23-IFN-gamma circuit may resemble or overlap CGD manifestations of refractory cutaneous atypical mycobacterial granuloma and salmonella pneumatocele.
Lee
Wen-I
WI
Primary Immunodeficiency Care And Research (PICAR) Institute, Chang Gung Memory and Children's Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. wen2707@hotmail.com
Huang
Jing-Long
JL
Lin
Tzou-Yien
TY
Hsueh
Chuen
C
Wong
Alex M
AM
Hsieh
Meng-Ying
MY
Chiu
Cheng-Hsun
CH
Jaing
Tang-Her
TH
D000328:Adult; D002648:Child; D005260:Female; D005799:Genes, Dominant; D006099:Granuloma / Q000175:diagnosis* / Q000382:microbiology; D006105:Granulomatous Disease, Chronic / Q000235:genetics*; D006547:Hernia / Q000175:diagnosis* / Q000382:microbiology; D006801:Humans; D007223:Infant; D053711:Interleukin-12 Receptor beta 1 Subunit / Q000235:genetics*; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics; D008171:Lung Diseases / Q000175:diagnosis* / Q000382:microbiology; D008297:Male; D009154:Mutation / Q000235:genetics; D009165:Mycobacterium Infections, Nontuberculous / Q000150:complications / Q000235:genetics / Q000382:microbiology; D010019:Osteomyelitis / Q000235:genetics / Q000382:microbiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics*; D012480:Salmonella Infections / Q000150:complications / Q000382:microbiology; D012871:Skin Diseases / Q000175:diagnosis* / Q000382:microbiology; D013624:Taiwan; D014057:Tomography, X-Ray Computed; D000096743:Interferon gamma Receptor
D053711:Interleukin-12 Receptor beta 1 Subunit; D053646:Interleukin-2 Receptor beta Subunit; D017382:Reactive Oxygen Species; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor