Patients with inhibitory and neutralizing auto-antibodies to interferon-γ resemble the sporadic adult-onset phenotype of Mendelian Susceptibility to Mycobacterial Disease (MSMD) lacking Bacille Calmette-Guerin (BCG)-induced diseases.
To recognize patients with inhibitory and neutralizing auto-antibodies to interferon-γ (AutoAbs-IFN-γ) presenting with the sporadic phenotype of Mendelian Susceptibility to Mycobacterial Disease (MSMD) mainly characterized by recurrent intracellular mycobacterium or/and salmonella infections, we comprehensively investigated IL12/23-IFN-γ signaling, candidate genetic sequencings or/and protein expressions of IL12RB1, IFNRG1, IL12p40, IFNRG2, STAT1, IKKA, NEMO, CYBB and IRF8 in four patients. Their serum was further titrated to detect AutoAbs-IFN-γ, for which the biological activity was assessed in Jurkat T cells. The patients mainly presented with recurrent non-tuberculous mycobacterium osteomyelitis and lymphadenopathy (Mycobacterium abscessus, chelonae and avium intracellular complex), and salmonella sepsis (S. enterica serogroup B, C2 and D). Additionally, Penicillium marneffei, varicella-zoster virus, and herpes simplex virus infections occurred. Inhibitory and neutralizing IFN-γ downstream signaling was elucidated in Jurkat cell lines as decreased MHC class I and phosphorylated STAT1 expression. Together with 24 patients from the PubMed search, the majority of the AutoAbs-IFN-γ patients were Asian (25/28). The most common involvement was lymph nodes (in 22/28), lungs (19/28) and bones (12/28). Mycobacterium avium complex (in 14) and chelonae (7) were the most common pathogens from 40 isolations. In contrast to those with the mild form of MSMD phenotype, AutoAbs-IFN-γ patients, in the absence of BCG-induced diseases, had a more persistent course and poor response to IFN-γ treatment. In conclusion, AutoAbs-IFN-γ patients may have a sporadic adult-onset MSMD phenotype in Asian regions endemic for mycobacterial infections.
Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital and Children's Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. wen2707@hotmail.com
Wen-I
WI
Lee
Jing-Long
JL
Huang
Ting-Shu
TS
Wu
Ming-Hsun
MH
Lee
I-Jung
IJ
Chen
Kuang-Hiu
KH
Yu
Chien-Ying
CY
Liu
Chih-Hsun
CH
Yang
Meng-Ying
MY
Hsieh
Yi-Ling
YL
Lin
Ying-Fan
YF
Shih
Tang-Her
TH
Jaing
Shih-Chiang
SC
Huang
Tseng-Tong
TT
Kuo
Cheng-Lung
CL
Ku
D017668:Age of Onset; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology*; D044466:Asian People; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003937:Diagnosis, Differential; D005786:Gene Expression Regulation / Q000276:immunology; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D019169:Jurkat Cells; D009165:Mycobacterium Infections, Nontuberculous / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology; D010019:Osteomyelitis / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D012480:Salmonella Infections / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D016207:Cytokines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma