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

• Published in: Immunobiology (1979) 2013-05, Vol.218 (5), p.762-771
• Main Authors: Lee, Wen-I, Huang, Jing-Long, Wu, Ting-Shu, Lee, Ming-Hsun, Chen, I.-Jung, Yu, Kuang-Hiu, Liu, Chien-Ying, Yang, Chih-Hsun, Hsieh, Meng-Ying, Lin, Yi-Ling, Shih, Ying-Fan, Jaing, Tang-Her, Huang, Shih-Chiang, Kuo, Tseng-Tong, Ku, Cheng-Lung
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Age of Onset; Allergy and Immunology; Antibodies, Neutralizing - biosynthesis; Antibodies, Neutralizing - immunology; Asian Continental Ancestry Group; Autoantibodies - biosynthesis; Autoantibodies - immunology; Autoantibodies to IFN-γ (AutoAbs-IFN-γ); Bacille Calmette–Guerin infection (BCGitis); Chronic Disease; Cytokines - biosynthesis; Cytokines - immunology; Diagnosis, Differential; Gene Expression Regulation - immunology; Genotype; Humans; IL-12/23-IFN-γ circuit; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - blood; Interferon-gamma - immunology; Jurkat Cells; Mendelian Susceptibility to Mycobacterial Disease (MSMD); Mycobacterium bovis - immunology; Mycobacterium Infections, Nontuberculous - diagnosis; Mycobacterium Infections, Nontuberculous - ethnology; Mycobacterium Infections, Nontuberculous - genetics; Mycobacterium Infections, Nontuberculous - immunology; Osteomyelitis - diagnosis; Osteomyelitis - ethnology; Osteomyelitis - genetics; Osteomyelitis - immunology; Phenotype; Primary immunodeficiency diseases (PIDs); Salmonella Infections - diagnosis; Salmonella Infections - ethnology; Salmonella Infections - genetics; Salmonella Infections - immunology; Signal Transduction - immunology; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - immunology
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/j.imbio.2012.08.281

Abstract 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.