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

Wen I. Lee*, Jing Long Huang, Ting Shu Wu, Ming Hsun Lee, I. Jung Chen, Kuang Hiu Yu, Chien Ying Liu, Chih Hsun Yang, Meng Ying Hsieh, Yi Ling Lin, Ying Fan Shih, Tang Her Jaing, Shih Chiang Huang, Tseng Tong Kuo, Cheng Lung Ku

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

34 Scopus citations

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.

Original languageEnglish
Pages (from-to)762-771
Number of pages10
JournalImmunobiology
Volume218
Issue number5
DOIs
StatePublished - 05 2013

Keywords

  • Autoantibodies to IFN-γ (AutoAbs-IFN-γ)
  • Bacille Calmette-Guerin infection (BCGitis)
  • IL-12/23-IFN-γ circuit
  • Mendelian Susceptibility to Mycobacterial Disease (MSMD)
  • Primary immunodeficiency diseases (PIDs)

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