Mycobacterial Disease and Impaired IFN-[gamma] Immunity in Humans with Inherited ISG15 Deficiency

• Published in: Science (American Association for the Advancement of Science) Vol. 337; no. 6102; p. 1684
• Main Authors: Bogunovic, Dusan, Byun, Minji, Durfee, Larissa A, Abhyankar, Avinash, Sanal, Ozden, Mansouri, Davood, Salem, Sandra, Radovanovic, Irena, Grant, Audrey V, Adimi, Parisa, Mansouri, Nahal, Okada, Satoshi, Bryant, Vanessa L, Xiao-Fei, Kong, Kreins, Alexandra
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 28.09.2012
• Subjects: Bacteria; Disease; Immunology; Patients
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1224026

Some children experience severe clinical disease when they are vaccinated against tuberculosis, an attenuated live vaccine that is normally innocuous in humans. Several germline mutations have been identified that account for this susceptibility, and now Bogunovic et al. (p. 1684, published online 2 August) add another to the list--ISG15. Uncovering this mutation, which is inherited in an autosomal recessive manner, was a surprise because studies with mice deficient in ISG15 showed enhanced susceptibility to some viral, but not bacterial, infections. Nevertheless, patients lacking ISG15 were not able to produce adequate amounts of interferon-γ, a cytokine critical for clearance of the bacteria. [PUBLICATION ABSTRACT] ISG15 is an interferon (IFN)-α/β-inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes--granulocyte, in particular--reduced the production of IFN-γ by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-γ-inducing secreted molecule for optimal antimycobacterial immunity. [PUBLICATION ABSTRACT]