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

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Science (Impact Factor: 33.61). 09/2012; 337(6102):1684-1688. DOI: 10.1126/science.1224026


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.

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    • "MSMD patients also often suffer from non-typhoidal, extra-intestinal salmonellosis. Since 1996, germline mutations in seven autosomal (IFNGR1, IFNGR2, IL12B, IL12RB1, STAT1, IRF8, ISG15) and two X-linked (NEMO, CYBB) genes have been discovered in MSMD patients [8,52–55]. High levels of locus and allelic heterogeneity have resulted in the definition of 17 different disorders, accounting for about half the known cases [56]. These defects are physiologically related, as they all result in an impairment of IFN-γ immunity. "
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    • "ISG15 is an IFN-induced gene that is regulated by USP18 [21]. In free form, ISG15 can activate NK cells and antigen presentation cells [22,23], and a recent study showed that human ISG15 deficiency leads to mycobacterial disease [24]. To detect ISG15 in the tumor microenvironment, tumor lysate was prepared from B16-OVA-GFP, B16-OVA-USP18 or B16-OVA-shUSP18 tumors, and ELISA or western blot analysis showed that the ISG15 level was higher in B16-OVA-USP18 tumor than in B16-OVA-GFP tumor, but lower in B16-OVA-shUSP18 tumor (Figure  4E, Additional file 1: Figure S6). "
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