Mycobacterial Disease and Impaired IFN-γ Immunity in Humans with Inherited ISG15 Deficiency
Open accessAbstract
Tuberculosis Vaccine Conundrum: 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.
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ISG15, an interferon-inducible protein necessary for viral protection in mice, does not have the same critical role in humans.
“Similarly, ISG15, an interferon-inducible protein necessary for viral protection in mice, does not have the same critical role in humans(48-50).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [50]
In later stages of ASH, massive hepatocyte cell death accompanied by IL33 release triggers the IL33/ST2 signalling axis, accelerating inflammation and liver injury/decompensation.
“In later stages of ASH, massive hepatocyte cell death accompanied by IL33 release triggers the IL33/ST2 signalling axis, accelerating inflammation and liver injury/decompensation (50).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [50]
The supplied passages and additional searches for IL-33/ST2, hepatocyte death, ASH, and liver decompensation found no discussion of the claimed mechanism. The paper’s indexed text instead discusses ISG15 secretion and IFN-γ responses in antimycobacterial immunity (section labeled Abstract; page unavailable). (LLM, conf=0.78)
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- Authors
- Bogunovic, D., Byun, M., Durfee, L. A., Abhyankar, A., Sanal, O., Mansouri, D., Salem, S., Radovanovic, I., Grant, A. V., Adimi, P., Mansouri, N., Okada, S., Bryant, V. L., Kong, X.-F., Kreins, A., Velez, M. M., Boisson, B., Khalilzadeh, S., Ozcelik, U., Darazam, I. A., Schoggins, J. W., Rice, C. M., Al-Muhsen, S., Behr, M., Vogt, G., Puel, A., Bustamante, J., Gros, P., Huibregtse, J. M., Abel, L., Boisson-Dupuis, S., & Casanova, J.-L.
- Affiliations
- Rockefeller University (US)
- The University of Texas at Austin (US)
- Immunology Division and Pediatric Chest Disease Department, Hacettepe University Children’s Hospital, 06100 Ankara, Turkey.
- Masih Daneshvari Hospital (IR)
- McGill University (CA)
- Inserm (FR)
- Division of Infectious Diseases and Clinical Immunology, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Teheran, Iran.
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
- Prince Naif Center for Immunology Research, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, 11211, Saudi Arabia.
- McGill University Health Centre (CA)
- Hôpital Necker-Enfants Malades (FR)
- Corresponding author
- Durfee, Larissa A.
- Abhyankar, Avinash
- Mansouri, Davood
- Salem, Sandra
- Bustamante, Jacinta
- Gros, Philippe
- Huibregtse, Jon M.
- Abel, Laurent
- Casanova, Jean-Laurent
- ORCID
- Bogunovic, Dusan
- Byun, Minji
- Abhyankar, Avinash
- Mansouri, Davood
- Salem, Sandra
- Radovanovic, Irena
- Grant, Audrey V.
- Mansouri, Nahal
- Okada, Satoshi
- Bryant, Vanessa L.
- Kong, Xiao-Fei
- Kreins, Alexandra
- Boisson, Bertrand
- Khalilzadeh, Soheila
- Darazam, Ilad Alavi
- Schoggins, John W.
- Rice, Charles M.
- Behr, Marcel
- Vogt, Guillaume
- Puel, Anne
- Bustamante, Jacinta
- Gros, Philippe
- Huibregtse, Jon M.
- Abel, Laurent
- Casanova, Jean-Laurent
- Venue
- Science
- Published
- 2012-09-28
- Volume
- 337
- Issue
- 6102
- Pages
- 1684-1688
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3507439
- OpenAlex
- W2103433909
- Cited by
- 572
- References
- 1
- Citations by year
- 2026: 38 · 2025: 35 · 2024: 39 · 2023: 53 · 2022: 45 · 2021: 36 · 2020: 52 · 2019: 31 · 2018: 40 · 2017: 44 · 2016: 29 · 2015: 35 · 2014: 43 · 2013: 47 · 2012: 5
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000043)
- National Cancer Institute (R01CA072943, CA072943)
- National Institute of Allergy and Infectious Diseases (R01AI035237, AI096090, R01AI091707, R37AI095983, R01AI096090)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Keywords
- ISGylation, interferon-gamma, mycobacterial infection, antimycobacterial immunity, natural killer cells, type I interferon, antiviral immunity, granulocytes
- MeSH terms
- Animals, Antibodies, Viral, Female, Granulocytes, Humans, Immunity, Interferon-gamma, Killer Cells, Natural, Male, Mycobacterium Infections, Pedigree, T-Lymphocytes, Ubiquitins, Virus Diseases, Cytokines, Interleukin-12, Mice
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