Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease
Open accessAbstract
The TAFRO clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare hematologic illness involving episodic disease flares of thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO) and progressive multiple organ dysfunction. We previously showed that the mTOR signaling pathway is elevated in lymph nodes of iMCD-TAFRO patients and that an mTOR inhibitor is effective in a small cohort of patients. However, the upstream mechanisms, cell types, and mediators involved in disease pathogenesis remain unknown. Here, we developed a targeted approach to identify candidate cellular drivers and mechanisms in iMCD-TAFRO through cellular and transcriptomic studies. Using paired iMCD-TAFRO PBMC samples collected during flare and remission, we identified T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD-TAFRO flare. These changes were associated with increased Type I IFN (IFN-I) response gene signatures across CD8 + T cells, NK cells, and monocytes. Finally, we found that IFN-β stimulation of monocytes and T cells from iMCD-TAFRO patient remission samples induced increased mTOR activation compared with healthy donors, and this was abrogated with either mTORC1 or JAK1/2 inhibition. The data presented here support a potentially novel role for IFN-I signaling as a driver of increased mTOR signaling in iMCD-TAFRO.
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Other elevated serum cytokines and cellular signaling pathways that could be considered for therapeutic targeting in idiopathic multicentric Castleman's disease include CXCL13, CXCL10, VEGF-A, type I interferon, mTORC1, and JAK-STAT3.
“Other elevated serum cytokines and cellular signaling pathways that could be considered for therapeutic targeting include CXCL13, CXCL10 (interferon-inducible protein 10 [IP-10]), VEGF-A,82 type I interferon,83 mTOR complex 1 (mTORC1),84 and JAK-STAT3.”
From Cytokine storm (2020) · cites this paper as [83]
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- Authors
- Pai, R.-A. L., Japp, A. S., Gonzalez, M., Rasheed, R. F., Okumura, M., Arenas, D., Pierson, S. K., Powers, V., Layman, A. A. K., Kao, C., Hakonarson, H., van Rhee, F., Betts, M. R., Kambayashi, T., & Fajgenbaum, D. C.
- Affiliations
- Department of Medicine and
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
- ORCID
- Venue
- JCI Insight
- Published
- 2020-05-07
- Volume
- 5
- Issue
- 9
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC7253017
- OpenAlex
- W3023502777
- Cited by
- 68
- References
- 39
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 11 · 2023: 7 · 2022: 15 · 2021: 10 · 2020: 4
- FWCI
- 6.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1R01HL141408-01)
- Perelman School of Medicine, University of Pennsylvania (Hematologic Malignancies Translational Center of Excellence Pilot Grant, Penn Center for Precision Medicine Pilot Grant)
- Castleman Disease Collaborative Network (CDCN-2018-003-R)
- Topics
- Health Sciences › Medicine › Rheumatology › IgG4-Related and Inflammatory Diseases
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- idiopathic multicentric Castleman disease, type I interferon, mTOR signaling, interferon-beta, T cell activation, natural killer cells, monocytes, disease flares, mTORC1, JAK1/2 inhibition, multiple organ failure
- MeSH terms
- Adolescent, Adult, Aged, Female, Castleman Disease, Humans, Interferon Type I, Killer Cells, Natural, Longitudinal Studies, Male, Middle Aged, Monocytes, CD8-Positive T-Lymphocytes, TOR Serine-Threonine Kinases
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