Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

David C. Fajgenbaum

Second Advisor

Taku Kambayashi

Abstract

Idiopathic multicentric Castleman disease (iMCD) is a rare, deadly hematologic illness of unknown etiology involving disease flares of systemic inflammation and multiple organ system dysfunction. This work shows increased activation of the mTORC1 signaling pathway in lymph nodes of iMCD patients and demonstrates that an mTOR inhibitor is effective in preventing disease flares in a small cohort of patients. We next ask what upstream mechanisms drive mTORC1 activation and downstream clinical features. We develop a targeted approach to identify candidate cellular drivers and mechanisms in iMCD patients with thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly (iMCD-TAFRO). We leverage paired iMCD-TAFRO PBMC samples collected during flare and remission (n = 10) for cellular and transcriptomic characterization. These studies highlight T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD-TAFRO flare, associated with increased Type I Interferon (IFN-I) response gene signatures across CD8+ T cells, NK cells, and monocytes and mTOR signaling gene signatures within monocytes. Moreover, we find a positive correlation between the IFN-I response genes and mTOR gene signature in classical monocytes as well as increased mTOR activation in T cells and monocytes from iMCD-TAFRO patients in remission, compared to healthy donors, in response to IFNβ. This increased IFN-I mediated mTOR activation is dependent on JAK signaling and may be abrogated with JAK inhibition. Further data demonstrate that mutations in CABIN1, a negative regulator of T cell activation and myeloid cell differentiation, may lead to an aberrant immune response to infection. We identify compound heterozygous CABIN1 mutations in our iMCD-TAFRO index case patient and generate and characterize knock-in mice containing these mutations. While the immunophenotype of these knock-in mice appear normal at baseline, they display increased rates of mortality upon infection with LCMV Clone 13. Further study may reveal the cell types and immune mechanisms driving this mortality phenotype and also further our understanding of iMCD-TAFRO pathogenesis. Altogether, these data support further investigation of CABIN1 mutations and T cell and monocyte activation, demonstrate a novel role for IFN-I as mechanistic driver of increased mTORC1 activation, and identify mTORC1 and JAK as potential therapeutic targets in iMCD-TAFRO.

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Available to all on Saturday, May 11, 2024

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