Abstract
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.
Highlights
The TAFRO clinical subtype of idiopathic multicentric Castleman disease is a rare hematologic illness characterized by episodic disease flares of systemic inflammation and multiple organ system dysfunction [1,2,3]
Recent work has led to further classification of iMCD into 2 distinct subsets: the thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), reticulin myelofibrosis, renal dysfunction, and organomegaly clinical subtype and iMCD–not otherwise specified subtype characterized by thrombocytosis, milder clinical features, and hypergammaglobulinemia [7,8,9,10,11]. iMCD-TAFRO patients are more often acutely ill, and clinical features appear more clinically homogeneous compared with iMCD-NOS, making iMCD-TAFRO a more suitable subtype for study [7,8,9,10,11,12]
We observed significantly elevated absolute neutrophil counts (ANC) and absolute monocyte counts (AMC) in flare compared with remission, but we observed no difference in absolute lymphocyte count (ALC) (Figure 1, B–D)
Summary
The TAFRO clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare hematologic illness characterized by episodic disease flares of systemic inflammation and multiple organ system dysfunction [1,2,3]. Recent work has led to further classification of iMCD into 2 distinct subsets: the thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), reticulin myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO) clinical subtype and iMCD–not otherwise specified (iMCD-NOS) subtype characterized by thrombocytosis, milder clinical features, and hypergammaglobulinemia [7,8,9,10,11]. Combination chemotherapy is recommended for second-line treatment if there is progressive organ dysfunction, but it is variably effective and difficult to tolerate, highlighting an unmet need for additional targeted therapies [13]
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