Type I interferon signature and cycling lymphocytes in macrophage activation syndrome
Zhengping Huang, … , Peter A. Nigrovic, Pui Y. Lee
Zhengping Huang, … , Peter A. Nigrovic, Pui Y. Lee
Published September 26, 2023
Citation Information: J Clin Invest. 2023;133(22):e165616. https://doi.org/10.1172/JCI165616.
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Clinical Research and Public Health Immunology Inflammation

Type I interferon signature and cycling lymphocytes in macrophage activation syndrome

Abstract

BACKGROUND Macrophage activation syndrome (MAS) is a life-threatening complication of Still’s disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS.METHOD We profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies.RESULTS Bulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38+HLA-DR+ cells within CD4+ T cell, CD8+ T cell, and NK cell populations. CD38+HLA-DR+ lymphocytes exhibited prominent IFN-γ production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38+HLA-DR+ lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38+HLA-DR+ lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15 — both elevated in MAS patients — synergistically augmented the generation of CD38+HLA-DR+ lymphocytes, while Janus kinase inhibition mitigated this response.CONCLUSION MAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38+HLA-DR+ cycling lymphocytes that produce IFN-γ.

Authors

Zhengping Huang, Kailey E. Brodeur, Liang Chen, Yan Du, Holly Wobma, Evan E. Hsu, Meng Liu, Joyce C. Chang, Margaret H. Chang, Janet Chou, Megan Day-Lewis, Fatma Dedeoglu, Olha Halyabar, James A. Lederer, Tianwang Li, Mindy S. Lo, Meiping Lu, Esra Meidan, Jane W. Newburger, Adrienne G. Randolph, Mary Beth Son, Robert P. Sundel, Maria L. Taylor, Huaxiang Wu, Qing Zhou, Scott W. Canna, Kevin Wei, Lauren A. Henderson, Peter A. Nigrovic, Pui Y. Lee

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Figure 3

scRNA-Seq analysis of cycling lymphocyte subsets in patients with MAS.

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scRNA-Seq analysis of cycling lymphocyte subsets in patients with MAS. (...
(A) Circular plot illustrating cellular communication between cycling lymphocytes and other PBMC subsets. Cell populations are as defined in Figure 2. (B) heatmap display and (C) chord diagram of projected sender(s) and receiver(s) of IFN-γ and TNF signaling in PBMC cell subsets based on CellChat analysis of scRNA-Seq data from patients with MAS. (D) UMAP display of cycling lymphocytes from people in the healthy control group (n = 5), patients with SD without MAS (n = 10), and patients with MAS (n = 9). (E) Feature plot illustrating the expression of lineage and phenotypic markers in cells from patients with MAS. Cell populations are as defined in panel D. (F) Heatmap display of gene expression in cycling lymphocytes and major T and NK cell subsets in patients with MAS. Each column represents data from a single patient. Genes were selected from the leading edge of GSEA comparing cycling lymphocytes and all other cell subsets. (G) Quantification of average IFNG expression in indicated immune cell subsets in patients with MAS. Cycling lymphocytes were shown as a group and as individual subsets of T cells and NK cells. (H) Feature plot illustrating expression of IFNG in cycling lymphocytes from patients with MAS.