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 6

Generation of CD38+HLA-DR+ T lymphocytes and NK cells in vitro.

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Generation of CD38+HLA-DR+ T lymphocytes and NK cells in vitro. (A) Repr...
(A) Representative flow cytometry plot and (B) quantification of CD38+HLA-DR+ lymphocyte subsets induced by coculturing PBMC from healthy controls (n = 5) with the indicated cytokine combinations for 2 days. Each color in panel B represents a unique healthy donor. Results for each healthy donor represent the average of duplicate samples. (C) Plasma IL-15 levels in healthy controls (n = 19), and patients with nonsystemic JIA (n = 10), inactive SD (n = 11), active SD without MAS (n = 11), or active SD with MAS (n = 11) as measured by proximity extension assay. (D) Representative flow cytometry plots and (E) Quantification of CD38+HLA-DR+ lymphocyte subsets induced by IL-15 (10 ng/mL) and IFN-α2 (10 ng/mL) in PBMCs (from 4–5 healthy donors) pretreated with ruxolitinib (100 nM), tofacitinib (100 nM), rapamycin (1 μM), or DMSO (vehicle control). Inhibitors or DMSO were added 30 minutes prior to IL-15 and IFN-α2 stimulation, and analysis was performed after 2 days. Statistical analysis: Bars represent median and error bars represent interquartile range. Kruskal-Wallis test was used for comparison of multiple groups in panels B and C, and Dunn’s correction was applied for the indicated comparisons. Mann-Whitney U test was applied for panel E. *P < 0.05, **P < 0.01.