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Journal Article Epublish 17 citations

PubMed: 37751296 DOI: 10.1172/JCI165616

Type I interferon signature and cycling lymphocytes in macrophage activation syndrome.

J Clin Invest 133(22)

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

Affiliations

  • Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, China.
  • Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Department of Rheumatology, Immunology and Allergy, Zhejiang University School of Medicine, Hangzhou, China.
  • Department of Cardiology, Department of Pediatrics, and.
  • Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • The MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

BACKGROUNDMacrophage 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.METHODWe 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.RESULTSBulk 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.CONCLUSIONMAS 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.

MeSH

Interferon Type I, Macrophages, Cells, Cell Proliferation, T-Lymphocytes, Macrophage Activation Syndrome, Rna-Seq

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