Type I interferon signature and cycling lymphocytes in macrophage activation syndrome
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 contro...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-11-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI165616 |
| _version_ | 1827768118637756416 |
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| author | Zhengping Huang Kailey E. Brodeur Liang Chen 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 |
| author_facet | Zhengping Huang Kailey E. Brodeur Liang Chen 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 |
| author_sort | Zhengping Huang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:07:47Z |
| format | Article |
| id | doaj.art-81b3a17577a741b6be6230b306b10f60 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:47Z |
| publishDate | 2023-11-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-81b3a17577a741b6be6230b306b10f602023-11-07T16:21:05ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-11-0113322Type I interferon signature and cycling lymphocytes in macrophage activation syndromeZhengping HuangKailey E. BrodeurLiang ChenDuHolly WobmaEvan E. HsuMeng LiuJoyce C. ChangMargaret H. ChangJanet ChouMegan Day-LewisFatma DedeogluOlha HalyabarJames A. LedererTianwang LiMindy S. LoMeiping LuEsra MeidanJane W. NewburgerAdrienne G. RandolphMary Beth SonRobert P. SundelMaria L. TaylorHuaxiang WuQing ZhouScott W. CannaKevin WeiLauren A. HendersonPeter A. NigrovicPui Y. LeeBACKGROUND 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.https://doi.org/10.1172/JCI165616ImmunologyInflammation |
| spellingShingle | Zhengping Huang Kailey E. Brodeur Liang Chen 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 Type I interferon signature and cycling lymphocytes in macrophage activation syndrome The Journal of Clinical Investigation Immunology Inflammation |
| title | Type I interferon signature and cycling lymphocytes in macrophage activation syndrome |
| title_full | Type I interferon signature and cycling lymphocytes in macrophage activation syndrome |
| title_fullStr | Type I interferon signature and cycling lymphocytes in macrophage activation syndrome |
| title_full_unstemmed | Type I interferon signature and cycling lymphocytes in macrophage activation syndrome |
| title_short | Type I interferon signature and cycling lymphocytes in macrophage activation syndrome |
| title_sort | type i interferon signature and cycling lymphocytes in macrophage activation syndrome |
| topic | Immunology Inflammation |
| url | https://doi.org/10.1172/JCI165616 |
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