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Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics.

ABSTRACT: Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM. Furthermore, we find that these changes in B cells are paralleled by signatures of Th2-mediated inflammation. Additionally, our work identified SIGLEC-1 expression in monocytes as a composite measure of heterogeneous type I interferon activity in disease. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with dysfunctional protein processing and regulation of cell death programming. This analysis separated the ubiquitously expressed type I interferon response into a central hub and revealed previously masked cell states. Together, these findings reveal the coordinated immune dysregulation underpinning JDM and provide novel insight into strategies for restoring balance in immune function.

SUBMITTER: Rabadam G

PROVIDER: S-EPMC10659396 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics.

Rabadam Gabrielle G Wibrand Camilla C Flynn Emily E Hartoularos George C GC Sun Yang Y Ye Chun Jimmie CJ Kim Susan S Gartner Zev Z Sirota Marina M Neely Jessica J

bioRxiv : the preprint server for biology 20231110

Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood ...[more]

PMID: 37986917

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Project description:BackgroundSince the emergence of COVID-19 at the end of 2019, the disease has led to widespread acute respiratory distress syndrome (ARDS), particularly among kidney transplant recipients (KTRs), who are at increased risk due to long-term immunosuppressive therapy. This study aims to explore the differences in immune responses between kidney transplant recipients and non-kidney transplant recipients in COVID-19-induced ARDS to identify potential therapeutic targets for improving outcomes. Single-cell RNA sequencing was performed on 108,320 cells derived from peripheral blood samples to construct a global single-cell map of COVID-19 induced ARDS in kidney transplant recipients(ARDSKT), COVID-19 induced ARDS in non transplant recipients(ARDSNKT), and healthy controls. Subsequently, using cellular clustering analysis, we obtained single-cell maps of different cell types. We employed enrichment analysis to determine the pathways involved in different subpopulations and focused on the role of key immune cells such as monocytes, megakaryocytes, B cells, and CD8+ T cells in the pathogenesis of ARDS. Significant immune differences were observed between ARDSKT and ARDSNKT. In ARDSKT, the S100A9+ MK subpopulation, which activates the NF-κB signaling pathway, was elevated, promoting inflammation. In contrast, the S100A12+ monocyte subpopulation that activates the chemokine signaling pathway was more abundant in ARDSNKT, reflecting a stronger inflammatory response, while its abundance was reduced in ARDSKT due to immunosuppression. The CXCR4+ B subpopulation, crucial for adaptive immunity, was significantly reduced in ARDSKT. Additionally, the XAF1+ Teff subpopulation, associated with apoptosis, was more abundant in ARDSKT, potentially impairing immune recovery. This study highlights the immune differences between ARDSKT and ARDSNKT, revealing the impact of immunosuppression on immune dysregulation. These findings suggest that targeting specific immune pathways can improve therapeutic strategies for ARDSKT.

Dataset Information

Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics.

Publications

Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics.

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