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单细胞基因组学揭示青少年皮肌炎中协调的免疫失调

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

作者信息

Rabadam Gabrielle, Wibrand Camilla, Flynn Emily, Hartoularos George C, Sun Yang, Ye Chun Jimmie, Kim Susan, Gartner Zev, Sirota Marina, Neely Jessica

机构信息

UC Berkeley-UC San Francisco Graduate Program in Bioengineering, UCSF, San Francisco, California, USA.

Department of Pharmaceutical Chemistry, UCSF, San Francisco, California, USA.

出版信息

bioRxiv. 2023 Nov 10:2023.11.07.566033. doi: 10.1101/2023.11.07.566033.

DOI:10.1101/2023.11.07.566033
PMID:37986917
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10659396/
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.

摘要

幼年皮肌炎（JDM）是几种儿童期发病的自身免疫性疾病之一，其特征为I型干扰素反应和自身抗体。由于对该疾病如何从免疫系统失调的细胞状态中产生的理解不完整，治疗选择有限。因此，我们使用单细胞转录组学结合表面蛋白表达，研究了处于疾病活动不同阶段的JDM患者的血液。通过对外周血单核细胞进行免疫表型分析，我们观察到B细胞区室向未成熟幼稚状态的偏移是JDM的一个标志。此外，我们发现B细胞的这些变化与Th2介导的炎症特征并行。此外，我们的研究确定单核细胞中SIGLEC-1的表达是疾病中异质性I型干扰素活性的综合指标。我们应用网络分析揭示，所有免疫群体中I型干扰素反应的过度激活与蛋白质加工功能失调和细胞死亡程序调节有关。该分析将普遍表达的I型干扰素反应分为一个中心枢纽，并揭示了以前隐藏的细胞状态。总之，这些发现揭示了JDM潜在的协调免疫失调，并为恢复免疫功能平衡的策略提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/f12428e6682c/nihpp-2023.11.07.566033v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/51402dbda4cd/nihpp-2023.11.07.566033v1-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/2542a9f46e58/nihpp-2023.11.07.566033v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/c445f1469a1e/nihpp-2023.11.07.566033v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/1ccb37956fe2/nihpp-2023.11.07.566033v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/95c24b24de57/nihpp-2023.11.07.566033v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/f12428e6682c/nihpp-2023.11.07.566033v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/51402dbda4cd/nihpp-2023.11.07.566033v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/13fa2ed62f20/nihpp-2023.11.07.566033v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/2542a9f46e58/nihpp-2023.11.07.566033v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/c445f1469a1e/nihpp-2023.11.07.566033v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/1ccb37956fe2/nihpp-2023.11.07.566033v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/95c24b24de57/nihpp-2023.11.07.566033v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d1/10659396/f12428e6682c/nihpp-2023.11.07.566033v1-f0007.jpg

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本文引用的文献

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Front Cell Dev Biol. 2023 Apr 20;11:1166017. doi: 10.3389/fcell.2023.1166017. eCollection 2023.
2
Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers.血液记忆 B 和 T 细胞亚群缺乏滤泡标志物与幼年皮肌炎疾病活动的关联。
Arthritis Rheumatol. 2023 Jul;75(7):1246-1261. doi: 10.1002/art.42446. Epub 2023 May 18.
3
Expansion of a novel population of NK cells with low ribosome expression in juvenile dermatomyositis.
在幼年型皮肌炎中，低核糖体表达的新型 NK 细胞群体的扩增。
Front Immunol. 2022 Oct 31;13:1007022. doi: 10.3389/fimmu.2022.1007022. eCollection 2022.
4
Mapping hormone-regulated cell-cell interaction networks in the human breast at single-cell resolution.以单细胞分辨率绘制人类乳腺中激素调节的细胞-细胞相互作用网络。
Cell Syst. 2022 Aug 17;13(8):644-664.e8. doi: 10.1016/j.cels.2022.06.005. Epub 2022 Jul 20.
5
Multi-Modal Single-Cell Sequencing Identifies Cellular Immunophenotypes Associated With Juvenile Dermatomyositis Disease Activity.多模态单细胞测序鉴定与青少年皮肌炎疾病活动相关的细胞免疫表型。
Front Immunol. 2022 Jun 21;13:902232. doi: 10.3389/fimmu.2022.902232. eCollection 2022.
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Imaging Mass Cytometry Reveals Predominant Innate Immune Signature and Endothelial-Immune Cell Interaction in Juvenile Myositis Compared to Lupus Skin.成像质谱细胞术揭示了幼年皮肌炎中先天免疫特征和血管内皮免疫细胞相互作用显著，与狼疮皮肤相比。
Arthritis Rheumatol. 2022 Dec;74(12):2024-2031. doi: 10.1002/art.42283. Epub 2022 Oct 18.
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