Population-level single-cell genomics reveals conserved gene programs in systemic juvenile idiopathic arthritis.
Population-level single-cell genomics reveals conserved gene programs in systemic juvenile idiopathic arthritis.
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DOI：
10.1172/jci166741
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发表时间：
2023-11-15
影响因子：
15.9
通讯作者：
Schulert, Grant S.
中科院分区：
文献类型：
--
作者：
Verweyen, Emely L.;Thakkar, Kairavee;Dhakal, Sanjeev;Baker, Elizabeth;Chetal, Kashish;Schnell, Daniel;Canna, Scott;Grom, Alexei A.;Salomonis, Nathan;Schulert, Grant S.
全身性自身免疫性和自身炎症性疾病的特点是遗传和细胞异质性。虽然目前的单细胞基因组学方法提供了对已知疾病亚型的洞察，但这些分析方法并不容易揭示在不同的患者亚群中共享的新的细胞类型扰动程序。在这里，我们对包括巨噬细胞激活综合征(MAS)和肺部疾病(LD)在内的不同临床表现的系统性幼年特发性关节炎(SJIA)患者的PBMC进行了单细胞RNA-SEQ。我们引入了两个新的计算框架，称为UDON和SATAY-UDON，它们根据患者潜在的被破坏的细胞程序以及相关的生物标记物或临床特征来定义患者的亚型。在12个独立确定的亚型中，这项分析发现了我们认为在SJIA-LD单核细胞中发现的一种新的补体和干扰素激活程序。将这些分析扩展到成人和儿童狼疮患者，发现了新的但也与SJIA共享的疾病计划，包括干扰素和补体激活。最后，在编制的1000多名健康捐赠者的单细胞泛免疫图谱中，监督比较这些计划，发现少数正常健康捐赠者有单核细胞和血小板亚群早期炎症激活的证据，并提名了可能的早期疾病检测生物标记物。因此，综合泛免疫单细胞分析解决了我们认为是炎症性疾病发病机制和相关并发症潜在的新的保守基因程序。
Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.
影响因子：
7.3
作者：
Pascarella A;Bracaglia C;Caiello I;Arduini A;Moneta GM;Rossi MN;Matteo V;Pardeo M;De Benedetti F;Prencipe G
通讯作者：
Prencipe G