Charakterisierung von PBMC- und Monozytenpopulationen in systemischer Juveniler Idiopathischer Arthritis (sJIA) durch Einzel-Zell RNA Sequenzierung: Rolle von IL-18 und Interferonen
Kinder- und Jugendmedizin
Zusammenfassung der Projektergebnisse
Systemic juvenile idiopathic arthritis (SJIA) is a clinically heterogenous systemic inflammatory disorder sometimes complicated by macrophage activation syndrome (MAS) and lung disease (LD), which are thought to be driven by IFN signaling. To identify cellular sources and novel gene programs underlying SJIA pathogenesis, we performed the first in-depth singlecell RNA Sequencing (scRNA-Seq) analysis of 21 SJIA, SJIA-LD, and SJIA-MAS patient PBMCs. To define novel heterogenous patient-subtypes associated with shared transcriptional responses and associate these with diagnostic biomarkers, we developed two new computational approaches: UDON and SATAY-UDON. These tools identify hidden patient-subtypes, including a novel complement and IFN signaling gene program expressed by SJIA-LD monocytes, implicate CD4 T cells and monocytes as the source of increased IFN signaling in SJIA-MAS, and identify a previously unknown role for platelets and S100 proteins as drivers of systemic inflammation. We also performed a secondary analysis of whole-blood gene expression microarrays using blood samples obtained from healthy controls and SJIA patients at baseline and on day 3 after canakinumab (anti IL-1 antibody) treatment. Such pre-and post treatment patient samples could not be obtained during the pandemic to perform scRNA-Seq, which is why we employed an already existing microarray dataset to address questions of treatment associated gene expression changes. Here, we identify a gene signature mediated by neutrophil- and IL-1-associated genes in systemic JIA patients prior to receiving treatment that distinguishes strong responders to canakinumab from nonresponders. We also identified a signature including up-regulated CD163 expression that was associated with canakinumab nonresponse. Intriguingly, canakinumab treatment induced either up- or down-regulation of type I interferon (IFN) genes, independent of clinical response. In order to address the evolving impacts of the Covid-19 pandemic, we also dedicated research focus towards Multisystem inflammatory syndrome in children (MIS-C), in which we focused on characterizing cytokine and chemokine expression. Our findings show MIS-C is distinguishable from Kawasaki disease (a self-limited vasculitis of unknown cause) primarily by elevated CXCL9 concentrations, a chemokine induced by IFNg, and also provides support for SJIA-MAS-like pathophysiology in patients with severe MIS-C. Overall, these data provide insights into underlying gene pathways, new potential therapeutic targets as well as secreted biomarkers for SJIA complications and Covid-19 induced MIS-C.
Projektbezogene Publikationen (Auswahl)
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Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis. Arthritis & Rheumatology, 73(7), 1334-1340.
Verweyen, Emely L.; Pickering, Alex; Grom, Alexei A. & Schulert, Grant S.
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Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study. The Lancet Rheumatology, 3(8), e574-e584.
Rodriguez-Smith, Jackeline J.; Verweyen, Emely L.; Clay, Gwendolyn M.; Esteban, Ysabella M.; de Loizaga, Sarah R.; Baker, Elizabeth Joy; Do, Thuy; Dhakal, Sanjeev; Lang, Sean M.; Grom, Alexei A.; Grier, David & Schulert, Grant S.
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Interfering with interferons: targeting the JAK-STAT pathway in complications of systemic juvenile idiopathic arthritis (SJIA). Rheumatology, 61(3), 926-935.
Verweyen, Emely L. & Schulert, Grant S.
