Characterization of PBMC and monocyte subsets in systemic juvenile idiopathic arthritis (sJIA) by single-cell RNA Sequencing: Role of IL-18 and Interferons

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Systemic Juvenile Idiopathic Arthritis (sJIA) is a chronic autoinflammatory disease with onset in childhood. Patients suffer from episodes of systemic inflammation, which can further develop into the life-threatening complications macrophage activation syndrome (sJIA-MAS) and chronic lung disease (sJIA-LD). These complications are defined by innate immune cell activation, resulting in a cytokine storm with strongly increased levels of interleukin (IL-) 18 and interferon (IFN)y. Intriguingly, previous pilot experiments suggest a shift of monocyte polarization in active sJIA observed by single cell RNA Sequencing (scRNA-Seq). To understand changes in immune cell and particularly monocyte subpopulations in different sJIA disease states and their contribution to driving IL-18 and IFN overexpression, we aim to identify and characterize immune cell subpopulations and transcriptional profiles in various disease states of sJIA, sJIA-MAS and sJIA-LD and matched healthy controls utilizing scRNA-Seq and an established flow cytometry panel.A further objective of this project will focus on sJIA patients treated with IL-1β blockade. IL-1β blockade is commonly used to treat sJIA patients and results in disease remission in at least 40% of patients. However, it has been found that IL-1β blockade upregulates type I IFNs. As we have previously established a requirement for type I IFNs as driver of IL-18 gene expression in sJIA-MAS, this has potential implications for the application of IL-1β blockade in sJIA. We hypothesize that IL-1β blockade changes immune cell subpopulations by priming type I IFN related pathways that downstream can contribute to IL-18 overexpression. Therefore, we aim to define changes in immune cell subpopulations of sJIA patients using scRNA-Seq and flow cytometry before IL-1β blockade and after treatment initiation. An exploratory aim will be to investigate whether cellular phenotypic changes relate to the degree of clinical response and MAS risk. A specific focus will lie on type I IFN genes and transcriptional pathways that characterize the relationship of IL-1β and IFNs. The proposed objectives will create valuable input for understanding which dysregulated immune pathways drive sJIA pathogenesis and the life-threatening complications sJIA-MAS and sJIA-LD, and how immune cells are shifting their phenotype during different states of sJIA to facilitate disease progression and the onset of complications driven by IL-18. These findings may result in new therapeutic approaches for treatment refractory children with sJIA.