Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children; yet, the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk and single-cell RNA sequencing, DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4 + , CD8 + , and gd T cells expressed Th1-related markers, while Th17 cells were not enriched. Th1 skewing was prominent in CD4 + T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4 + T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. While synovial fluid CD4 + T cells displayed an overall Th1 phenotype, scRNA-seq uncovered heterogeneous effector and regulatory sub-populations, including interferoninduced Tregs, peripheral helper T cells, and cytotoxic CD4 + T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

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Objective To compare clinical outcomes in children with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) who were managed before and after implementation of an evidence-based guideline (EBG). Methods A management algorithm for MAS-HLH was developed at our institution based on literature review, expert opinion, and consensus building across multiple pediatric subspecialties. An electronic medical record search retrospectively identified hospitalized patients with MAS-HLH in the pre-EBG (October 15, 2015, to December 4, 2017) and post-EBG (January 1, 2018, to January 21, 2020) time periods. Predetermined outcome metrics were evaluated in the 2 cohorts. Results After the EBG launch, 57 children were identified by house staff as potential patients with MAS-HLH, and rheumatology was consulted for management. Ultimately, 17 patients were diagnosed with MAS-HLH by the treating team. Of these, 59% met HLH 2004 criteria, and 94% met 2016 classification criteria for MAS complicating systemic juvenile idiopathic arthritis. There was a statistically significant reduction in mortality from 50% before implementation of the EBG to 6% in the post-EBG cohort (P = 0.02). There was a significant improvement in time to 50% reduction in C-reactive protein level in the post-EBG vs pre-EBG cohorts (log-rank P < 0.01). There were trends toward faster time to MAS-HLH diagnosis, faster initiation of immunosuppressive therapy, shorter length of hospital stay, and more rapid normalization of MAS-HLH–related biomarkers in the patients post-EBG. Conclusion While the observed improvements may be partially attributed to advances in treatment of MAS-HLH that have accumulated over time, this analysis also suggests that a multidisciplinary treatment pathway for MAS-HLH contributed meaningfully to favorable patient outcomes.