Background/Purpose: Macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis (HLH), is a potentially fatal complication of rheumatic diseases, most commonly systemic juvenile idiopathic arthritis (sJIA) or Still’s disease. MAS is driven by aberrant activation of lymphocytes and phagocytes with an important role for interferon gamma (IFNg). While monocytes and macrophages are thought to be important in MAS pathogenesis, their role remains poorly understood.

Methods: Subjects with MAS were defined based on the 2016 classification criteria by Ravelli and colleagues as well as the ratio of ferritin to ESR. We analyzed classical CD14+ monocytes from children with active MAS (6 subjects) compared to age/sex/race matched healthy children (8 subjects) by flow cytometry and RNA sequencing (RNA-Seq). Differentially expressed genes (DEGs) were defined as those with at least 2 fold change and false discovery rate less than 0.1. We also analyzed monocytes (n=8 per group) and lymphocytes (n=6 per group) using single cell RNA-Seq. We determined plasma concentrations of specific cytokines using Meso Scale Discovery assays. We used Tensor-cell2cell to determine significantly different interactions between MAS and HC lymphocytes and monocytes.

Results: We identified a cluster of monocytes with evidence of interferon (IFN) stimulation defined by high levels of interferon stimulated genes (ISGs) that was expanded in subjects with MAS compared to HC. Unexpectedly, cluster defining genes in ISGhigh monocytes were driven by type I IFN rather than IFNg by several metrics. Consistent with this finding, we detected increased levels of circulating IFNb in MAS subjects. We also found significant upregulation of CD16 surface expression during active MAS and showed that IFNb increased CD16 transcript, together suggesting that IFNb could play a previously unrecognized role in driving MAS monocytes responses. Using bulk RNA-Seq of CD14+ classical monocytes, we identified a MAS signature score that correlated with ferritin, a laboratory marker of hyperinflammation. This MAS signature score was higher in children with active sJIA than during inactive disease and higher in children with MAS than in sJIA without MAS. We also found that this signature score was elevated in monocytes from children with lupus where it correlated with disease activity and from adults with severe COVID-19, highlighting its utility across different inflammatory triggers. We identified a MAS-associated CD8+ T cell population defined by increased expression of multiple inhibitor receptors highly expressed by chronically activated T cells, including HAVCR2, LAG3, and CTLA4, in addition to CD27, which is typically expressed on proliferating T cells. Cell-cell interaction analyses revealed significantly enhanced immunoregulatory interactions between monocytes and T cells during MAS.

Conclusion: Together, these results provide new evidence for a role for IFNb during MAS, identify a signature score associated with disease severity in several inflammatory diseases, and identify a unique CD8+ T cell population that may contribute to MAS pathophysiology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/expansion-of-type-i-ifn-driven-isghigh-monocytes-and-identification-of-mas-associated-cd8-t-cell-population-during-macrophage-activation-syndrome/