Background/Purpose: Macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis (sHLH), is a potentially fatal complication of rheumatic diseases. MAS is characterized by a dysfunctional hyperinflammatory response in which there is abnormal activation of lymphocytes and phagocytes, leading to an overproduction of inflammatory cytokines and damage to host tissues. Circulating monocytes are highly responsive to their surrounding environment, are known to exhibit phenotypic and functional changes during inflammation, and can give rise to macrophages that phagocytose immune cells. However, monocytes and macrophages have not been well-studied in MAS. MAS is most commonly associated with systemic juvenile idiopathic arthritis (sJIA). At least 10% of sJIA patients will experience an overt episode of MAS with up to 50% exhibiting signs of subclinical inflammation. CD8+ T cells play a critical role during MAS through the secretion of the cytokine, interferon gamma (IFNg), which drives myeloid cell activation and excessive cytokine secretion. Expansion of a subpopulation of CD8+ T cells has recently been described in individuals with active sHLH/MAS which are CD38+ HLA-DR+.

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 monocytes from children with MAS (n=8) or age/sex/race-matched healthy children (n=4) by single cell RNA sequencing (scRNA-Seq). We analyzed lymphocytes from children with MAS (n=6) or healthy children (n=2) by scRNA-Seq. To generate TLR gene sets in monocytes, we isolated CD14+ monocytes by positive selection from 8 healthy controls, incubated them with TLR2, TLR4, TLR7, or TLR8 specific agonists, and analyzed the specific transcriptional signature using RNA sequencing.

Results: We identified a cluster of monocytes with evidence of interferon stimulation defined by high levels of interferon stimulated genes (ISGs). This ISG high cluster of monocytes was expanded in subjects with MAS as compared to healthy controls. We found evidence of both type I and type II interferons contributing to the gene signature in this cluster. We have generated specific TLR signatures in CD14+ monocytes to test whether specific TLRs contribute to the unique signature we identified in circulating monocytes during MAS. Lymphocytes from subjects with MAS revealed profound expansion of a CD8+ T cell subpopulation expressing markers of activation and exhaustion including LAG3, CTLA-4, and PD-1 as well as CD38 and HLA-DRA and were the primary source of IFNg.

Conclusion: These data provide evidence of a role for type I IFNs as well as TLRs in monocytes during MAS. Further our data identify expansion of a specific subpopulation of CD8+ T cells during MAS that is the primary source of IFNg. Together, our data show that CD14+ monocytes and CD8+ T cells have specific transcriptional signatures during MAS that likely contribute to pathophysiology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd8-t-cells-and-monocytes-from-children-with-macrophage-activation-syndrome-demonstrate-specific-transcriptional-changes-consistent-with-t-cell-activation-and-expansion-of-monocytes-shaped-by-interfe/