Background/Purpose: Macrophage Activation Syndrome (MAS) is a potentially lethal cytokine storm syndrome that complicates various rheumatic diseases. We have previously shown that Toll-like Receptor (TLR9) mediated MAS is Interferon gamma (IFNg) dependent, and others have demonstrated IFNg-dependence in models of Hemophagocytic Lymphohistiocytosis. We have also shown the critical role of IL-10 in regulating TLR9-induced MAS, and mice co-treated with TLR9-agonism and IL-10 receptor blockade (IL10RB) develop “fulminant MAS.” This study seeks to determine the role of IFNg in the fulminant MAS model.

Methods: We gave CpG1826 repeatedly to WT and transgenic mice as described. Antibodies inhibiting the action of the IL-10 receptor (IL10RB, 1B1.3A) and IL-12p40 (C17.8) were given as described. All injections were intraperitoneal. We then evaluated for signs of MAS.

Results: Fulminant MAS resulted in greatly enhanced serum IL-10, IL-12, and IFNg. While dendritic cell populations were dominant producers of IFNg in IL-10 sufficiency, in fulminant MAS IFNg was also produced by hepatic NK and CD8 T cells. When IL-12 was blocked in fulminant MAS mice, disease progression was unaltered, despite much lower serum IFNg. Strikingly, we also observed the continued presence of hemophagocytes (HPCs) despite IL-12 blockade. This observation caused us to question whether fulminant MAS was due to enhanced IFNg activity or whether, distinct from the IL-10 sufficient scenario, other proinflammatory forces were at work. Administration of CpG and IL10RB to IFNg-/- mice resulted in fulminant MAS nearly comparable to that seen in WT mice. Notably, IFNg-/- mice were spared from severe anemia and severe hepatitis but developed all other aspects of fulminant MAS including HPCs. Thus, while certain aspects of disease (anemia and hepatitis) are IFNg-dependent, fulminant MAS, including hemophagocytosis, occurs independent of IFNg. Interestingly, blockade of type I interferon signaling (using IFNAR-/- mice) did not prevent disease in the IL-10 sufficient situation, but partially abrogated fulminant MAS. HPCs also persisted despite Type I IFN receptor blockade.

Conclusion: In the TLR9-mediated model, IL-12 functions to induce IFNg. However, fulminant MAS is largely IFNg-independent. This suggests that therapeutic targeting of IFNg may not be sufficient in all cases of hemophagocytic syndrome. Furthermore, our results dissociate the development of IFNg-induced “consumptive” anemia and hepatitis, and the presence of HPCs. Thus, the goal of chemotherapeutic elimination of HPCs may not be of benefit for many aspects of the disease, since their presence does not correlate with either anemia or hepatitis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fulminant-toll-like-receptor-9-induced-macrophage-activation-syndrome-and-hemophagocytosis-occur-independently-of-interferon-gamma/