However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFNγ questions the absolute necessity of IFNγ in driving disease.
Human granulocytic anaplasmosis, caused by the tick-transmitted <i>Anaplasma phagocytophilum</i>, is not controlled by innate immunity, and induces a proinflammatory disease state with innate immune cell activation.In <i>A. phagocytophilum</i> murine infection models, hepatic injury occurs with production of IFNγ thought to be derived from NK, NKT cells, and CD8 T lymphocytes.Specific <i>A. phagocytophilum</i> ligands that drive inflammation and disease are not known, but suggest a clinical and pathophysiologic basis strikingly like macrophage activation syndrome (MAS) and hemophagocytic syndrome (HPS).
In contrast, IFNγ-deficient mice treated with both the TLR-9 agonist and IFNγ developed cytopenias, hepatitis, and hepatosplenomegaly, reproducing major clinical features of MAS.
Mice with MAS showed a significant upregulation of the IFN-γ pathway, as demonstrated by increased mRNA levels of Ifng and higher levels of phospho-signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-γ-inducible chemokines Cxcl9 and Cxcl10 in the liver and spleen, as well as in plasma.
On the basis of the first emerging data on the possibility of blocking IL-18, we here discuss the scientific rationale for neutralizing the IL-18/IFNγ axis in the prevention and treatment of sHLH and MAS.
Our data indicate that endogenous IL-18BP exerts a protective role in CpG-induced MAS and that IL-18, which acts upstream of IFN-γ, is involved in the severity of MAS.
The high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.
There was no significant difference in the expression of IFN-γ (306.89 ± 281.60 pg/ml vs 562.43 ± 399.86 pg/ml), IL-10 (20.40 ± 30.49 pg/ml vs 8.3 ± 13.14 pg/ml), IL-18 (463.33 ± 597.04 pg/ml vs 1247.82 ± 1318.58 pg/ml), TNF-α (61.48 ± 84.69 pg/ml vs 106.10 ± 77.21 pg/ml), and sCD25 (21062.1 ± 18515.26 pg/ml vs 11074.78 ± 11149.96 pg/ml) between pHLH and MAS.