Background/Purpose: Repeated TLR9 stimulation with CpG DNA has been found to result in a sHLH/MAS-like disease in mice (1). CpG-administered mice present with cytopenia, anemia, thrombocytopenia, splenomegaly, hepatitis and hyperferritemia. The use of IFNg deficient mice as well as treatment of wild type mice with the anti-IFNg monoclonal antibody (mAb), XMG1.2, suggested an important role for IFNg  in the pathogenesis of sHLH/MAS. Our aim was to extend these findings and perform biomarker studies to correlate the kinetics of IFNg production to sHLH/MAS disease endpoints.

Methods: C57BL/6 mice (n=10) were administered 5 x 50µg injections of CpG-1826 over a 10-day period (day 0, 2, 4, 7 and 9). XMG1.2 was administered i.v. at 30mg/kg 24hrs preceding each CpG injection. Quantitative Real-time PCR was used to analyze inflammatory gene expression. Luminex multiplex technology was used to detect serum inflammatory cytokines. Whole blood cell count, red blood cells and haemoglobin were assessed using a haematological counter.

Results: We observe a multi-phasic production of IFNg in serum with peak levels reaching 600pg/ml at day 7. Cytokine mRNA level expression confirms the multi-phasic production of IFNg in the liver and spleen following each exposure to CpG. The initial peak of IFNg production correlates with the rapid appearance of cytopenia and thrombocytopenia, while each additional injection of CpG sustains these symptoms and generates new features such as anemia, hemoglobinemia, splenomegaly, hypercytokinemia and ferritinemia, culminating in induction of acute phase protein SAA and severe disease. IFNg-induced gene signature biomarkers, e.g., CTIIA (MHC class II trans-activator gene) and CXCL10, are upregulated in spleen and liver as too inflammatory cytokines IL-6 and TNFα. Neutralization of IFNg by XMG1.2 reduces body weight loss and splenomegaly, normalizes white blood cell counts, significantly reverses the decrease in other laboratory parameters (e.g., platelets, haemoglobin and red blood cells) and controls hyperferritinemia.

Conclusion: Thus, IFNg production is intimately associated with the clinical and laboratory features in the CpG-induced sHLH/MAS model suggesting the inhibition of this cytokine as a therapeutic target for patients afflicted with this life-threatening disease.

(1) Behrens et al., J. Clin. Invest. 2011; 121(6):2264–2277

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ifng-production-is-intimately-associated-with-clinical-and-laboratory-features-of-cpg-induced-secondary-hemophagocytic-lymphohistiocytosis-shlhmacrophage-activating-syndrome-mas-in-mice/