A Mouse Model for XLP-2 Disease Uncovers a Critical Function for IL-1beta and TNF in Driving Hyper-Inflammation

The hyper-inflammatory syndrome X-linked lymphoproliferative syndrome type 2 (XLP-2) is defined by mutations in BIRC4 (XIAP). XLP-2 is often diagnosed in paediatric patients and is characterized by hyper-inflammation triggered by common viral infections. Symptoms include splenomegaly, HLH, fevers, and chronic haemorrhagic colitis among others. Recent work has also shown that mutations in BIRC4 predispose to the development of early-onset IBD, which is not necessarily associated with symptoms of systemic hyper-inflammation. Symptoms of XLP-2 are mostly attributed to the aberrant activation of macrophages and dendritic cells (DC) and the subsequent accumulation of activated T-lymphocytes.

We have characterized the inflammatory response of mice deficient for BIRC4 (XIAP) to viral infections with the murine herpes virus 68 (MHV-68) as the closest murine model for human EBV-driven mononucleosis. Xiap^-/- mice were capable of clearing the virus normally during early infection (day 6, 16), but failed to do so during the course of the infection measured as elevated viral genomic loads during late (day 43) and very late (day 84) latency. Xiap^-/- mice responded to intranasal application of the virus with systemic hyper-inflammation exemplified by elevated IL-1beta levels, splenomegaly and increased activation of peripheral T lymphocytes such as CD4⁺ effector T cells, regulatory T cells (Treg), and IFNg⁺ T cells. In previous work, we have shown that TNF is critically required to drive the hyper-inflammatory phenotype of macrophages and dendritic cells of XIAP-deficient mice. Indeed, genetic deletion of TNF in vivo or, alternatively, anti-TNF treatment in vivo using Eternacept (Enbrel) ameliorated the symptoms of XIAP-deficient mice in response to viral infection.

Elevated IL-1beta levels were also observed in human peripheral blood-derived monocytes from XLP-2 patients (7 patients from 5 different families) when compared to healthy controls. In conclusion, this data supports the notion that anti-TNF treatment might be able to ameliorate the hyper-inflammatory responses in XLP-2 patients, when used early during an infection.