of the clinical manifestations of NLRC4 hyperactivity in September 2014. Since that time, we have been continuously working to link this genotypic observation with the associated phenotypes of early-onset enterocolitis, Macrophage Activation Syndrome (MAS), and chronically elevated serum IL-18. Using CRISPR/Cas9 technology, we have two novel transgenic mice, each bearing one of the reported activating mutations in NLRC4. The first of these mice, which bears the T337S mutation, spontaneously overproduces IL-18. We have exposed these mice to several innate immune stimuli, but have yet to recapitulate the conditions that may predispose to development of entercolitis or MAS. Additionally, we have identified that activated macrophages induce lymphocyte apoptosis in a very short time period via the production of reactive oxygen species. Uptake of locally apoptotic cells, may serve as the mechanism for hemophagocytosis in MAS. Since apoptotic cell uptake is known to be anti-inflammatory and induce macrophage IL-10 production, this process may actually be homeostatic in regulating inflammatory macrophage activity. Concomitantly, we have evaluated 8 new patients with recurrent MAS who do not bear NLRC4 mutations, as well as revisited several patients already seen with this phenotype. Strikingly, these patients ALSO have chronically elevated serum IL-18 levels. We have recently undertaken a broad biomarker correlation study to determine what disease-activity or IL-18 related markers may covary with this striking elevation in serum IL-18. This project also received support in FY2014 ($50,000) from the Arthritis National Research Foundation as part of the Kelly Award in Juvenile Arthritis research.
