Autoimmune rheumatologic diseases
Inflammasomes are complex cytoplasmic structures that become activated in the presence of bacterial ligands or cellular damage. Inflammasome activation leads to massive amplification of pro-inflammatory signals, and so is tightly regulated. Formation of the NLRC4 inflammasome leads to incorporation and activation of procaspase-1 and results in the release of IL-1 and IL-18. Human gain-of-function (GOF) mutations in NLRC4 impair its autoinhibition and lead to inappropriate inflammasome activation and increased levels of IL-18. A spectrum of human autoinflammatory disease is associated with NLRC4 mutations ranging from mild cutaneous involvement to fatal neonatal entercolitis with macrophage activation syndrome (MAS). Autoimmunity has not been reported in NLCR4-inflammasomopathy. We present a unique patient with systemic lupus erythematosus and a novel NLRC4 variant (p.I287T) who displayed highly elevated levels of serum IL-18. Using a bimolecular fluorescence complementation (BiFC) assay, we show that while previously published NLRC4 mutations (p.V341A, p.T337S and p.S171F) lead to enhanced activation of caspase-1 compared to wild-type (WT) NLRC4, p.I287T activation of caspase-1 was significantly less than WT. Neither p.I287T nor known NLRC4 GOF mutations lead to increased activation of other inflammatory caspases (-4 and -5). Co-immunoprecipitation studies using WT NLRC4 or known NLRC4 GOF variants revealed protein complex formation with caspase-1, but p.I287T did not immunoprecipitate with caspase-1. We describe a phenotypic expansion of the clinical features associated with NLRC4 mutations to include autoimmunity. We further show p.I287T led to elevated IL-18 without enhanced activation of caspase-1. Further investigations to determine how p.I287T leads to elevated IL-18 are ongoing.