BACKGROUND: Genetic defects in components of inflammasomes can cause autoinflammation. Biallelic loss-of-function mutations in DPP9, a negative regulator of the NLRP1 and CARD8 inflammasomes, have recently been shown to cause an inborn error of immunity characterized by pancytopenia, skin manifestations, and increased susceptibility to infections.

OBJECTIVE: We studied the molecular basis of autoinflammation in a patient with severe infancy-onset hyperinflammation associated with signs of fulminant hemophagocytic lymphohistiocytosis.

METHODS: Using heterologous cell models as well as patient cells, we performed genetic, immunological, and molecular investigations to identify the genetic cause and to assess the impact of the identified mutation on inflammasome activation.

RESULTS: The patient exhibited pancytopenia with decreased neutrophils, T, B, and NK cells, markedly elevated levels of LDH, ferritin, soluble IL-2 receptor, and triglycerides. In addition, serum levels of IL-1β and IL-18 were massively increased, consistent with inflammasome activation. Genetic analysis revealed a previously undescribed de novo mutation in DPP9, c.755G>C, p.Arg252Pro, affecting a highly conserved amino acid residue. The mutation led to destabilization of the DPP9 protein as shown in transiently transfected HEK293T cells and in patient-derived induced pluripotent stem cells. Using functional inflammasome assays in HEK293T cells, we demonstrate that mutant DPP9 failed to restrain the NLRP1 and CARD8 inflammasomes, resulting in constitutive inflammasome activation. These findings suggest that the Arg252Pro DPP9 mutation acts in a dominant-negative manner.

CONCLUSION: A de novo mutation in DPP9 leads to severe infancy-onset autoinflammation due to unleashed inflammasome activation.