The following is a summary of “Hemophagocytic lymphohistiocytosis–like hyperinflammation due to a de novo mutation in DPP9,” published in the NOVEMBER 2023 issue of Allergy & Immunology by Wolf, et al.

Autoinflammatory disorders can arise from genetic abnormalities affecting inflammasomes. Recent findings have associated biallelic loss-of-function mutations in dipeptidyl peptidase 9 (DPP9), a negative regulator of NLRP1 and CARD8 inflammasomes, with an inborn error of immunity characterized by pancytopenia, skin manifestations, and heightened infection susceptibility. For a study, researchers sought to elucidate the molecular underpinnings of severe infancy-onset hyperinflammation in a patient displaying signs of fulminant hemophagocytic lymphohistiocytosis.

Genetic, immunologic, and molecular investigations were conducted using heterologous cell models and patient cells to identify the genetic cause and evaluate the impact of the identified mutation on inflammasome activation.

The patient presented with pancytopenia, reduced immune cell counts, and elevated markers of inflammation. Genetic analysis revealed a novel de novo mutation in DPP9 (c.755G>C, p.Arg252Pro), affecting a highly conserved amino acid. The mutation destabilized the DPP9 protein, observed in transfected cells and patient-derived induced pluripotent stem cells. Functional assays demonstrated that the mutant DPP9 failed to inhibit NLRP1 and CARD8 inflammasomes, resulting in constitutive inflammasome activation. The Arg252Pro DPP9 mutation exerted a dominant-negative effect.

The study identified a de novo mutation in DPP9 as the cause of severe infancy-onset autoinflammation, leading to uncontrolled inflammasome activation. It expands the understanding of the genetic basis of autoinflammatory disorders and highlighted the critical regulatory role of DPP9 in inflammasome function.

Source: jacionline.org/article/S0091-6749(23)00978-8/fulltext