TY - JOUR
T1 - Hemophagocytic lymphohistiocytosis–like hyperinflammation due to a de novo mutation in DPP9
AU - Wolf, Christine
AU - Fischer, Hannah
AU - Kühl, Jörn Sven
AU - Koss, Sarah
AU - Jamra, Rami Abou
AU - Starke, Sven
AU - Schultz, Jurek
AU - Ehl, Stephan
AU - Neumann, Katrin
AU - Schuetz, Catharina
AU - Huber, Robert
AU - Hornung, Veit
AU - Lee-Kirsch, Min Ae
N1 - Funding Information:
This work was supported by grants from the Deutsche Forschungsgemeinschaft (grant nos. CRC237 369799452/B21 to M.L.-K., CRC237 369799452/A06 to C.W., CRC237 369799452/A27 to V.H., CRC1054 210592381/B17 to V.H., and CRC1160 256073931/A01 to S.E.), the Federal Ministry of Education and Research (grant nos. BMBF GAIN 01GM2206C to M.L.-K. and BMBF GAIN 01GM2206A to S.E.), Rosemarie-Germscheid Stiftung (to C.S.), and the European Research Council grant ERC-2020-ADG ENGINES (grant no. 101018672 to V.H.).
Publisher Copyright:
© 2023 American Academy of Allergy, Asthma & Immunology
PY - 2023/8/5
Y1 - 2023/8/5
N2 - Background: Genetic defects in components of inflammasomes can cause autoinflammation. Biallelic loss-of-function mutations in dipeptidyl peptidase 9 (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 sought to study 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, immunologic, 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 and T, B, and natural killer cells, and markedly elevated levels of lactate dehydrogenase, 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 demonstrated 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. Conclusions: A de novo mutation in DPP9 leads to severe infancy-onset autoinflammation because of unleashed inflammasome activation.
AB - Background: Genetic defects in components of inflammasomes can cause autoinflammation. Biallelic loss-of-function mutations in dipeptidyl peptidase 9 (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 sought to study 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, immunologic, 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 and T, B, and natural killer cells, and markedly elevated levels of lactate dehydrogenase, 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 demonstrated 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. Conclusions: A de novo mutation in DPP9 leads to severe infancy-onset autoinflammation because of unleashed inflammasome activation.
KW - autoinflammation
KW - CARD8
KW - DPP9
KW - hemophagocytic lymphohistiocytosis
KW - IL-18
KW - IL-1β
KW - Inborn error of immunity
KW - inflammasome
KW - NLRP1
KW - proinflammatory cytokines
UR - http://www.scopus.com/inward/record.url?scp=85170078512&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37544411
U2 - 10.1016/j.jaci.2023.07.013
DO - 10.1016/j.jaci.2023.07.013
M3 - Article
C2 - 37544411
AN - SCOPUS:85170078512
SN - 0091-6749
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
ER -