RESUMO
Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo is not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1. The removal of a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates in mice. Similarly, dpp9 deficiency was partially rescued by the inactivation of asc, an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish. These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1ß signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in two animal models of the disease.
Assuntos
Proteínas Reguladoras de Apoptose , Dipeptidil Peptidases e Tripeptidil Peptidases , Inflamassomos , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Inflamassomos/metabolismo , Interleucina-1/metabolismo , Proteínas NLR/genética , Peixe-ZebraRESUMO
Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA.
Assuntos
Anemia Aplástica , Adulto , Humanos , Anemia Aplástica/genética , Anemia Aplástica/patologia , Alelos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos HLA-B/genética , Antígenos HLA/genéticaRESUMO
This case report describes a 67-year-old woman who had received adoptive immunotherapy with chimeric antigen receptor T cells for multiple myeloma and was experiencing parkinsonism-like symptoms.