IADR Abstract Archives

Role of Interferon Regulatory Factor 8 (IRF8) in Periodontal Disease

Objectives: Periodontal disease, characterized by dysregulated immune response to oral microbiome, affects nearly 50% of adults worldwide. We sought to identify genetic defects and immunopathological mechanisms contributing to multiple idiopathic cervical root resorption (MICRR), a form of periodontal disease with unknown etiology.
Methods: Following IRB approval, dental/medical histories, x-rays, and saliva samples were collected from a family (3 affected and 3 unaffected members) exhibiting MICRR. Whole exome sequencing was performed to identify SNPs associated with MICRR. Bioinformatics and functional analyses were employed to delineate the pathogenic effects of observed mutations.
Results: All subjects reported non-contributory medical history. The affected family members presented multiple progressive resorptive lesions that were asymptomatic, unassociated with any predisposing factors, and first identified during the fourth-to-sixth decades of life. Micro-CT and histology of extracted teeth revealed a unique pattern of cervical root resorption distinct from tooth decay. In all affected members, a novel autosomal dominant heterozygous mutation c.1219 G>A (G388S) was identified in interferon regulatory factor 8 (IRF8) gene, which was confirmed by Sanger sequencing. IRF8 is a transcription factor expressed in immune cells and is a key regulator of innate immunity, inflammatory response and osteoclastogenesis. The G388S substitution in the highly conserved C-terminal motif of IRF8 is predicted to cause a large shift in 3D protein folding, likely impairing IRF8 heterodimerization with other transcription factors including ETS, IRF and NFAT family members. Consistent with this prediction, we noted 3-fold increased osteoclast numbers with mutant human IRF8G388S vector transduced into Irf8-/- macrophages compared to IRF8WT. Furthermore, we noted that Irf8-/- mice exhibit (without exogenous inflammatory challenge) several features of periodontal disease, including enhanced osteoclastogenesis, widened periodontal ligament space and alveolar bone loss.
Conclusions: This is the first study to identify a genetic mutation associated with MICRR and results indicate IRF8 plays a key role in maintaining periodontal tissue homeostasis.
AADR/CADR Annual Meeting
2016 AADR/CADR Annual Meeting (Los Angeles, California)
Los Angeles, California
2016
1421
Periodontal Research-Pathogenesis
  • Thumbigere Math, Vivek  ( National Institutes of Health , Bethesda , Maryland , United States )
  • Foster, Brian  ( The Ohio State University College of Dentistry , Columbus , Ohio , United States ;  National Institutes of Health , Bethesda , Maryland , United States )
  • Neely, Anthony  ( University of Detroit-Mercy School of Dentistry , Detroit , Michigan , United States )
  • Yoshii, Hiroak  ( National Institute of Child Health and Human Development , Bethesda , Maryland , United States )
  • Ozato, Keiko  ( National Institute of Child Health and Human Development , Bethesda , Maryland , United States )
  • Somerman, Martha  ( National Institutes of Health , Bethesda , Maryland , United States )
  • NIAMS Intramural Research Program
    None
    Poster Session
    Periodontal Pathogenesis-In vivo and Clinical
    Friday, 03/18/2016 , 03:30PM - 04:45PM