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