title: Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection.
abstract: Periodontitis, a prime cause of tooth loss in humans, is implicated in the increased risk of systemic diseases such as heart failure, stroke, and bacterial pneumonia. The mechanisms by which periodontitis and antibacterial immunity lead to alveolar bone and tooth loss are poorly understood. To study the human immune response to specific periodontal infections, we transplanted human peripheral blood lymphocytes (HuPBLs) from periodontitis patients into NOD/SCID mice. Oral challenge of HuPBL-NOD/SCID mice with Actinobacillus actinomycetemcomitans, a well-known Gram-negative anaerobic microorganism that causes human periodontitis, activates human CD4(+) T cells in the periodontium and triggers local alveolar bone destruction. Human CD4(+) T cells, but not CD8(+) T cells or B cells, are identified as essential mediators of alveolar bone destruction. Stimulation of CD4(+) T cells by A. actinomycetemcomitans induces production of osteoprotegerin ligand (OPG-L), a key modulator of osteoclastogenesis and osteoclast activation. In vivo inhibition of OPG-L function with the decoy receptor OPG diminishes alveolar bone destruction and reduces the number of periodontal osteoclasts after microbial challenge. These data imply that the molecular explanation for alveolar bone destruction observed in periodontal infections is mediated by microorganism-triggered induction of OPG-L expression on CD4(+) T cells and the consequent activation of osteoclasts. Inhibition of OPG-L may thus have therapeutic value to prevent alveolar bone and/or tooth loss in human periodontitis.
authors.affiliation: Divisions of Periodontics and Oral Biology, and Department of Microbiology and Immunology, Faculty of Medicine and Dentistry, the University of Western Ontario, London, Ontario, Canada. yateng@julian.uwo.ca
authors.forename: Y T
authors.initials: YT
authors.lastname: Teng
authors.forename: H
authors.initials: H
authors.lastname: Nguyen
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: Y Y
authors.initials: YY
authors.lastname: Kong
authors.forename: R M
authors.initials: RM
authors.lastname: Gorczynski
authors.forename: B
authors.initials: B
authors.lastname: Singh
authors.forename: R P
authors.initials: RP
authors.lastname: Ellen
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000328:Adult; D016976:Aggregatibacter actinomycetemcomitans / Q000276:immunology*; D016301:Alveolar Bone Loss / Q000150:complications / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D000818:Animals; D001426:Bacterial Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism; D006651:Histocytochemistry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010010:Osteoclasts / Q000276:immunology / Q000473:pathology; D053244:Osteoprotegerin; D010518:Periodontitis / Q000150:complications / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D053245:RANK Ligand; D016601:RNA-Binding Proteins / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D014157:Transcription Factors / Q000032:analysis
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; C079092:MtrB protein, Bacteria; D053244:Osteoprotegerin; D053245:RANK Ligand; D016601:RNA-Binding Proteins; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors