G(-) anaerobes-reactive CD4+ T-cells trigger RANKL-mediated enhanced alveolar bone loss in diabetic NOD mice.
Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism remains unclear. We investigated the contribution of antibacterial T-cell-mediated immunity to enhanced alveolar bone loss during periodontal infection in nonobese diabetic (NOD) mice by oral inoculation with Actinobacillus actinomycetemcomitans, a G(-) anaerobe responsible for juvenile and severe periodontitis. The results show that 1) inoculation with A. actinomycetemcomitans in pre-diabetic NOD mice does not alter the onset, incidence, and severity of diabetes; 2) after A. actinomycetemcomitans inoculation, diabetic NOD mice (blood glucose >200 mg/dl and with severe insulitis) exhibit significantly higher alveolar bone loss compared with pre-diabetic and nondiabetic NOD mice; and 3) A. actinomycetemcomitans-reactive CD4+ T-cells in diabetic mice exhibit significantly higher proliferation and receptor activator of nuclear factor kappaB ligand (RANKL) expression. When diabetic mice are treated with the RANKL antagonist osteoprotegerin (OPG), there is a significant reversal of alveolar bone loss, as well as reduced RANKL expression in A. actinomycetemcomitans-reactive CD4+ T-cells. This study clearly describes the impact of autoimmunity to anaerobic infection in an experimental periodontitis model of type 1 diabetes. Thus, microorganism-reactive CD4+ T-cells and the RANKL-OPG axis provide the molecular basis of the advanced periodontal breakdown in diabetes and, therefore, OPG may hold therapeutic potential for treating bone loss in diabetic subjects at high risk.
Mahamed
Deeqa A
DA
Laboratory of Molecular Microbial Immunity, Eastman Department of Dentistry and Center for Oral Biology, Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14620, USA.
Marleau
Annette
A
Alnaeeli
Mawadda
M
Singh
Bhagirath
B
Zhang
Xiaoxia
X
Penninger
Joseph M
JM
Teng
Yen-Tung A
YT
D000189:Actinobacillus Infections / Q000276:immunology*; D016976:Aggregatibacter actinomycetemcomitans; D016301:Alveolar Bone Loss / Q000382:microbiology / Q000503:physiopathology*; D000818:Animals; D001421:Bacteria, Anaerobic; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D002352:Carrier Proteins / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000382:microbiology*; D006023:Glycoproteins / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D053244:Osteoprotegerin; D011236:Prediabetic State / Q000276:immunology / Q000382:microbiology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; 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