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. actinomycetem-comitans 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 kappa B 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 RANYL-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.