Bone loss in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis

Abstract

Periodontal disease (PD) is a chronic pro-inflammatory response to oral pathogens such as Porphyromonas gingivalis which culminates in alveolar bone loss and loss of dental structure and function. Like rheumatoid arthritis (RA), periodontal disease is influenced strongly by lifestyle factors such as tobacco use, but also greatly influenced by genetic components, such as the “shared epitope,” which refers to a conserved linear sequence of amino acids in the DRβ1 chain of the HLA-DRα/β heterodimer between amino acids 67 and 74. Aggressive PD (the most destructive form of PD) is also now thought to be associated with specific HLA haplotypes including DRβ1. Using IL-17Frfp and Foxp3gfpreporters engineered into I-A° C57BL/6 mice expressing chimeric mouse/human HLA-DRβ1 (B6.DR1 mice), we find that gingival brushing with P gingivalis results in a rapid Th17 response in the peripheral blood and cervical lymph nodes, which decreases shortly after brushing. Evidence of a chronic infection can be detected in these nodes three months after oral inoculation. In addition to Th17 responses, we also find a concomitant increase in Th17-related cytokine production that parallels the Th17 activity. Furthermore, we measured a brisk production of antibodies directed against P. gingivalis and also against cyclic citrullinated peptides (these ACPAs are widely used as the principle early diagnostic for RA) as well as a loss in trabecular bone that can be detected in peri-articular bone structures, e.g. distal to the alveolar bone structures normally measured in PD models. Our findings suggest that periodontal disease can have far-reaching effects in bone morphology which may be driven by Th17/cytokine/ACPA activity even in the absence of other pathologies.