Bone loss and aggravated autoimmune arthritis in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis

Abstract

BackgroundThe linkage between periodontal disease and rheumatoid arthritis is well established. Commonalities among the two are that both are chronic inflammatory diseases characterized by bone loss, an association with the shared epitope susceptibility allele, and anti-citrullinated protein antibodies.MethodsTo explore immune mechanisms that may connect the two seemingly disparate disorders, we measured host immune responses including T-cell phenotype and anti-citrullinated protein antibody production in human leukocyte antigen (HLA)-DR1 humanized C57BL/6 mice following exposure to the Gram-negative anaerobic periodontal disease pathogen Porphyromonas gingivalis. We measured autoimmune arthritis disease expression in mice exposed to P. gingivalis, and also in arthritis-resistant mice by flow cytometry and multiplex cytokine-linked and enzyme-linked immunosorbent assays. We also measured femoral bone density by microcomputed tomography and systemic cytokine production.ResultsExposure of the gingiva of DR1 mice to P. gingivalis results in a transient increase in the percentage of Th17 cells, both in peripheral blood and cervical lymph nodes, a burst of systemic cytokine activity, a loss in femoral bone density, and the generation of anti-citrullinated protein antibodies. Importantly, these antibodies are not produced in response to P. gingivalis treatment of wild-type C57BL/6 mice, and P. gingivalis exposure triggered expression of arthritis in arthritis-resistant mice.ConclusionsExposure of gingival tissues to P. gingivalis has systemic effects that can result in disease pathology in tissues that are spatially removed from the initial site of infection, providing evidence for systemic effects of this periodontal pathogen. The elicitation of anti-citrullinated protein antibodies in an HLA-DR1-restricted fashion by mice exposed to P. gingivalis provides support for the role of the shared epitope in both periodontal disease and rheumatoid arthritis. The ability of P. gingivalis to induce disease expression in arthritis-resistant mice provides support for the idea that periodontal infection may be able to trigger autoimmunity if other disease-eliciting factors are already present.

The aggravation of arthritis by periodontitis is dependent of IL‐17 receptor A activation

“…A recent study demonstrated that the exacerbation of autoimmune arthritis in human leukocyte antigen-DR1 humanized C57Bl/6 mice under P. gingivalis infection was shown to be followed by a transitory increase of systemic Th17 population and in cervical lymph nodes. This same study also suggested a complementary mechanism because they detected the production of anti-citrullinated protein antibodies (ACPAs) - (Sandal et al, 2016); importantly, the generation of ACPAs was not detected in P. gingivalis-infected wild type C57Bl/6 mice. In this context of controversies, the present study showed that PD-induced arthritis aggravation in an AIA model is dependent on IL-17RA activation.…”

The Role of the Microbiome in Driving RA-Related Autoimmunity

“…This is an important differentiation from human PAD genes (which endocitrullinate) as one of the proposed mechanisms in which P. gingivalis induces arthritis is via the release of the virulence factor arginine-gingipanis (RpgB) which cleaves host proteins exposing the terminal arginine residue which is then free to undergo citrullination via PPAD with the creation of neo-epitopes and subsequent ACPA positivity ( Wegner et al, 2010 ). This hypothesis is supported by murine models which demonstrated that mice with laboratory induced arthritis had higher autoantibody production and joint destruction in those infected with wild type PPAD compared to those with mutated deficient PPAD genes ( Maresz et al, 2013 ; Gully et al, 2014 ; Sandal et al, 2016 ; Courbon et al, 2019 ). Sandel et al demonstrated this pathway was restricted via HLA-DRB1 positive mice suggesting that in addition to the presence of P. gingivalis and its associated expressed virulence factors, a genetic predisposition was also required.…”

Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation

“…The precise mechanism by which these microbial changes during the development of CIA modulate host immunity requires further study. However, using a known oral pathogen, Sandal et al demonstrated that oral infection with Porphyromonas gingivalis could transiently expand Th17 cells in the draining cervical lymph nodes and circulation and exacerbated disease in HLA–DRB1–transgenic mice with CIA, even in those that had previously resisted development of disease . Another study showed that treatment by oral gavage with Prevotella histicola attenuates CIA in HLA–DQ8–transgenic mice by increasing IL‐10–producing Treg cells and reducing Th17 cells in the gut .…”