Periodontitis and Experimental Arthritis in the Absence of PAD4
Objectives: There is evidence of a bidirectional relationship between periodontal disease (PD) and rheumatoid arthritis (RA), although the mechanisms underlying this relationship remain undefined. Both PD and RA are associated with inflammation and citrullination, a post-translational modification of proteins catalysed by peptidylarginine deiminases (PADs). RA is preceded by a breach of self-tolerance and anti-citrullinated protein antibodies (ACPAs). PAD4 is involved in formation of neutrophil extracellular traps (NETs) and hence plays a role both in generating potential auto-antigens and in host defence against bacterial infections. We sought to determine the effect of PAD4 in PD and RA.
Methods: An in vivo model of PD was established by oral infection with P. gingivalis, or carboxymethylcellulose carrier control, in PAD4 deficient (-/-) or wild type (+/+) control mice. A model of early arthritis and breach of immune tolerance was induced by transfer of ovalbumin-specific TCR transgenic Th1 T-cells and subsequent challenge with ovalbumin (or PBS control, all n=5/group), then footpad swelling was measured for 14 days. Serum anti-P. gingivalis, anti-ovalbumin and anti-collagen antibodies, and T-cell responses in the lymph nodes draining the footpads were evaluated. Alveolar bone loss was assessed to measure PD severity.
Results: Lack of PAD4 had no measureable impact on PD progression. Footpad swelling and serum antibody titres suggested a trend increase in experimental arthritis (EA) severity in the absence of PAD4, but this did not reach statistical significance. Combining both PD and EA models had no significant impact on progression of either disease, irrespective of presence of PAD4. The T-cell responses to ovalbumin were greatest in the +/+ and -/- EA groups, compared with all other groups (PBS controls, PD controls, or combined PD/EA group, P<0.05).
Conclusions: PAD4 activity may have a modest influence on EA disease progression and although the underlying mechanisms are likely to be subtle but merits further investigation.