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Spontaneous Arthritis Development in LPS-Induced Periodontitis Model

The pathologies underlying periodontal disease (PD) and rheumatoid arthritis (RA) share many commonalities: osteoclast-activation and bone resorption, high serum inflammatory cytokine levels (e.g. IL-1, IL-6, TNF-α), antibodies against citrullinated proteins, and accumulation of inflammatory cells in affected tissues. Given these commonalities, it may not be surprising that numerous epidemiological studies have shown patients with active RA have an increased occurrence and severity of PD compared to non-RA patients. The most well researched link between these two diseases centers around the citrullination of proteins by peptidylarginine deiminases (PADs) from Porphyromonas gingivalis (PG), a major PD pathogen, and the immune response to these citrullinated proteins. In fact, anti-citrullinated protein antibodies (ACPAs) is one of the strongest prognostic markers for RA.  

Recently, a paper published in the journal Inflammation serves to strengthen the longstanding link between PD and RA, with implications for the role of the gastrointestinal microbiome and their immune-stimulating components in systemic autoimmune responses. This paper reports, for the first time, the spontaneous development of arthritis using a mouse model of periodontitis, without concurrent use of traditional experimental arthritis models. 

In this model of periodontitis, CD-1 mice received periodontal injections of either 10 ng or 50 ng lipopolysaccharide (LPS) every 48 hours for a total of nine injections (experimental group). Control group mice received either periodontal injections of PBS or intradermal injections of LPS (50 ng) in their tail. As expected, mice that received 50 ng LPS via periodontal injection developed signs of periodontitis as shown by histological and micro-CT analysis. Interestingly, after the fifth periodontal injection of 50 ng LPS, mice began to develop inflammation in their hind paws. This inflammation persisted through day 33, when the mice were sacrificed for further analysis. 

Histological analysis of arthritic mice showed leukocyte infiltration and synovial proliferation in their ankles, with bone resorption and cartilage degradation also occurring. Serum cytokine analysis by ELISA showed high serum levels of CXCL1 (5-fold increase compared to controls), IL-6 (2-fold increase compared to controls) and TNF-α (8-fold increase compared to controls) in arthritic mice. There was no significant difference in the level of IL-1β between experimental and control groups. Additionally, there was no statistically significant difference in ACPA levels between arthritic and control mice. Notably, only mice that received 50 ng of LPS periodontally developed arthritis. Neither the group of mice receiving 50 ng LPS intradermally, nor the experimental group treated with 10 ng LPS periodontally, developed hind paw inflammation. Thus, LPS dosage and the administration route seem to be important factors for developing arthritis by periodontal LPS injection.  

LPS can be used as a trigger of inflammation in the traditional Collagen-Induced Arthritis and Collagen-Antibody Induced Arthritis models. However, each of these models still requires immunization with conventional methods: a CFA-type II collagen emulsion or anti-type II collagen antibody cocktail, respectively. This paper is the first reported instance of a co-occurrence of experiment PD and arthritis using periodontal injections of LPS alone. While this study is far from finding the definitive link between PD and RA, the results highlight the part that oral microbiota and their components can play in initiating and propagating systemic inflammatory responses. 

How the microbiome influences both local and systemic immune responses is an active area of investigation that may help explain the currently idiopathic instances of autoimmune diseases. But, teasing apart the contributions of commensal bacteria and their components to disease pathogenesis is no easy task. It will require a new strategies disease processes that considers gastrointestinal microbiome populations, the immune responses towards commensal bacteria and their components/toxins, as well as their involvement in immune regulation and the balance of pro-inflammatory/anti-inflammatory signaling.