Using tertiles, 600 participants were categorized into three groups of low, moderate, and high P

Using tertiles, 600 participants were categorized into three groups of low, moderate, and high P.g according to the relative quantity of P.g. and subsequently the development of rheumatoid arthritis (RA). Based on this hypothesis, we set out to investigate whether P.g is linked to ACPAs in a well-characterized German population. Participants and methods: A total of 600 participants (292 women and 308 men with a mean age of 67?years) of the European Prospective Investigation into Cancer and Nutrition-Potsdam study were selected in 2013, and paired saliva and serum samples were collected. Salivary P.g DNA and serum anticyclic citrullinated peptide (anti-CCP2) levels were quantified by real-time polymerase chain reaction and anti-CCP2 enzyme-linked immunosorbent assay, respectively. In selected participants, additional ACPA fine-specificities were also analysed on a custom-made multiplex peptide array. Results: Among participants with C-reactive protein greater than 3.0?mg/l, a one-unit increase in P.g RCGD423 DNA was associated with an almost twofold increase in anti-CCP2 levels. Moreover, participants with high P.g DNA had on average approximately 2.8-times higher anti-CCP2 levels when compared with participants with low P.g DNA, (Holm-adjusted value?=?0.01). Furthermore, citrullinated epitopes on -enolase and vimentin were common ACPA reactivities among participants who also had high P.g DNA and elevated C-reactive protein. Conclusions: Our study suggests that in specific subgroups of individuals with systemic inflammation, higher salivary P.g DNA is associated with elevated serum ACPA. These data support a role for P.g in the development of anticitrulline immunity. (P.g) is considered a key periodontal pathogen6 RCGD423 and P.g infection is highly prevalent in patients with chronic periodontitis. 7 Chronic periodontitis and P.g infection have been hypothesized to contribute to the development of rheumatoid arthritis (RA).8 In fact, chronic periodontitis and P.g infection were shown to be associated with the prevalence of RA in a systematic review.9 P.g has been suggested as an aetiological link due to its unique feature among prokaryotes to express an arginine-specific proteinase, referred to as peptidyl arginine deiminase enzyme (PPAD).10,11 The aetiological hypothesis is that P.g, through the actions of PPAD and gingipains, directly initiates protein citrullination (deamination of arginine residues) of both host and bacterial proteins, generating neoepitopes at mucosal surfaces.11,12 Continual spreading of neoepitopes and somatic hypermutation in genetically susceptible individuals eventually results in a breakdown of immune tolerance, upregulation of inflammatory responses, development of autoimmunity and the subsequent production of high-affinity antibodies to citrullinated proteins (ACPAs), a hallmark of RA.13,14 Local and systemic proinflammatory stimuli are essential for citrulline autoimmunity.15 Indeed, citrullinated proteins and ACPAs are present in inflamed gingival tissue, suggesting local ACPA production, which may prime an individual for robust systemic ACPA production.16 Observational epidemiological studies are commensurate with this hypothesis, in that higher ACPA titres were reported in the periodontium and serum of patients with periodontitis when compared with healthy controls.17,18 A small clinical study also suggests that ACPA titres in patients with periodontitis may be specifically associated with oral exposure to P.g.19 Previously, we have shown elevated anti-P.g antibody levels in patients with RA who are positive RCGD423 for ACPAs, compared with controls, and that these antibodies precede the clinical onset of RA.20,21 This was confirmed in a meta-analysis.22 Moreover, increased prevalence of periodontitis and P.g was shown recently in individuals at risk of being positive for ACPAs and unlike P.g, the abundance of another periodontal pathogen, was not increased in these individuals.23 In addition, oral exposure of rodents to P.g was found to trigger seropositive arthritis.24 Most of the evidence linking P.g to ACPA is from patient groups and clinical cohorts, and very few are based on the Fzd4 general population. Therefore, we set out to evaluate the association between the presence of P.g in saliva and serum ACPA levels in a well-characterized population-based cohort of apparently healthy individuals. Participants and methods Study design and population Our.