Periodontal Disease and Rheumatoid Arthritis
Periodontal Disease and Rheumatoid Arthritis
A number of studies have been reported since the initial identification of Pg-PAD to evaluate its function and potential roles in citrullination. To date, no other prokaryotes have been identified to have a PAD, though five human enzymes are expressed. In common with other PADs, Pg-PAD is susceptible to autocitrullination. Although human PAD autocitrullination may have functional consequences, the effect in Pg-PAD is unknown. The associations of anti-Pg and ACPA need to be re-examined; it is possible that anti-Pg assays were detecting bacterial ACPA as a reason for the concordance. Determining the properties of different PADs in terms of substrate specificity has been an area of active research, as it is now thought that specific citrullinated peptides are tightly coupled with specific shared epitope alleles. That human [alpha]-enolase, a putative rheumatoid arthritis autoantigen, had high homology with enolase found in Pg, and that an immunodominant peptide susceptible to citrullination [citrullinated enolase peptide-1 (CEP-1)] was identical and recognized by rheumatoid arthritis sera were important observations implicating Pg with rheumatoid arthritis autoantigen generation. Through a series of experiments with PAD-deficient and gingipain-deficient strains of Pg, Wegner et al. demonstrated that Pg could citrullinate its own proteins, but was dependent on the activity of its arginine-specific gingipain exposing carboxy-terminus residues for Pg-PAD activity. These studies contributed further evidence toward a mechanistic explanation for how Pg, through the cooperative interactions of its gingipains and PAD, could potentially initiate early citrullination, thus providing an initial break of tolerance in ACPA development and further epitope spreading. A recent report described an additional function of Pg-PAD on tissue invasion in periodontal disease through direct inhibition of epidermal growth factor via citrullination, an activity not seen with human PAD-2 or PAD-4.
The expression of PADs in target tissues has been studied, but only recently examined in oral tissue. A recent study demonstrated that citrullination is more abundant in inflammatory periodontitis than in noninflamed tissue, and localized to fibroblasts, endothelial cells, and infiltrating inflammatory cells. The study also reported increased expression of PAD-2 and PAD-4, associated with increasing inflammation. Of note, PAD-2 expression is upregulated with smoking, a risk for periodontal disease. Another recent study confirmed increased citrullination in inflammatory periodontal stroma but also expression in buccal epithelium of periodontitis and controls. There have been no reports of Pg-PAD expression in tissues or cells to date.
Roles of P. gingivalis in Citrullination
A number of studies have been reported since the initial identification of Pg-PAD to evaluate its function and potential roles in citrullination. To date, no other prokaryotes have been identified to have a PAD, though five human enzymes are expressed. In common with other PADs, Pg-PAD is susceptible to autocitrullination. Although human PAD autocitrullination may have functional consequences, the effect in Pg-PAD is unknown. The associations of anti-Pg and ACPA need to be re-examined; it is possible that anti-Pg assays were detecting bacterial ACPA as a reason for the concordance. Determining the properties of different PADs in terms of substrate specificity has been an area of active research, as it is now thought that specific citrullinated peptides are tightly coupled with specific shared epitope alleles. That human [alpha]-enolase, a putative rheumatoid arthritis autoantigen, had high homology with enolase found in Pg, and that an immunodominant peptide susceptible to citrullination [citrullinated enolase peptide-1 (CEP-1)] was identical and recognized by rheumatoid arthritis sera were important observations implicating Pg with rheumatoid arthritis autoantigen generation. Through a series of experiments with PAD-deficient and gingipain-deficient strains of Pg, Wegner et al. demonstrated that Pg could citrullinate its own proteins, but was dependent on the activity of its arginine-specific gingipain exposing carboxy-terminus residues for Pg-PAD activity. These studies contributed further evidence toward a mechanistic explanation for how Pg, through the cooperative interactions of its gingipains and PAD, could potentially initiate early citrullination, thus providing an initial break of tolerance in ACPA development and further epitope spreading. A recent report described an additional function of Pg-PAD on tissue invasion in periodontal disease through direct inhibition of epidermal growth factor via citrullination, an activity not seen with human PAD-2 or PAD-4.
The expression of PADs in target tissues has been studied, but only recently examined in oral tissue. A recent study demonstrated that citrullination is more abundant in inflammatory periodontitis than in noninflamed tissue, and localized to fibroblasts, endothelial cells, and infiltrating inflammatory cells. The study also reported increased expression of PAD-2 and PAD-4, associated with increasing inflammation. Of note, PAD-2 expression is upregulated with smoking, a risk for periodontal disease. Another recent study confirmed increased citrullination in inflammatory periodontal stroma but also expression in buccal epithelium of periodontitis and controls. There have been no reports of Pg-PAD expression in tissues or cells to date.
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