Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

Abstract

Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer’s disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.

Possible role of Porphyromonas gingivalis in orodigestive cancers

“…Porphyromonas gingivalis is currently known as the only pathogen that produces peptidyl-arginine deiminase (PAD) [89]. This enzyme modifies both bacterial and host proteins by deiminating arginine residues in proteins and peptides, converting them into citrulline [18,[90][91][92]. Protein citrullination deregulates the host's inflammatory signaling network by changing the spatial arrangement of the original 3D-structure and function of the protein [89,93].…”

“…In P. gingivalis, the most important virulence factors are lipopolysaccharide (LPS), fimbriae, gingipains and outer membrane vesicles. Major pathogenic mechanisms include ability to create a dysbiotic microbiota and a dysregulated immune defense [12][13][14][15][16][17][18]. It is also noteworthy that P. gingivalis can invade oral epithelial and endothelial cells [19][20][21] and induce potent production of proinflammatory cytokines [22].…”

Is there a link between genetic defects in the complement cascade andPorphyromonas gingivalisin Alzheimer’s disease?

“…This offers a plausible and exclusive link to disabling complement C5a enzymatic conversion of arginine to citrulline. Protein citrullination causes deregulation of the host's inflammatory signaling network by altering the spatial arrangement of the original 3D-structure and function of immune proteins [99]. It is likely that degradation of complement proteins allows colonization and proliferation of bacteria possessing higher sensitivity towards complement mediated killing than found in P. gingivalis itself [82].…”

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

“…Additional evidence that citrullination affects the functional protein-protein interactions derives from observation in macrophage differentiation, where citrullination of plasminogen activator inhibitor-2 inhibits its binding ability to proteasome subunit beta type-1 to then modulate the inflammatory response [12]. Changes in citrullination occur in several pathological conditions such as autoimmune disorders and chronic inflammation-related diseases, including periodontitis, rheumatoid arthritis, atherosclerosis, and diabetes [13][14][15] (see Alghamdi, M. et al [13] for a detailed review on the intrinsic role of citrullination in autoimmune disorders and Olsen, I. et al, [14] for a detailed review on citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis, and Alzheimer's disease). Altered levels of citrullination have also been shown in neurological disorders and prion diseases, [16,17] and respiratory disorders [18,19].…”