Porphyromonas gingivalis is a leading pathogen in chronic periodontitis, a disease process involving progressive destruction of tissues that support the teeth. Recently, the organism has been reported to produce a unique bacterial enzyme, P. gingivalis peptidylarginine deiminase (PPAD), which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function, hence, PPA may be involved in dysregulation of the host's signaling network for immune evasion. Further, accumulating evidence has revealed the role of autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contributes to the breakdown of immune tolerance to citrullinated epitopes, chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and initiation of RA. Thus, PPAD may represent the mechanistic link between periodontitis and rheumatoid arthritis - diseases that are known to be significantly associated to each other at the epidemiological level. We hypothesize that citrullination of bacterial and host proteins in periodontal/gingival tissues by PPAD, within the chronic inflammatory environment and immune system stimulation by bacteria- derived "danger signals", leads to the initial break of immune tolerance to citrullinated proteins and peptides. In addition PPAD may manipulate immune responses in inflamed periodontal tissues by modifying important effector molecules of the innate immunity, including C3a and C5a anaphylatoxins and bradykinin. Biological activity of these peptides depends on the C-terminal arginine, which is also a preferential target for PPAD. Hence, this research proposal will investigate the important and innovative concept that PPAD as a virulence factor of P. gingivalis and mechanistic link between periodontitis and RA with the following specific aims: (i) in vivo and ex vivo examination of PPAD's role in the pathogenesis of RA;(ii) functional and structural studies of various forms of PPAD;and (iii) investigate the immunomodulatory effect of PPAD that is relevant to the pathogenesis of periodontal disease. Thus, the proposed research will illuminate the PPAD's contribution to chronic inflammation driven by P. gingivalis infection and shed light on the possible link between periodontal disease and rheumatoid arthritis. This knowledge will create new perspectives in the treatment of periodontitis and prevention of rheumatoid arthritis in susceptible individuals.
Rheumatoid arthritis is characterized by the development of autoantibodies against citrullinated proteins within the joints in susceptible individuals. Porphyromonas gingivalis, a known periodontal pathogen, is the only known bacterium, which produces an enzyme (PPAD) that is capable of converting arginine residues in proteins into citrullin. It is hypothesized that PPAD activity in inflamed, infected periodontal tissues not only contributes to the pathology of periodontitis, but also may promote breakdown of immunotolerance and initiates the development of rheumatoid arthritis.
|Wilensky, Asaf; Tzach-Nahman, Rinat; Potempa, Jan et al. (2015) Porphyromonas gingivalis gingipains selectively reduce CD14 expression, leading to macrophage hyporesponsiveness to bacterial infection. J Innate Immun 7:127-35|
|Bryzek, D; Ksiazek, M; Bielecka, E et al. (2014) A pathogenic trace of Tannerella forsythia - shedding of soluble fully active tumor necrosis factor ? from the macrophage surface by karilysin. Mol Oral Microbiol 29:294-306|
|Eick, Sigrun; Puklo, Magdalena; Adamowicz, Karina et al. (2014) Lack of cathelicidin processing in Papillon-Lefèvre syndrome patients reveals essential role of LL-37 in periodontal homeostasis. Orphanet J Rare Dis 9:148|
|Akiyama, Tomohito; Miyamoto, Yoichi; Yoshimura, Kentaro et al. (2014) Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor-? and interleukin-1? but suppresses that by interleukin-17A: importance of proteolytic degradation of osteoprotegerin by lysine gingipai J Biol Chem 289:15621-30|
|Gawron, K; Bereta, G; Nowakowska, Z et al. (2014) Peptidylarginine deiminase from Porphyromonas gingivalis contributes to infection of gingival fibroblasts and induction of prostaglandin E2 -signaling pathway. Mol Oral Microbiol 29:321-32|
|Koziel, Joanna; Bryzek, Danuta; Sroka, Aneta et al. (2014) Citrullination alters immunomodulatory function of LL-37 essential for prevention of endotoxin-induced sepsis. J Immunol 192:5363-72|
|Koro, Catalin; Bielecka, Ewa; Dahl-Knudsen, Anders et al. (2014) Carbamylation of immunoglobulin abrogates activation of the classical complement pathway. Eur J Immunol 44:3403-12|
|Pyrc, Krzysztof; Milewska, Aleksandra; Kantyka, Tomasz et al. (2013) Inactivation of epidermal growth factor by Porphyromonas gingivalis as a potential mechanism for periodontal tissue damage. Infect Immun 81:55-64|
|Zhou, Xiao-Yan; Gao, Jin-Long; Hunter, Neil et al. (2013) Sequence-independent processing site of the C-terminal domain (CTD) influences maturation of the RgpB protease from Porphyromonas gingivalis. Mol Microbiol 89:903-17|