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BEDREHELSE-Bedre helse og livskvalitet

Bacterial peptidylarginine deiminase, a link between gums and joint disease

Alternative title: Bakteriell peptidylarginin deiminase, en forbindelse mellom tannkjøtt og leddsykdom

Awarded: NOK 6.5 mill.

In recent years, the influence of the human microbiota on health and disease has been of considerable and increasing interest. According to an emerging paradigm, a dysbiotic shift in the composition of the microbial flora in various bodily compartments could result in serious pathological consequences, ranging from metabolic diseases through obesity and cancer to mental disorders. While the gut microbiota is in the spotlight of much of this research due to its high microbial density, the oral microbiota, being the second-largest and the most diverse microbial community in the human body, is being recognized to play an increasingly important role in human health and disease. Porphyromonas gingivalis, an established periodontal pathogen, is able to produce citrullinated proteins through the action of an enzyme (PPAD) unique to this bacterium. Citrullinated bacterial proteins are able to induce human fibroblasts to produce prostaglandin E2 (PGE2) which can stimulate the bone resorption process implicated in the pathogenesis in periodontitis and rheumatoid arthritis (RA). PPAD may also directly promote breakdown of self-tolerance in susceptible individuals to generate autoantibodies against citrullinated self proteins in the development of RA. Successful completion of this project will drive the field forward by providing a novel perspective to the understanding the pathogenesis of PD-RA associations, thus offering venues to develop novel strategies to treat these debilitating diseases.

P. gingivalis, a keystone pathogen in chronic periodontitis secretes a large variety of virulence factors, including an enzyme, peptidylarginine deiminase (PAD), unique for pathogenic species of the Porphyromonas genus. Alike human endogenous PADs, the bacterial enzyme converts arginine residues in proteins to citrulline but it has a strong preference for C-terminal Arg. We postulated that P. gingivalis PAD (PPAD) activity not only contributes to pathogenesis of periodontitis but also it may be involved in the breakdown of immunotolerance and the development of RA, a diseases driven by autoantibodies targeting citrullinated epitopes. This contention is supported by findings that PPAD, in conjunction with Arg-specific gingipain proteases (Rgps), can generate a large spectrum of citrullinated peptides derived from bacterial and host proteins. Also, citrullinated proteins of P. gingivalis stimulate human gingival fibroblasts (HGF) to produce prostaglandin E2 (PGE2), one of the most potent mediators of bone resorption implicated in the pathogenesis of PD and RA. Finally, we discovered two allelic forms of the ppad gene among P. gingivalis clinical isolates, one encoding a superactive isoform of the enzyme, which binds substrates with higher affinity than the other form of PPAD. The tighter substrate binding may contribute to proposed second important function of PPAD as the carrier protein of haptens (bacteria and/or host protein- derived citrullinated peptides) presented to B cell, followed by T cell activation and the breakdown of immunotolerance in a hapten/carrier mechanism. Based on these findings we postulate that PPAD is directly responsible for the breakdown of immunotolerance and subsequent anti-citrullinated protein antibody (ACPA) production - key pathological events preceding clinical onset of RA; and the severity of PD and its link to RA is associated with the occurrence of a superactive variant of PPAD expressed by subset of P. gingivalis strains.

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BEDREHELSE-Bedre helse og livskvalitet