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Inflammasomes as contributors to periodontal disease.

ABSTRACT: A genome-wide association study of ?2.5 million markers identified unique biologically informed periodontal complex traits with distinct microbial communities and interleukin-1? (IL-1?) levels. Each trait was associated with different single nucleotide polymorphisms. These variants include genes associated with immune responses, microbial colonization, and the epithelial barrier function. The specific set of variants leads to individual biological paths that converge into an overlapping clinical phenotype of periodontal tissue destruction. This concept suggests that periodontal disease is a group of distinct conditions. We identified polymorphisms in inflammasome genes interferon gamma inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) that were associated with increased severity of periodontal disease. Inflammasomes respond to pathogen or tissue "danger" signals and assemble into multiprotein "machineries" that are essential for the cleavage of proinflammatory mediator IL-1? into an active form. Thus, understanding how variants of IFI16 and AIM2 contribute to periodontal disease pathogenesis may lead to treatment options that address individual biological variations and precision therapies for oral health.

SUBMITTER: Marchesan JT

PROVIDER: S-EPMC7689877 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Inflammasomes as contributors to periodontal disease.

Marchesan Julie T JT

Journal of periodontology 20200806

A genome-wide association study of ≈2.5 million markers identified unique biologically informed periodontal complex traits with distinct microbial communities and interleukin-1β (IL-1β) levels. Each trait was associated with different single nucleotide polymorphisms. These variants include genes associated with immune responses, microbial colonization, and the epithelial barrier function. The specific set of variants leads to individual biological paths that converge into an overlapping clinical ...[more]

PMID: 32533779

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Project description:Inflammasomes are a group of multimolecular intracellular complexes assembled around several innate immune proteins. Recognition of a diverse range of microbial, stress and damage signals by inflammasomes results in direct activation of caspase-1, which subsequently induces the only known form of secretion of active interleukin-1β and interleukin-18. Although the importance of interleukin-1β in the periodontium is not questioned, the impact of inflammasomes in periodontal disease and its potential for therapeutics in periodontology is still in its very early stages. Increasing evidence in preclinical models and human data strongly implicate the involvement of inflammasomes in a number of inflammatory, autoinflammatory and autoimmune disorders. Here we review: (a) the currently known inflammasome functions, (b) clinical/preclinical data supporting inflammasome involvement in the context of periodontal and comorbid diseases and (c) potential therapies targeting inflammasomes. To clarify further the inflammasome involvement in periodontitis, we present analyses of data from a large clinical study (n = 5809) that measured the gingival crevicular fluid-interleukin-1β and grouped the participants based on current periodontal disease classifications. We review data on 4910 European-Americans that correlate 16 polymorphisms in the interleukin-1B region with high gingival crevicular fluid-interleukin-1β levels. We show that inflammasome components are increased in diseased periodontal tissues and that the caspase-1 inhibitor, VX-765, inhibits ~50% of alveolar bone loss in experimental periodontitis. The literature review further supports that although patients clinically present with the same phenotype, the disease that develops probably has different underlying biological pathways. The current data indicate that inflammasomes have a role in periodontal disease pathogenesis. Understanding the contribution of different inflammasomes to disease development and distinct patient susceptibility will probably translate into improved, personalized therapies.

Project description:BACKGROUND:Current periodontal disease taxonomies have limited utility for predicting disease progression and tooth loss; in fact, tooth loss itself can undermine precise person-level periodontal disease classifications. To overcome this limitation, the current group recently introduced a novel patient stratification system using latent class analyses of clinical parameters, including patterns of missing teeth. This investigation sought to determine the clinical utility of the Periodontal Profile Classes and Tooth Profile Classes (PPC/TPC) taxonomy for risk assessment, specifically for predicting periodontal disease progression and incident tooth loss. METHODS:The analytic sample comprised 4,682 adult participants of two prospective cohort studies (Dental Atherosclerosis Risk in Communities Study and Piedmont Dental Study) with information on periodontal disease progression and incident tooth loss. The PPC/TPC taxonomy includes seven distinct PPCs (person-level disease pattern and severity) and seven TPCs (tooth-level disease). Logistic regression modeling was used to estimate relative risks (RR) and 95% confidence intervals (CI) for the association of these latent classes with disease progression and incident tooth loss, adjusting for examination center, race, sex, age, diabetes, and smoking. To obtain personalized outcome propensities, risk estimates associated with each participant's PPC and TPC were combined into person-level composite risk scores (Index of Periodontal Risk [IPR]). RESULTS:Individuals in two PPCs (PPC-G: Severe Disease and PPC-D: Tooth Loss) had the highest tooth loss risk (RR = 3.6; 95% CI = 2.6 to 5.0 and RR = 3.8; 95% CI = 2.9 to 5.1, respectively). PPC-G also had the highest risk for periodontitis progression (RR = 5.7; 95% CI = 2.2 to 14.7). Personalized IPR scores were positively associated with both periodontitis progression and tooth loss. CONCLUSIONS:These findings, upon additional validation, suggest that the periodontal/tooth profile classes and the derived personalized propensity scores provide clinical periodontal definitions that reflect disease patterns in the population and offer a useful system for patient stratification that is predictive for disease progression and tooth loss.

Project description:The use of Next Generation Sequencing (NGS) techniques has generated a wide variety of blood microbiome data. Due to the large variation in bacterial DNA profiles between studies and the likely high concentrations of cell-free bacterial DNA in the blood, it is still not clear how such microbiome data relates to viable microbiota. For these reasons much remains to be understood about the true nature of any possible healthy blood microbiota and of bacteraemic events associated with disease. The gut, reproductive tracts, skin, and oral cavity are all likely sources of blood-borne bacteria. Oral bacteria, especially those associated with periodontal diseases, are also commonly associated with cardiovascular diseases such as infective endocarditis, and also have been linked to rheumatoid arthritis and Alzheimer's disease. Periodontal treatment, dental probing, and toothbrushing have been shown to cause transient bacteraemia and oral bacteria from the phyla Firmicutes (e.g. Streptococci) and Bacteroidetes (e.g. Porphyromonas) are found in cardiovascular lesions (CVD). Many studies of blood bacterial DNA content however, find Proteobacteria DNA to be the dominant microbiome component, suggesting a gut origin. Most studies of this type use total DNA extracted from either whole blood or blood fractions, such as buffy coat. Here, using a method that purifies DNA from intact bacterial cells only, we examined blood donated by those with active, severe periodontitis and periodontally healthy controls and show that 43-52% of bacterial species in blood are classified as oral. Firmicutes, consisting largely of members of the Streptococcus mitis group and Staphylococcus epidermidis, were predominant at 63.5% of all bacterial sequences detected in periodontal health and, little changed at 66.7% in periodontitis. Compared to studies using total DNA Proteobacteria were found here at relatively low levels in blood at 13.3% in periodontitis and 17.6% in health. This study reveals significant phylogenetic differences in blood bacterial population profiles when comparing periodontal health to periodontal disease cohorts.

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Inflammasomes as contributors to periodontal disease.

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Inflammasomes as contributors to periodontal disease.

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