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Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (T H 17) cells in human periodontitis. Phenocopying humans, T H 17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral T H 17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)-dependent manner, periodontitis-associated expansion of T H 17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. T H 17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of T H 17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in T H 17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human T H 17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of T H 17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Uncontrolled inflammation of the periodontal area may arise when complex microbial communities transition from a commensal to a pathogenic entity. Communication among constituent species leads to polymicrobial synergy between metabolically compatible organisms that acquire functional specialization within the developing community. Keystone pathogens, even at low abundance, elevate community virulence, and the resulting dysbiotic community targets specific aspects of host immunity to further disable immune surveillance while promoting an overall inflammatory response. Inflammophilic organisms benefit from proteinaceous substrates derived from inflammatory tissue breakdown. Inflammation and dysbiosis reinforce each other, and the escalating environmental changes further select for a pathobiotic community. We have synthesized the polymicrobial synergy and dysbiotic components of the process into a new model for inflammatory diseases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The oral bacterium Porphyromonas gingivalis has special nutrient requirements due to its asaccharolytic nature subsisting on small peptides cleaved from host proteins. Using proteases and other virulence factors, P. gingivalis thrives as a component of a polymicrobial community in nutritionally favorable inflammatory environments. In this regard, P. gingivalis has a number of strategies that subvert the host immune response in ways that promote its colonization and facilitate the outgrowth of the surrounding microbial community. The focus of this review is to discuss at the molecular level how P. gingivalis subverts leukocytes to create a favorable environment for a select community of bacteria that, in turn, adversely affects the periodontal tissues.

The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis.

In periodontitis, dysbiotic microbial communities exhibit synergistic interactions for enhanced protection from host defenses, nutrient acquisition, and persistence in an inflammatory environment. This review discusses evidence that periodontitis-associated communities are 'inflammo-philic' (=loving or attracted to inflammation) in that they have evolved to not only endure inflammation but also to take advantage of it. In this regard, inflammation can drive the selection and enrichment of these pathogenic communities by providing a source of nutrients in the form of tissue breakdown products (e.g. degraded collagen peptides and heme-containing compounds). In contrast, those species that cannot benefit from the altered ecological conditions of the inflammatory environment, or for which host inflammation is detrimental, are likely to be outcompeted. Consistent with the concept that inflammation fosters the growth of dysbiotic microbial communities, the bacterial biomass of human periodontitis-associated biofilms was shown to increase with increasing periodontal inflammation. Conversely, anti-inflammatory treatments in animal models of periodontitis were shown to diminish the periodontal bacterial load, in addition to protecting from bone loss. The selective flourishing of inflammophilic bacteria can perpetuate inflammatory tissue destruction by setting off a 'vicious cycle' for disease progression, in which dysbiosis and inflammation reinforce each other. Therefore, the control of inflammation appears to be central to the treatment of periodontitis, as it is likely to control both dysbiosis and disease progression., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Certain low-abundance bacterial species, such as the periodontitis-associated oral bacterium Porphyromonas gingivalis, can subvert host immunity to remodel a normally symbiotic microbiota into a dysbiotic, disease-provoking state. However, such pathogens also exploit inflammation to thrive in dysbiotic conditions. How these bacteria evade immunity while maintaining inflammation is unclear. As previously reported, P. gingivalis remodels the oral microbiota into a dysbiotic state by exploiting complement. Now we show that in neutrophils P. gingivalis disarms a host-protective TLR2-MyD88 pathway via proteasomal degradation of MyD88, whereas it activates an alternate TLR2-Mal-PI3K pathway. This alternate TLR2-Mal-PI3K pathway blocks phagocytosis, provides "bystander" protection to otherwise susceptible bacteria, and promotes dysbiotic inflammation in vivo. This mechanism to disengage bacterial clearance from inflammation required an intimate crosstalk between TLR2 and the complement receptor C5aR and can contribute to the persistence of microbial communities that drive dysbiotic diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Complement plays a key role in immunity and inflammation through direct effects on immune cells or via crosstalk and regulation of other host signaling pathways. Deregulation of these finely balanced complement activities can link infection to inflammatory tissue damage. Periodontitis is a polymicrobial community-induced chronic inflammatory disease that can destroy the tooth-supporting tissues. In this review, we summarize and discuss evidence that complement is involved in the dysbiotic transformation of the periodontal microbiota and in the inflammatory process that leads to the destruction of periodontal bone. Recent insights into the mechanisms of complement involvement in periodontitis have additionally provided likely targets for therapeutic intervention against this oral disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Recent advancements in the periodontal research field are consistent with a new model of pathogenesis according to which periodontitis is initiated by a synergistic and dysbiotic microbial community rather than by select 'periopathogens', such as the 'red complex'. In this polymicrobial synergy, different members or specific gene combinations within the community fulfill distinct roles that converge to shape and stabilize a disease-provoking microbiota. One of the core requirements for a potentially pathogenic community to arise involves the capacity of certain species, termed 'keystone pathogens', to modulate the host response in ways that impair immune surveillance and tip the balance from homeostasis to dysbiosis. Keystone pathogens also elevate the virulence of the entire microbial community through interactive communication with accessory pathogens. Other important core functions for pathogenicity require the expression of diverse molecules (e.g. appropriate adhesins, cognate receptors, proteolytic enzymes and proinflammatory surface structures/ligands), which in combination act as community virulence factors to nutritionally sustain a heterotypic, compatible and proinflammatory microbial community that elicits a non-resolving and tissue-destructive host response. On the basis of the fundamental concepts underlying this model of periodontal pathogenesis, that is, polymicrobial synergy and dysbiosis, we term it the PSD model. [ABSTRACT FROM AUTHOR]