Immune Regulation and Tissue Remodeling during Gingivitis and Periodontitis

Abstract

Immune and tissue homeostasis are crucial to maintain periodontal health and to prevent further tissue destruction. Orchestrating crosstalk among immune cells and tissues, mediators modulate equilibrium between tissue and immune homeostasis. Once homeostasis is disrupted, progression of periodontal disease could lead to irreversible tissue destruction, resulting in tooth loss. Recent findings suggested tissue remodeling might be initiated as early as 4 days after plaque accumulation. Comprehensive analyses of this tissue homeostasis will benefit the understanding the pathogenesis, diagnosis, and the treatment of periodontal diseases. This thesis investigated clinical and molecular changes of gingivitis in individuals in terms of periodontal health, experimental gingivitis, naturally occurring gingivitis, and periodontitis. A systematic review was first conducted to summarize the profiles of immune and tissue regulation during the induction of experimental gingivitis. We further analyzed gingival crevicular fluid samples in either experimental or naturally occurring gingivitis to compare their differences in immune regulation, angiogenesis, and tissue remodeling. Another cross-sectional study was also conducted to investigate the clinical and mediator profiles among inflammatory sites in patient populations with gingivitis only and severe (stage III grade B) periodontitis, including gingivitis sites in gingivitis only patients, gingivitis sites in periodontitis patients, and periodontitis sites in periodontitis patients. Commercially available bead-based multiplex immunoassays were used to analyze the gingival crevicular fluid samples. Our results demonstrated that the induction of experimental gingivitis increased the expression of MPO, IL-1α and IL-1β, along with the decreases of MIP-1β and MCP-1/CCL2. The involvement of angiogenesis and tissue remodeling was limited during experimental gingivitis. Among 74 investigated mediators, previously published experimental gingivitis studies did not always show consistent outcomes in most of the mediator expression levels. Several factors were found to contribute to these inconsistencies, including stress, age, systemic status, and individual variability. Comparing experimental and naturally occurring gingivitis, the former exhibited greater level of IL-1β and MPO; whereas the latter had greater expression of angiogenin, C3a, MMP-13, BMP-2, OPG, and RANKL. Among naturally occurring diseases, gingivitis sites in gingivitis only patients shared several similarities with the gingivitis sites in periodontitis patients, except less plaque index, lower level of CCL2 and CCL3. Within individuals with periodontitis, gingivitis sites showed less expression of CCL5, GM-CSF, IL-6, SDF-1, MMP-2, MMP-7, MMP-12, and similar level of mediators associated with bone metabolism. In addition, most of the investigated mediators were significantly greater in the group of periodontitis compared with the group of gingivitis only. With the limitations, this thesis revealed that the characteristics of gingivitis varied in the individuals with different states of periodontal health and diseases. Experimental gingivitis represented a self-limiting and acute inflammatory lesion with limited involvement of angiogenesis and tissue remodeling. Naturally occurring gingivitis was a chronic lesion with involvement of diverse immune regulation, including neutrophils, monocytes, and macrophages. It also displays more activities in angiogenesis and tissue remodeling compared with experimental gingivitis. Compared with periodontitis, furthermore, gingivitis exhibited less complexity in immune and tissue regulations; whereas periodontitis exhibits more diversity in immune regulation and greater activities in tissue turnover. The gingivitis sites in periodontitis population showed the transitional profiles between gingivitis and periodontitis. To our knowledge, this thesis is the first study summarizing the features of experimental gingivitis and providing the most comprehensive comparisons between experimental and naturally occurring gingivitis in terms of immune regulation and tissue remodeling. These findings revealed the limitations of these gingivitis models and their indications. It also provides a foundation for personalized periodontal therapy in diagnosis, treatments, and prevention of periodontal diseases. Further investigation is required to explore the interaction of these biomarkers and the comparison between experimental gingivitis and naturally occurring gingivitis in disease resolution.